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Journal of Chemistry-JuniperPublishers

                                     Abstract

With the rise of the average life expectancy in the last century, the prevalence of life-threatening diseases has greatly increased. Thus, the need for effective, cost efficient and easy to produce therapeutic systems, combined with recent technological advances, boosted nanotechnology research. Since their discovery more than 30 years ago, naturally occurring exosomes are an increasingly interesting vehicle for drug delivery, with the disadvantage that they are difficult and expensive to extract, characterize and their encapsulation efficiency is poor. Liposomes, known since the mid-60’s, can be used for various types of therapies for their capacity to encapsulate almost any molecule, with efficient production and encapsulation processes, but are less biocompatible. A new type of systems, exosome-like nanoparticles, that combine the advantages of these two systems, mitigating their limitations, show potential to be excellent therapeutic options with almost no side-effects.

Keywords: Nanotechnology; Liposomes; Exosome-like; Exosomes; Nanoparticles

Introduction

In recent decades, in the nanotechnology field, many new approaches have been developed, in basic and clinical research, to obtain a better diagnosis and an early effective therapy for the most debilitating diseases such as cancer or neurodegenerative disorders [1]. Extracellular vesicles are naturally occurring molecular vehicles, having an important role in the transport of molecules-being misfolded proteins to be degraded in the lysosome, or nucleic acids - and in intercellular communication [2,3]. Extracellular vesicles can be divided into three subpopulations according to their size and origin: exosomes, Microvesicles and apoptotic bodies [1]. These vesicles naturally do what some of the industrially manufactured nanoparticles aim to do: the encapsulation of molecules and their controlled release into a target cell [4]. Exosomes are becoming an increasingly interesting vehicle for the delivery of drugs due to their biocompatibility, capacity to cross biological barriers and to encapsulate hydrophilic and lipophilic molecules [3,5-7]. However, exosomes can also be difficult to extract and to characterize, and the costs of extraction and encapsulation of bioactive molecules can be high. Moreover, the encapsulation process can be difficult, very time-consuming, and can lead to poor encapsulation efficiencies [4.8].

Similarly, to exosomes, liposomes have a bilayer of lipid molecules, that can be synthetic or natural occurring ones, on the membrane of cells or vesicles [9,10]. This type of intensively studied synthetic vesicles have been used for various types of therapies, from imaging to the treatment of a wide range of diseases, since they can encapsulate almost every molecule [4,11]. These nanocarriers, while similar to exosomes to a certain degree, have a simple and efficient production process, and can encapsulate bioactive drugs more efficiently than exosomes, with the drawback that they can be far less biocompatible than these natural occurring nanovesicles [9]. Mitigating the drawbacks of these two systems, while retaining their excellent properties, exosome-like liposomes have been recently considered for therapy, with some very interesting systems-that can encapsulate biomolecules efficiently and deliver them safely in the targeted area - have been developed through various types of approaches. These can be considered as some of the most promising drug delivery nanoparticles, and more research in the area may lead to a more efficient and safe delivery of biomolecules.

Exosomes are the smallest in the extracellular vesicle class [12], with a diameter of 30 to 150 nm, which is why they are considered nanovesicles, are highly heterogeneous and with different molecular and charge compositions, depending on the type of producing cell [2], its structure is formed by a lipid bilayer with associated proteins on its membrane [13]. Exosomes can be produced by almost all human cells [14], wherein the mechanism is maintained for several classes of organisms. Exosomes can also be considered a waste disposal mechanism [1]. For drug delivery, exosomes have some advantages, one of which is to encapsulate lipids, proteins, DNA, mRNA, non-coding RNA or other bioactive substances [1,12], they can also circulate in biofluids and thus transport messages from one cell to another; when the exosome reaches the recipient cell, it can modify its behavior depending on the message received. Exosomes are an efficient platform for drug delivery, due to their biodistribution, biocompatibility and low immunogenicity. Moreover, they can also cross most biological barriers, allowing the delivery of biomolecules in all organs of the human body [12].

Liposomes have a spherical structure with one or more phospholipid bilayer [9,10], which can be classified according to size (small, large, and giant); number of bilayer (unilamellar, oligolamellar and multilamellar) and charge (neutral; anionic and cationic) [10,11]. While liposomes’ size can range from 50 to 200nm, they are more efficient when they have 100 to 140nm since they have a longer half-life in the blood stream. Moreover, these particles are not so easily detected by the immune system and are relatively more difficult to be recycled or eliminated from the body [10,15]. Liposomes can encapsulate antimicrobial drugs, nucleic acids, and antioxidants, within their bilayer or their aqueous area. This delivery is directed and controlled [16]. Since liposomes can be made by various types of naturally occurring or synthetic lipids, the toxicity of the system must be extensively studied, often limiting the use of these systems for various types of therapies [9,11].

Exosome-like nanoparticles often have a similar size to liposomes (60nm–150nm) [17,18], joining the advantages such as the ease of production, tuning of the formulation, and encapsulation efficiencies of liposomes with the biocompatibility, longer circulation time, stability, and ability to cross biological barriers better than exosomes. Moreover, the cytotoxicity of this type of nanocarrier is often negligible since their composition is like naturally occurring exosomes. This type of nanoparticles can be obtained from various processes, such as the fusion of liposomes with exosomes [19], their extraction from plants [20,21], or serial extrusion of animal cells [17,22,23]. Exosomelike vesicles from plants are some of the most like exosomes, as they have a composition very similar to exosomes from human cells. More than that, their encapsulated molecules are like the ones found in animal exosomes, but differ in number, containing a lesser quantity of both nucleic acids and proteins than the animal ones [24], being non cytotoxic and being able to deliver biomolecules for the treatment of various diseases such as brain tumors [25].

Conclusion

Exosome-like nanoparticles, while newly discovered, have already been the target of multiple studies, with some interesting results [1,2]. In fact, their biocompatibility is excellent, and they can effectively encapsulate a fair number of biomolecules, being an interesting therapeutic option on their own, when they are extracted from plants. Studies in animals prove that they can effectively bioaccumulate in the desired therapeutic area and attenuate some of the most debilitating diseases as brain tumors or cancer [2,11,15]. While liposomes and exosomes remain more commonly studied and used systems for therapy, the advantages of exosome-like nanoparticles cannot be ignored as they continue to rise in interest among the scientific community.

Journal of Chemistry-JuniperPublishers

Abstract

Anthraquinone derivatives have antineoplasmatic effects. Our goal was to design and synthesize, for the first time, an anthraquinone derivative conjugated with a couple of immunomodulatory peptide analogues of Myelin Basic Protein MBP [1-11] [4Y] and a peptide analogue of IL-2Rb receptor with inhibitory effects. MBP [1-11] [4Y] was the analogue of our choice because it has previously shown that is a very strong binder to T cell receptor and could limit cellular infiltration into the Central Nervous System, protecting male mice from EAE. Furthermore, IL-2Rβ (107-118) epitope, has shown inhibitory effect on proliferation assays in PBMCs.

Keywords: Anthraquinone derivatives; Multiple sclerosis; Peptide analogues; IL-2

Introduction

Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the Central Nervous System (CNS), characterized by activation of T-cells subset, CD4+ and other cells of the immune system. After the activation and proliferation of the above cells, they infiltrate into the CNS through the Blood Brain Barrier (BBB). Then, they are secondary activated against the Myelin sheath. The destruction of the Myelin sheath leads to neurological dysfunction and the emerge of neurological symptoms. MS is a devastated disease resulting in neurological disability if not treated from early stages [1-4].

Myelin Protein consists of major and minor lipoproteins which form the Myelin sheath. The major proteins are MBP, PLP and MOG. T-cells are activated against specific epitopes which are called immunodominant epitopes such as MBP83-99, MBP1-11, PLP139-145 and MOG35-55 [4-6]. Furthermore, IL-2, is a cytokine, playing a critical role on the activation of the immune system against foreign attacks by viruses and bacteria. It is known that the IL-2 receptor is ex-pressed on the surface of activated T-cells and not on the “rest” T cells [7-9]. The design was based on the binding information of the high affinity IL-2 receptor with specific epitopes, linear and cyclic, of the extracellular segment of the β chain. Monoclonal antibodies are bound to these epitopes and prevent the connection of the cytokine with the IL-2R.

1,4-bis(substituted alky-1-amino)-anthraquinones are considered as molecules with antineoplasmatic properties [10-12]. These compounds intercalate with the DNA helix and inhibit the DNA transcription. They have also shown a strong inhibitory effect on Topoisomerase II enzyme and demonstrate a down regulation effect on Pgp activity, resulting in inhibition of mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) [13-15]. Moreover, such derivatives act against Leukemia P-388 in mice [16]. 9,10-Dihydroxy-2,3-dihydro-1,4- anthraquinone (leucoquinizarin), is the derivative of our choice in the present synthesis.

Numerous of organic compounds have been synthesized so far to modulate the MS patients’ immune system. In this study, we describe the synthesis of mono substituted amino, ethyl-amino anthraquinone and bis substituted 2-amino, ethyl-amino anthraquinone derivatives con-jugated with mutated peptide analogues (APLs) of the immunodominant epitope MBP(1-11) with mutation at position 4 (4Y) and a peptide inhibitor of the IL-2Rb receptor. The design of the peptide analogues was based on the primary structure of the MBP1-11 epitope and β subunit receptor extracellular area, IL-2Rβ (107-118). The peptide RELFRQSLSQRETALV does not share any amino acid sequence with the extracellular area of the IL-2 receptor β-subunit and in the present study was used as control.

In addition, the epitope AcMBP1-11 when injected in PL/J mice induced EAE. Replacement of Lys at position 4 with Ala and Tyr results in peptide analogues with antagonistic effects [17- 20]. Moreover, these peptide analogues demonstrate stronger binding affinity characteristics to Major Histocompatibility Complex (MHC). Based on the above, we synthesized 4 peptidylanthraquinone compounds (mono and bis substituted) to discover new molecules towards the potential immunomodulation of MS. It is worth to note that the described conjugation was carried out in liquid phase for the first time.

Experimental Section

Synthesis of the mono and 1,4 bis-ethylene-diamine substituted anthraquinone.

At first, the 1,4 dihydroxy-anthraquinone (1.5mmol) was dissolved in 25ml of methanol. Boc protected ethylene-diamine (1.5mmol) was added dropwise. The procedure was executed in N2 atmospheric conditions for 30min. The duration of the reaction was 1h reflux at temperature of 50-55oC. Control of the temperature is crucial due to the formation of “by-products” which decrease the final yield [21]. After 1h, the solution was freeze and was oxygen-exposed for 15h to get mild oxidation at atmospheric conditions. Two main products were isolated. The mono-ethylenediamine substituted anthraquinone product (blue light colored) and the bis-ethylene-diamine anthraquinone (dark blue colored). Both were Boc protected. The removal of Boc protecting group was accomplished by treating the solution with TFA/DCM (65/35, v/v) for ap-proximately 2h. Both products, were monitored by HPLC and were identified by Thin Layer Chromatography (TLC) and Mass Spectrometry. In the following Schemes 1 & 2, the synthesis of the two products is described. The products were identified by ESI-MS, purified and isolated using HPLC semi-preparative and a Nucleosil 100-5 C18 (250x4mm) and 5μm particle diameter, using AcN and H2O gradient eluent (10% -60% AcN). More details are included in Table 1.

Peptide synthesis

The synthesis of the Bocamino protected peptide analogues used in this study has been accomplished in solid phase using Fmoc/tBu methodology. The mutated peptides (APLs) had amino acid alterations in critical positions for their activity known by recent literature. This synthetic procedure has been extendedly described by our group [22,23].

Conjugation of bis-ethylene-diamine anthraquinone with peptide analogues of MBP[1-11] [4Y] and IL-2Rβ (107-118) The conjugation of peptide analogues was carried out in liquid phase using N,N’-Dicyclo-hexyl-carbodiimide (DCC) as coupling agent. The excess of the protected intermediate that was used was 4x fold. Triethylamine was used as base, distilled Dimethyl formamide (DMF) as solution and the reaction was accomplished after 24h. The final products were identified by TLC and HPLC. The final deprotection mixture was consisted of Trifluoracetic acid (TFA) and specific scavengers [Dithiothreitol (DTT), anisole and water (25/65/4/6, v/v, 7ml) in Dichloromethane (DCM).The reaction was terminated after 5h and the final products 1 and 2 were identified and isolated as described above (Scheme 2).

Results

Preliminary assays of the synthesized analogues 3a and 4a were carried out using T cell line specific for AcMBP [1-9]. The proliferation assays were carried out in different concentrations, with a range of 0.00001μg/ml to 10μg/ml. The proliferation value effect of AcMBP1-9 epitope T-cell lines was used as a reference. Moreover, the proliferation of the analogue 3a was higher than the control in the concentration of 0.00001μg/ml. Whereas, in the concentration of 10μg/ml showed lower proliferation effect compared to control. The epitope IL-2 Rβ (107-118) has shown a decrease of 27.95% of PBMC and a decrease of 56.69% of IL-2 secretion compared to the control. The analogue 3b showed a respective decrease of PBMCs of MS patients but not of IL-2 secretion.

Discussion

This synthetic approach describes for the first time the conjugation of two immunodominant epitopes and an anthraquinone derivative in liquid phase. The peptide analogues were synthesized in solid phase according to Fmoc/tBu methodology. The anthraquinone derivatives were synthesized according to literature in liquid phase as well as the conjugation procedure. The isolation of mono and bissubstituted derivatives was accomplished using cation exchange chromatographic techniques. The characterization of the final conjugated products was carried out using IR and Mass Spectra.

The preliminary assays have shown that the IL-2Rβ (107-118) interfere with the extracellular β subunit of IL-2 receptor and may prevent the binding of IL-2. In addition, the synthesized analogues inhibit the activation and proliferation of T cells by an antigen or mitogen. This could happen because both analogues are found to have toxic characteristics. The IL-2 is a very important cytokine (Th1 immunological response), for the immune system activation. The regulation of IL-2 is a crucial step towards relief of the disease symptoms.

Conclusion

The use of several different peptide analogues conjugated to anthraquinone derivatives could be an attractive approach towards its biological evaluation. This new approach is giving us a new generation of molecules consist of two or more organic compounds and could be potential immunotherapeutic. Many research groups have used different carriers such as nanoparticles or PEGylated parts to combine organic molecules with biological activity, aiming in new synthetic compounds with limited side effects, to a specific target within the body. In conclusion, the synthesis of conjugated compounds consists of peptide analogues and anthraquinone derivatives could be a different methodology towards the modulation of the disease and to design more effective mimetic analogues against MS.

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Journal of Chemistry-JuniperPublishers

Abstract

The natural biopolymer chitosan was applied to textile substrates by ultraviolet photo grafting to confer antibacterial activity against a wide range of microorganisms. In this way an efficient and solid textile finishing was ensured by a low environmental impact process. The use of an environmentally friendly product is thus coupled to the adoption of an eco-sustainable process, that can guarantee the protection of both health and environment and produce fabrics complying with current regulations. Fabrics treated in this way can find application in all cases where it is necessary to counteract the proliferation of bacteria: medical devices, hospital and hygienic textiles, technical and furniture fabrics, but also in the field of water purification, as active biological filters.

Keywords: Chitosan; Antibacterial agent; Textiles; Cotton; UV-grafting; Water purification; Escherichia coli; Staphylococcus aureus; Klebsiella

Introduction

In last decades, globalization and even more stringent ecological regulations push textile companies to search for product quality improvements by environmentally friendly processes. Among targets, the use of processes with low water and energy consumption and the replacement of polluting or toxic chemicals with others of natural origin, with low or no environmental impact, are prominent. Furthermore, the frequent spread of diseases and infections highlights the importance of health and hygiene, promoting the production of antibacterial fabrics not only to avoid the degradation of the fabrics themselves, but also to effectively prevent the propagation of pathogens.

Fibers and fabrics of natural origin, hydrophilic and biodegradable, provide an optimal and favorable environment for the growth and proliferation of bacterial colonies; therefore, an antibacterial finishing, through appropriate chemical modification of the fibers surface, is particularly useful on these textiles. Metal ions (Ag+), quaternary ammonium salts, phosphonium salts or Triclosan are the chemical biocides commonly used today, but they were proved to be toxic or carcinogenic, so application on textiles, especially if in direct contact with the human skin, is not recommended considering the possible release of the antibacterial agent during use.

Biopolymers with intrinsic antibacterial activity, of natural origin from renewable sources, applied by an economic and ecological finishing process, is an interesting alternative for the development of bioactive textiles by eco-sustainable treatments. The proposed solution focuses on the finishing of textile fabrics by chitosan, grafted on fibers by photocuring [1]. Moreover, the application of a chitosan treated gauze for water filtration was also studied, aimed to disinfection and elimination of the same pathogenic microorganisms [2]. Water sanitation is an important issue worldwide: every year, more than 3 million people die in the world from diseases related to unhealthy water, responsible for 88% of diarrhea cases. The study has therefore a high application potential, with positive impacts in both scientific and socio-economic fields.

Chitosan UV grafting

Chitosan is a natural biopolymer mainly obtained from the exoskeleton of crustaceans. It is an abundant, low-cost by-product of the food industry, with well-known antibacterial properties against both Gram positive and negative bacteria, due to its combined bactericidal and bacteriostatic action, against fungi and viruses. Chitosan has no toxicity, and it is not a strong oxidant, avoiding the release of dangerous by-products during use; moreover, it is inert in water. For all these reasons chitosan can be considered as a sustainable alternative to other antimicrobial agents. Chitosan is already used in some textile finishing, applied by wet thermal curing with energy consumption, costs, and possible fabric degradation. Moreover, the addition of toxic reagents, such as glutaraldehyde [3], or expensive, such as genipin, is required as crosslinking agents to impart the required durability to repeated washings [4].

Therefore UV-curing of chitosan on fibers to confer antimicrobial activity was proposed as an alternative process to thermal curing or chemical crosslinking, obtaining a good effectiveness and fastness of the treatment. In UV-curing, radical species are generated by the interaction of UV light with a suitable photo initiator, which induces grafting reactions of reactive monomers and oligomers at low temperature and quickly, avoiding the emission of VOC, with lower environmental impact and lower cost than thermal process. Both chitosan and fibers, mainly cellulosic fibers, take part to this photochemical process. If a chitosan and initiator mixture is adsorbed onto the fibers and subsequently UV-cured, the polymeric chains can form inside the textile structure, which can also establish graft bonds, making the treatment solid and resistant. Moreover, the interpenetration of components and homogeneous distribution of monomers, even at a low concentration, contribute to obtain textile materials with modified surface properties, without high polymer add-on [5]. Consequently, the fabrics may retain their original properties of hand and breathability. Finally, the technology is easily implemented in the textile supply chain.

Chitosan as antibacterial finishing for textiles

Chitosan was applied by photograflting to several natural and synthetic fabrics, namely cotton, silk [5], wool [6], polyester and polyamide. The process was optimized, in terms of polymer add-on, ultraviolet exposure, impregnation and drying modality. The antimicrobial activity of treated samples was tested against Escherichia Coli, Staphylococcus Aureus and Klebsiella pneumonia, and compared with same samples treated by a commercial antibacterial agent based on Triclosan and quaternary ammonium salts.

The study confirmed the efficiency of chitosan against the tested bacteria and an excellent solidity of the treatment. A process yields equal to 100% was obtained on cotton and silk, while the hand and color of the treated fabrics were unaffected up to 2% add-on. However, the bacterial colonies were totally removed on fabrics treated with chitosan add-ons equal to just 0.3% owf, a very low amount unaffecting the peculiar properties of natural fibers. This strong antibacterial activity was unchanged after 30cycles washing, confirming the fastness of the treatment and the effectiveness of ultraviolet radiation to form strong radical bonds between chitosan and fibers.

The comparative test with the commercial product showed that it was less performing than chitosan, since after 30 washing cycles the antibacterial activity decreased to 98%, due to a certain release or inactivation of the antibacterial agent by surfactant action, while chitosan treated fabrics keep 99,999% of colony reduction [7]. Similar results were obtained, in terms of antibacterial activity, also on wool and synthetic fibers, but in this case a surface pretreatment was required to increase hydrophilicity and promote the absorption of the chitosan solution, due to hydrophobicity of this kind of fibers [6].

Chitosan for water purification

Water filtration tests were carried out on a cotton gauze treated with chitosan. The process for chitosan grafting was the same as for fabrics, but the add-on was increased till 25% owf. The as treated gauze was tested for continuous filtration of water contaminated by Escherichia, Staphylococcus or Klebsiella. The functionalized gauzes were tested in dynamic conditions, with bacteria inoculum continuously flowed through the filter several times. Results showed that a contact time, between the gauze and the contaminated water, of 4seconds was enough for the total elimination of Escherichia and Staphylococcus from the water, while after 8sec the Klebsiella was reduced by 98%. It is highly interesting since this fast speed of action guarantees total disinfection with a rapid flow of water, making the chitosan treated gauze an excellent candidate as biological filter. The comparison was made in this case with a cationized cotton gauze, but the material was not suitable for filtration, reaching only 40% of bacterial reduction after a contact time of 20 seconds [2]. Considering water treatments, it is noteworthy that in previous studies the same chitosan treated gauze was found active also against other water pollutants: for the capture of heavy metals, like copper or chrome, present in water [8], and for sequestration of dyes from textile dyeing wastewaters [9].

Conclusion

Chitosan UV-grafting on both natural and synthetic fibers yields strong antimicrobial properties against different classes of microorganisms. The coupling of a natural, biocompatible, and renewable biopolymer with an ecofriendly photo grafting process makes it competitive and interesting versus the traditional toxic antibacterial agents applied by thermal processes, energy and water consuming. Therefore, the possibility to replace the established antibacterial finishing processes, based on hard and energy demanding chemical treatments, with an ecofriendly low temperature process using ultraviolet light and a natural and safe biopolymer such as chitosan, is undoubtedly an interesting result which can contribute to change the production of antibacterial fabrics toward a sustainable development.

It was confirmed by a semi-industrial scale-up and a deep cost analysis of the whole process. On the other hand, chitosan shows also promising applications in the field of water purification. In fact, it can totally remove pathogenic microorganisms from contaminated water in few times, allowing the continuous treatment of great amount of water with a little amount of filtering material. Some literature [10] suggests that chitosan and its derivatives can also suppress viral infections in various biological systems. However, the mechanism of this antiviral activity is poorly understood. Future studies could be focused on the investigation about antiviral properties conferred to textiles treated by chitosan photo grafting. If it will be confirmed, the potentialities for chitosan applications would be even more interesting.

Journal of Chemistry-JuniperPublishers

                                       Abstract

Air purification is one of the most widely known environmental applications of activated carbons. In order to guarantee the successful removal of contaminants and pollutants on activated carbons, the development of new adsorbents has been increasing in the last few years. This paper presents a systematic study for cleaning vehicles emissions of CO, SO2, NO2 and H2S using the process of physical adsorption on novel adsorbents obtained from tropical biomasses. Use of this simple method is a valuable alternative to meet emission standards in Developing Countries. It is known that the agricultural wastes studied here are a feasible alternative for granular activated carbons preparation for pollutants removal during engines operation, approaching its efficiency to the commercial Catalytic Converters.

Keywords: Combustion gases purification; Activated carbons; Adsorption and adsorbents; Pollutants removal

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Introduction

“Quality Can Be Planned.”-Joseph Juran

Wastes cannot be introduced to the environment in unlimited amounts, especially in case of air pollutants. Different measures have been taken to limit the pollution emission. These are e.g.: the elimination of technological processes generating a lot of waste, introduction of new technologies which minimize the contamination, etc. If it is not possible to reduce the emissions, the waste gas must be purified [1,2]. Nowadays, the economic conditions of Developing Countries don’t allow that all individuals own a new automotive. It is necessary to develop alternatives to reduce the negative environmental impact associated with obsolete engines operation. The best way to address it is by reducing certain exhaust gas components during fuel combustion. The answer therefore is to look at vehicles as an integral whole to identify which solutions would be more feasible. Taking this holistic approach to vehicle improvement as a basis, three main exhaust emission control strategies can be defined:

a.Reduction of fuel consumption;

b.Exhaust gas treatment, and

c.Performance monitoring.

From these three alternatives the second one is currently the more effective for air quality improvement. The main gas treatment currently used is the Catalytic Converter, typically comprises of an expensive porous ceramic substrate with large surface area [3]. Unfortunately some users in Central America and the Caribbe an Countries tend to remove the Catalytic Converter from the vehicles to get better power loads. Over the last decade, the study of combustion gas treatment has been focused on more sophisticated Catalytic Converters. Consequently, the study of other alternatives for exhaust gas purification is important. There are a few methods to purify harmful combustion gases such as physical adsorption [4,5], chemical absorption [6], catalytic methods, etc. [7,8]. It is necessary then to select a suitable method to purify harmful gas for Developing Countries. Besides, standards for vehicles become more mandatory day to day. The more feasible alternative would be the development of customized activated carbons filters for the betterment of the environment. This can be accomplished by reducing the emissions that contribute to smog and acid rains [9].

Activated carbons can be obtained from different precursors, with benefits to the environment [10-12]. Due to its chemical composition, forest biomasses are valuable sources in the synthesis of adsorbents materials. Several examples of activated carbons preparation can be found in the open literature [13,14]. They have been used among others in the purification of pollutants gases such as carbon dioxide, sulfur dioxide, hydrogen sulfide, nitrogen oxides and mercury [15-17]. Taking into account this background, the main objectives of this work can be summarized as follows:

I.Study the feasibility of some agricultural wastes as raw material for activated carbons production with high specific surface area, high mechanical resistance and wide availability.

II. Definition of the best experimental conditions for “chemical activation” with H3PO4 such as “physical activation” with steam water for each precursor.

III. Study of the elimination of pollutant gases in vehicles engines with filters of the adsorbents produced.

IV. Proposal of a methodology for filters evaluation in the removal of undesirable pollutants (CO, SO2, NO2 and H2S) during engines operation.

The practical aspects addressed in this research cover the broad spectrum of applications for air cleaning. Better engines performances can be obtained with an adsorption technique of activated carbons, through an extremely economic method.

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Materials and Methods

The raw materials selected for the study are presented in Tables 1-3.

Preparation of Activated Carbons

The starting raw materials were cut up in small pieces and next subjected to pyrolysis. This process was carried out in a tubular reactor in nitrogen atmosphere. The samples were heated (10 °C/ min) from room temperature to the final pyrolysis temperature of 500. In the final pyrolysis temperature, samples were kept for 60 minutes and then cooled down. The solid products of pyrolysis were next subjected to physical activation [18]. In the case of chemical activation the raw materials were the original precursors which were overnight impregnated into H3PO4 and later submitted to pyrolysis into a stainless steel reactor of 30cm of length per 3cm of diameter. Once the reactor reached the desired temperature the samples were kept at the final temperature according to the experimental conditions of the specific experiment. The activated products then cooled down and washed with enough water till get a neutral pH. Finally, the products were dry at 120°C and then stored [19]. Two different processes were used for the synthesis of the activated carbons from the chars previously obtained by pyrolysis. [18,19]. The experimental conditions used were:

Factorial experimental designs 32 were executed to evaluate the simultaneous influence of the activation conditions on the final product features [14,20]. Following the details for both synthesis processes:

Key properties of the activated carbons prepared were analyzed:

a. Raw material availability;

b. High specific surface area;

c. High mechanical resistance;

d. High adsorption speed.

Characterization of the Raw Materials and Synthetized Activated Carbons

Elemental Analysis: The amount of elements (carbon, hydrogen, nitrogen and oxygen) in the raw materials was determined by an Elemental Analyzer by flash combustion. The samples were firstly dried in an oven at 110°C before the measurement was carried out. The materials was burned at a temperature of 1000°C in flowing oxygen for C, H and N analysis in the analyzer. The CO2, H2O and NOx combustion gases were passed through a reduction tube with helium as the carrier gas to convert the NOx nitrogen oxides into N2 and bind the free oxygen. The CO2 and H2O were measured by selective IR detector. After corresponding absorption of these gases, the content of the remaining nitrogen was determined by thermal conductivity detection. The oxygen was calculated by the difference of carbon, hydrogen and nitrogen.

Apparent Density Measurement: Apparent Density is a measure of the mass per unit volume of a material. It is also called Bulk Density and provides a measure of the “fluffiness” of a material in its natural form. In this work the Standard ASTM D1895 was used. According to this standard the materials are poured into a cylinder of known volume (e.g. 100 mL pipettes) and later weight. Apparent density was calculated as the mass of material divided by the volume occupied into the cylinder [21].

Specific Surface Area Measurement: In order to examine the structure of the synthetized materials, the measurement of the specific surface area of the activated carbons was carried out by gas adsorption isotherms using a Sorptometer applying BET Model. All samples were degassed at 200°C prior to N2 adsorption measurements. Specific surface area was determined by a multipoint BET method using the adsorption data in the relative pressure range: 0.05-0.3 [22,23].

Mechanical Resistance Measurement: The mechanical resistance of the obtained activated carbons was measured through a simple method. A know mass of the granular material was impacted by six glass balls into a semispherical container of stainless steel. The percentage relation between the fragmented mass retained in a 0.5mm mesh and the initial mass is used to estimate the mechanical resistance [24].

Adsorption Speed Evaluation: The adsorption speed was determined by Arrhenius Equation:

where: dX/dt is speed of the adsorption process studied; α is the residual concentration of the adsorbed; and k'ads the apparent kinetic constant of the adsorption process that can be determined by:

Applying logarithm to (Equation 2) brings the possibility to change an exponential equation into a linear dependence, see below:

Plotting ln k'ads vs 1 the activation energy (EA) and the preexponential factor (k0) of the adsorption process studied can be calculated. In the Results discussion ads k'ads will be refers as K for practical reasons.

Designing Process of Activated Carbon Filters

Figure 1 illustrates the process of activated carbon units customized assembling. These filters are very useful to study pollutant gases elimination in automotive engines with the adsorbents produced [25]. The samples, in the form of granules of 2-5 mm in diameter, were packed into a steel column (length 300 mm and internal diameter 90 mm). The gas was passed through the bed of the adsorbent at 0.50 L/min. The concentration of CO, SO2, NO2 and H2S were monitored using a Gas Chromatograph Equipment with standard TCD detector. The concentrations were calculated by integration of the area above the curves.

Pollutants Monitoring at Laboratory Scale

There is no known method available in the open literature which is capable of simultaneously determining all components of combustion gas evaluated here [2]. So the method developed in this work in an innovative alternative for Developing Countries. In order to determine the suitability of the obtained adsorbents in the elimination of CO, SO2, NO2 and H2S, the pollutants removal rate was determined. Figure 2 show a schematic diagram of the customized laboratory system for pollutants monitoring. The system includes, among others:

a. 6 cylinder automotive engine;

b. Activated carbon filter;

c. Exhaust gas analyzer device (Gas Chromatograph);

d. Computer system for data acquisition and recording, etc.

Gas Monitoring System: A standard gas chromatography was used with the following specs:

i. Detector: TCD;

ii. Carrier: Helium;

iii. Column: Porapak Q and Molecular Sieve 5A;

iv. Oven Temperature: 100°C;

v. Sample volume: 1 ml;

vi. Carrier Flow: 25 ml/min;

vii. Detector Temperature: 120°C

Under the described chromatographic conditions, the four gases could be easily separated and quantified [25,26].

The methodology used starting with the preparation of the calibration gas sample by injecting known volumes of each of the four pure gases (CO, SO2, NO2 and H2S) and balance nitrogen into adequate Gas Sampling Bag through the bag’s rubber septum. One mL of the calibration gas mixture and the combustion gases were analyzed by a GC system. Randomly measures of combustion gases before and after the purification process were made on a similar manner in order to evaluate the removal rate of the undesirable pollutants.

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Results and Discussion

Composition and Physical Properties of Raw Materials and Synthetized Products

Table 4 brings a summary of the chemical composition (elemental analysis), such as some physical properties of the 5 precursors studied. Elemental nitrogen, carbon and hydrogen were determined from the elemental analyzer by flash combustion while oxygen was determined by the difference of these three elements. Table 4 shows that the largest amount of element in the raw materials was carbon (except for Corncob which had smaller amount of carbon than oxygen), followed by oxygen, and the smallest amount was nitrogen. The lower content of carbon for Corncob can be attributed to a higher content of volatiles in the structure, translated into a high porosity for the raw material. All precursors do not contain sulfur in their structure, which is very favorable from the ecological and technological points of view.

dap: apparent density; dr: real density; P: porosity

The activation process increases carbon amount (~20- 40%) after modification. On the contrary, there was a reduction in the oxygen content (~20-30%) after physical and chemical modifications. There will be also a reduction of hydrogen amount. The amount of nitrogen was so small for all materials. In Table 4 it can be observed that the initial porosity of all material, except corncobs, have lower values, below 0.5, it makes these materials adequate for activated carbons preparation through chemical or physical activation. The best products synthetized by each process will be reported in Tables 5 & 6.

S: specific surface; K: apparent kinetic constant of the adsorption process; Y: yield; Mr: mechanical resistance; dap: apparent density.

S: specific surface; K: apparent kinetic constant of the adsorption process; Y: yield; Mr: mechanical resistance; dap: apparent density.

Activated carbon from Central American Mahogany was the more reactive material with a significant porosity development (S = 847 m2/g). Should be noted also that Activated carbon from Mamey Zapote was the best adsorbent (S=940m2/g) and also have the higher mechanical resistance, yield and apparent density, very important for filters durability, but it’s the less available material. Finally it’s necessary to remark that Common Corncobs, a widely available agricultural by-product in Central American Countries, showed the worst results for all adsorbents properties; it can be attributable to the higher porosity of the initial raw material (P = 0.79%).

Table 6 show that activated carbon from Central American Mahogany was again the more reactive material but registered now the higher yield and adsorbent area (S = 832 m2/g). Furthermore, Activated carbon from Mamey Zapote was the second better adsorbent (S = 805 m2/g) and again have the higher mechanical resistance and apparent density. One more time activated carbon from Common Corncobs was the worst adsorbent (S = 470 m2/g). This fact is a consequence of poorly porous structure development during the activation process. Further analysis of the data from Tables 5 & 6 indicates that irrespectively of the variant used, the process of activation leads to further changes in the structure of carbonaceous material. The activated carbons synthetized from different materials studied here differ significantly mainly in the specific surface area development. The adsorbents differ not only in the surface properties but also in their texture and morphology that depend first of all on the variant of activation and the pyrolysis conditions of the initial material. Figure 3 illustrates the differences in specific surface development with both methods and the same materials.

In Figure 3, it can clearly be observed that larger specific surface area developments were achieved with physical activation processes. Those products were the better adsorbents to remove the undesirable pollutants. It also confirms that the factorial experimental designs used are the most suitable to optimize the conditions for activated carbon preparation. Textural parameters significantly affect the adsorption properties of the samples studied. [5] This observation suggests that the functional groups of the surface also have considerable influence on the abilities for combustion gases removal. All adsorbents studied had a rapid decrease in CO, SO2, NO2 and H2S concentration after gases interacted with the corresponding filters. High intensity of these harmful gas reductions at ambient conditions can be the reason for much better adsorption on higher surface area products. This explains the lower efficiency of gases removal by chemically activated carbons. The chemical activation process has the additional disadvantage of the required product washing after preparation which inevitably aggregates additional costs.

Gas Monitoring System

The calibrating gas analysis through the regression equations obtained from triplicate analysis of the gas mixtures at identical concentrations, revealed excellent agreement with the known concentrations. The pollutants monitoring system and analytical method used were effective for the simultaneous analyses of the four toxic combustion gases. Figure 4 shows two examples of 2 chromatograms obtained during the analysis of combustion gases purified with activated carbons from Mamey Zapote physically activated. In this figure it can clearly be observed the significant difference before and after gases interaction with adsorbents that can remove large amount of these undesirable gases with the associated environmental benefits.

The analyses of combustion gases revealed moderate concentrations of H2S and CO but very high concentrations of SO2 and NO2. The most effective adsorbent to remove these gases were the physically activated ones. At the present state of knowledge we can only speculate about the reasons for such poor results obtained from the chemically activated samples. Most probably the reason is the presence of a large number of acidic groups on their surface, in contrast to the physically activated samples, that probably have more basic functional groups present on the surface of the samples. Other chemicals present in the combustion atmospheres did not appear to interfere with the analyses. The chromatographic peaks were well separated and defined and the gases were present in amounts that could be easily determined. An excellent precision with relative standard deviations significantly below 2% were achieved in all gas monitoring analysis. The speed, sensitivity and selectivity of the used method make it suitable for analyzing combustion gas mixture of the four gases studied. Table 7 shows the overall average values of pollutants removal with activated carbons (A.C.) during automotive engines combustion.

In Table 7 it can clearly be observed that SO2 and NO2 amounts monitored are remarkable higher than the average limit values for 24 h. The good news is that the activated carbons studied can efficiently remove about 80% of pollutants in exhaust gases from automotive engines with the added value that the harmful gases concentration goes below the limit values. Figure 5 show the correlation between pollutants removal rate and specific surface area of activated carbons during automotive engines operation. In Figure 5 it can be clearly be observed that higher activated carbons specific surface area translated into higher pollutants removal rates that could be estimated by the equation 4 with a correlation coefficient R2 = 0.995:

A proper choice of the parameters of chemical and physical activation such as temperature, activation time, activates agent, etc., permits getting universal adsorbents showing very good adsorption properties towards such pollutants as SO2, CO, NO2 and H2S, however more studies are needed.

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Conclusion

Agricultural wastes studied here are a feasible alternative for the synthesis of activated carbons for pollutants removal during automotive engines operation. The main features that make these products feasible for the diminishing of automotive engines emission are their high adsorption capacity, approaching its efficiency to the commercial Catalytic Converters such as the cheaper costs and its renewability. Based on these results the granular activated carbons studied, produced in large amounts, are fully exploitable for combustion gases treatment. The complex composition of the flue gas with SO2, CO, NO2 and H2S can be successfully analyzed with good compound separation and repeatability. The method used in this investigation would be also be suitable for combustion toxicology researches and could possibly be easily modified to analyze these gases when they are liberated from biological sources [27].

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Acknowledgement

The author wishes to acknowledge Maria Andrea Camerucci and Ana Lia Cavalieri from Mar del Plata University, Argentina, they provided a crucial help in the experiments of this work.

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                                Abstract

Quality by Design is the new-age path chosen towards achieving the demanding quality standards in pharmaceutical industry. The present paper aims to throw light on Pharmaceutical Quality byDesign (QbD) and how its implementation will help manufacture better quality of Pharmaceuticals. Quality by Design is introduced along with its key elements to help make the understanding process easier. To attain built-in quality is the primary objective of Quality by Design. Finally, it can be said that the quality that is achieved by end product testing is not something that can be guaranteed unlike the quality assurance that can be provided by Quality by Design.

Keywords: Quality by Design (QbD); Quality Target Product Profile; Design Space; Critical Quality Attributes

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Introduction

“Quality Can Be Planned.”-Joseph Juran

The above quote is self-explanatory when it comes to product quality in the pharmaceutical manufacturing industry. Quality by design (QbD) is not very old but a recent inclusion in the pharmaceutical industry. It`s sole objective is to achieve better quality standards that is especially important in the pharmaceutical industry. The QbD approach consists of various components, important ones being risk assessment, assessment and management of the identified risks, design of experiments (DoE), quality target product profile (QTPP), and establishing a control strategy to keep the product within the design space that was created with the QbD study [1]. Out of all the components, a lot of pharmaceutical development studies have incorporated DoE for a more rational approach [2].

The target of analytical QbD approach is to establish a design space (DS) of critical process parameters (CPPs) where the critical quality attributes (CQAs) of the method have been assured to fulfil the desired requirements with a selected probability [3-4].

The principles that are involved in the pharmaceutical development and are relevant to QbD are all described in the ICH guidelines (ICHQ8-11) [5].

Any Pharmaceutical Development Process Typically Covers the Following Sections:

a) Complete portfolio including all the details as well as analysis of the Reference Listed Drug Product

b) Quality Target Product Profile (QTTP) compilation.

c) Figuring out the Critical Quality Attributes (CQA)

d) Complete characterization of API &CMA (Components of Drug product) identification of the API

e) Excipient selection& excipients CMA identification

f) Formulation Development

g) Manufacturing Process Development [6]

Quality Target Product Profile (QTPP) describes the design criteria for the product, and should therefore form the basis for development of the CQAs, CPPs, and control strategy.

Critical Quality Attributes (CQA) – A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8) Critical Process Parameter (CPP) – A process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8) Critical Process Parameters (CPP) identification and their impact analysis is done by conducting a preliminary risk analysis for every process parameter (PP) that is involved in the individual unit operations.

Need for QbD in Pharmaceutical Industry [7,8]:

a) To integratepatient needs, quality requirements and scientific knowledge all in one design while the pharmaceutical product is still under developmentand further extending to the manufacturing process.

b) To have a better understanding about the impact of raw materials and process parameters on the quality of the final product. This is especially important for biopharmaceutical products since raw materials like cell culture media can be the risk for variability, effecting important factors likecellular viability, cell growth and specific productivity.

c) To collaborate closely with rest of the industries and the regulators and successfully keep up with the regulatory reviews

d) To maintain harmonization in all the regions so that a single CMC submission worldwide is all that is needed.

e) To encourage continuous quality improvement for the benefit of patients.

f) To enable better product design that will have less problems while manufacturing, thus facilitating more efficiency in the manufacturing process.

g) To make post-approval changes easier since it will be contained within a pre-defined design space, thus resulting in regulatory flexibility.

Every production process in a pharmaceutical industry to implement certain control strategies with the ultimate goal of a robust process. A robust process is the gateway to high product quality at the end of the day [9]. Process variability stands as a hurdle to process robustness, and this originates from lack of control on the process parameters. Thus, QbD steps-in to avoidbatch to batch variability in pharmaceutical products [10].

The net outcome of the detailed QbD study (applied in any product) is the segregation of process parameters with respect to their criticality and the finalization of a proven acceptable range (PAR) for every operation. The knowledge that is gained post the QbD evaluation encompasses every minute detail of the operational process as well as the product in general, and lead to the defining of a Design Space. This way, the impact that the manufacturing process might have with regard to the variability of the CQAs becomes apparent, which helps in strategizing testing, quality and monitoring of batches [11].

Process Evaluation: Linking Process Parameters to Quality Attributes

It is important to carefully evaluate the process completely before applying QbD to it. The better knowledge you have of the process, the more effective your QbD will be. Moreover, process characterization is required to specify the proven acceptable ranges (PAR) for critical process parameters (CPPs). In the traditional approach that is implemented in biopharmaceutical production, existing empirical process knowledge is used on a daily basis. However, this approach leads tolaborious and time consuming post approval changes during process adaptation and any new technology implementation that may have become necessary for raising the efficiency of the process. Also, the effects aprocess scale-up can have on the quality of the final product cannot be predicted when using the empirical process development.

This can increase costs and also can cause difficulty in implementing any changes in the set manufacturing process. Thus was born a way to achieve deeper understanding of processes which would lead to greater flexibility and freedom to effect changes. The concept of operation under a pre-defined design space gave this flexibility. Design space is nothing but a concept that is a part of the “Quality by Design” (QbD) paradigm. Now, manufacturers are to follow a science-based process development than their empirical counterpart.

The QbD Concept is Best Explained in this Flowchart Below

Define a Quality Target Product Profile (QTPP) for product performance

⇩

Identify its Critical Quality Attributes (CQAs)

⇩

Create experimental design (DoE)

⇩

Analysis done to understand the impact of Critical Process Parameters (CPP) on CQAs

⇩

Identify and control the sources of variability.

Process characterization sets the ball rolling in any process development, which employs a sound risk assessment rating the various critical process parameters according to their importance [12-14].

Downstream Processing in Biotransformation

Downstream processes of biopharmaceutical industry essentially include the following steps:

a) Harvesting

b) Isolation

c) Purification

Various unit operations that constitute any biopharmaceutical process follow a designed sequence to form an integrated process [15]. Thus, any change in any one of the one-unit operation can affect the functioning of the subsequent unit operations. This is the reason why interaction effects between participating parameters across unit operations should also be taken into account during the process development. Interactions are said to happen when setting of a parameter will show effect on the response of another parameter. Due to this dependence between the parameters, the combined effects of any two parameters hailing from different unit operations cannot be predicted from their individual effects. Regulatory authorities demand inclusion of interactions of parameters within the QbD approach during any process optimization [16]

Example: Downstream processing of 1, 3-propanediol

Process: Fermentation

Fermentation broth that uses flocculation, reactive extraction, and distillation was studied. Flocculation of soluble protein as well as cellular debris that were present in the broth was carried out by using optimal concentrations of chitosan (150 ppm) and polyacrylamide (70 ppm). It was seen that the soluble protein that was present in the broth decreased to 0.06 g L-1. Recovery ratio (supernatant liquor: broth was found to be greater than 99% (Figure 1) [17,18].

The above flowchart shows a typical fermentation process broken down in steps. Glycerol fermentation process is taken as example for the illustration [19].

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Case Study for API

API product development from the very nascent stages require a lot of planning when implementing QbD at every stage. Whether it is two-step process or a multi-step process, each and every operation and parameter needs to be scrutinized before creating a relevant design space. Brainstorming every possible roadblock that might threaten the quality of the final pharma product is what will help design a top-quality process. A futuristic vision is important in the initial steps of QbD planning. The most important part is to pay sufficient attention to detail lest critical aspects might be missed. This is best done by sitting with the entire development team and taking every minor detail into account. Given below is a case study for a API intermediate development process with the help of QbD that highlights the important steps as to how to go about implementing it from the very beginning of your research. QbD is done best, when it is implemented from the very nascent stage of product development.

Quality Target Product Profile

When making your QTPP, make sure you list down everything from your vendor details to target costing. This step basically asks you to think of every aspect of your product and make a comprehensive profile of it. The specification of quality must be highlighted here with all the challenging impurities that might threaten your quality. Everything from stability testing requirements to raw material quality [20] is encompassed in this stage of QbD.

CQA Determination

Given below are some typical CQA parameters that are considered in most of the enzymatic methods of API intermediate preparations.

a) Purity

b) Chiral purity

c) Enzyme residue

d) Assay

e) Appearance

f) Residual Solvent

g) Yield

h) Polymorphic forms

i) Moisture content

j) Melting point (Table 1)

Initial Risk Assessment

The risk assessment can be done in various ways and is the customizable step in QbD. This part calls for a group-discussion or a team meeting where everyone can list down all possible risks related to the project in discussion and grade each one in the list with the amount of risk that it poses. The simplest module suggests you number them 1, 2, 3 with the increasing or decreasing order of the risk threat. A more complicated and detailed risk assessment requires linking of CQAs and CPAs to highlight the risk of their interdependence (Figure 2) [21].

Post risk assessment, comes the control strategies to be followed to tackle the possible risks that are probable. The control strategies are for you to think and execute to achieve your target quality specifications.

Design of Experiment

This is a valuable tool for channelizing your experimental work, to move ahead in a systematic manner. Design of experiments can be of several types: comparative, screening, response surface modeling, and regression modeling [1].

Comparative Experiments: The aim of this study is simple, i.e., picking best out of two options. The selection can be done by the comparison data generated, which is the average of the sample of data.

Screening Experiments: If you want to zero-in on key factors affecting a response, screening experiments would be the best bet. For this, list down concise list of factors that might have critical effects on response that you desire. This model serves as preliminary analysis during development studies.

Response Surface Modeling: Once you have identified the critical factors that affect your desired response, response surface modeling comes handy to identify a target and/or minimize or maximize a response.

Regression Modeling: This is used to estimate the dependence of a response variable on the process inputs.

A step by step guide is given for the DoE step of the QbD process (Figure 3).

Response columns were filled post experimentation as per the design creation (Figure 4).

Factorial Design Analysis Done as Given Under

Analysis Done First for One of the Responses, “Yield”: (Table 2)

P-Values Were Checked for Significance and Higher P-Value Term Eliminated First to Create a Reduced Model:

(Table 3) (Figures 5 & 6)

Observation

From the above graph, significant interaction between the two terms can be inferred.

Analysis Done for the Response “Diacid”: (Table 4)

P-values Checked for Significance and Higher P-Value Term Eliminated First to Create a Reduced Model: (Table 5) (Figure 7)

Observation

From the above graph, significant interaction between the two terms can be inferred.

Response Optimizer Was Used to Optimize Both The Terms With Respective to The Given Responses- Yield and Diacid: (Table 6) (Figure 8)

The optimized parameters predicted for maximum yield and minimum impurity (of di-acid) was found to be 8pH and 37C.

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Case Study 2

As mentioned before, regression analysis is another important tool that can be used to study existing data. This means that if you have done some experiments (without designing them beforehand), you can quickly run a regression analysis of the collected data to derive a relationship between CPPs and the reaction results.

A lot of times, when one follows the one-factor-at-a-time optimization process, by the time any CPP is optimized, a lot of data stands generated. Instead of just tabulating the data and wasting time manually making sense out of them, regression analysis can come to your rescue. As always, graphical data representation seems much easier to understand and also saves your valuable time.

The effect of pH was studied [22] separately in the preparation of deoxynojirimycin base (stage III). The reaction involved N-formyl amino sorbitol, water, oxygen and whole cells of Gluconobacter oxydans DSM2003. Later involvement of sodium hydroxide and sodium borohydride gave rise to deoxynojirimycin. Further work-up and 2-methoxy ethanol facilitated crystallization yielded Deoxynojirimycin base. In this experiment, pH of the reaction was changed to find out its role during the reaction and a regression analysis was run using Minitab to study this affect.

Observations recorded showed that reaction did not occur at pH2 and at pH8, the reaction did not reach completion. The optimum pH range between 4 to 6 showed certain effect on yield and purity. The significance of pH variation during the reaction was thus established as described below (Graphs 1-3):

When null hypothesis p-test was carried out, no significant effect of pH was to be found on product purity, impurity1 and impurity2, but its significant influence was seen in minimizing impurity3.

Furthermore, large-scale batches conducted were statistically analyzed as well to achieve better understanding of the influence of list of parameters on the output obtained. The following parameters were studied during the stage III reaction described above:

a) pH, RPM and Oxygen cylinders consumed during the course of the reaction.

Their effect on the output and reaction completion time was studied. It was seen that only RPM showed statistically significant effect on the reaction completion time and rest of the factors did not contribute to any significant effect on the output or reaction completion time.

During biotransformation process, i.e. during oxidation of N-formyl using Gluconobacter oxydans DSM2003 whole cell, three main unknown impurities peaks were observed in HPLC chromatogram while reaction monitoring. This process is capable of removing these three impurities during down streaming, work up & isolation to the levels mentioned below:

a) Impurity 1 (has defined RRT on HPLC chromatogram) not more than 3%

b) Impurity 2 (any other unknown impurity) not more than 1%

c) Impurity 3 (has defined RRT on HPLC chromatogram) not more than 10 %

Since higher level of impurities affect the yield of the process, efforts were carried out to study the factors which can reduce the formation of process impurities.

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Conclusion

The concept of Quality by Design (QbD) is highly reliable when it comes to achieving foolproof quality of your product. This is a modern tool that is going viral in Pharmaceutical industry especially because this industry demands high quality standards and tolerates no compromise when it comes to the quality. Breaking down QbD, it essentially comes down to identifying the critical parameters of the process and assigning a particular design space for every single critical attribute. Thus, QbD can be considered as an intelligent approach to quality that yields robust processes. QbD also ensures that there is continuous improvement in the process during the entire lifecycle of a Pharmaceutical product [23].

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Acknowledgement

Our group would like to thank the Department of Scientific and Industrial Research India, Dr. Hari Babu (COO Mylan), Sanjeev Sethi (Chief Scientific Office Mylan Inc); Dr. Abhijit Deshmukh (Head of Global OSD Scientific Affairs); Dr. Yasir Rawjee {Head - Global API}, Dr. Sureshbabu Jayachandra (Head of Chemical Research); Dr. Suryanarayana Mulukutla (Head Analytical Dept MLL API R & D) as well as analytical development team of Mylan Laboratories Limited for their encouragement and support. We would also like to thank Dr. Narahari Ambati (AGC- India IP) & his Intellectual property team for their support.

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                                       Image Article

In the current study, we have experimentally and comparatively investigated and compared malignant human cancer cells and tissues before and after irradiating of synchrotron radiation using Correlation Spectroscopy (COSY), Exclusive Correlation Spectroscopy (ECOSY), Total Correlation Spectroscopy (TOCSY), Incredible Natural-Abundance Double-Quantum Transfer Experiment (INADEQUATE), Heteronuclear Single-Quantum Correlation Spectroscopy (HSQC), Heteronuclear Multiple-Bond Correlation Spectroscopy (HMBC), Nuclear Overhauser Effect Spectroscopy (NOESY) and Rotating Frame Nuclear Overhauser Effect Spectroscopy (ROESY). It is clear that malignant human cancer cells and tissues have gradually transformed to benign human cancer cells and tissues under synchrotron radiation with the passage of time (Figures 1-8) [1-75]. It should be noted that malignant human cancer cells and tissues were exposed under white synchrotron radiation for 30 days. Furthermore, there is a shift of the spectrum in all of spectra after irradiating of synchrotron radiation that it is because of the malignant human cancer cells and tissues shrink post white synchrotron irradiation with the passage of time. In addition, all of the figures are related to the same human cancer cells and tissues. Moreover, in all of the figures y-axis shows intensity and also x-axis shows energy (keV).

It can be concluded that malignant human cancer cells and tissues have gradually transformed to benign human cancer cells and tissues under synchrotron radiation with the passage of time (Figures 1-8) [1-152]. It should be noted that malignant human cancer cells and tissues were exposed under white synchrotron radiation for 30 days. Furthermore, there is a shift of the spectrum in all of spectra after irradiating of synchrotron radiation that it is because of the malignant human cancer cells and tissues shrink post white synchrotron irradiation with the passage of time. In addition, all of the figures are related to the same human cancer cells and tissues. Moreover, in all of the figures y-axis shows intensity and also x-axis shows energy (keV).

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                                          Abstract

Classical chelating agents (especially aminopolycarboxylates, APCs and phosphonates) are till date the commonly used in industrial and home processes. This is due to their ability to strongly bind metals, and perhaps their being available in the market over a long time now. Abundant evidences proved that they are not environmentally benign. This has spurred the quest of industrialists and academia, as prompted by environmental policies, towards low toxicological profile and environmentally friendly chelating agents. The desire has resulted into annual rise in formulations and proposals of Greener alternative chelators such as glutamic diacetic acid (L-GLDA), ethylenediamine disuccinic acid [S, S]- EDDS, polyaspartic acid, citrate, gluconic acid, amino acids, lipophilic β-diketone (14,16)-hentriacontanedione, plant extracts etc. to be used in place of the classical chelating agents. For reasons of environmental compatibility, low toxic profile and sustainability, these Greener alternative chelants are better employed for industrial uses (such as metals extraction and recovery etc.) and home applications.

Keywords: Greener Chelators; Metals Recovery; Stability Constant

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Introduction

Metals are extensively used by industries in various applications such as electronics, materials, catalysts, chemicals, modern low-carbon energy technologies [1] (nuclear, solar, wind, bioenergy, carbon capture and storage (CCS)) and electricity grids [1,2]. Greater pressure has been placed on metal utilisation because of population growth coupled with a higher standard of living. Furthermore, industrialisation has led to the increasing demand for critical metals, as many of these are required in modern technologies. This is causing concern over the supply of critical metals for future generations. Therefore, according to Hunt et al. [3] the sustainable use of metals is vital so that both the current and future generations have access to them without hitches. Industries or nations classify metals as critical depending on the purpose and need of assessment [4]. Some metals have been identified as critical metals because of their significance [3]. However, elements with significant supply restriction issues (geopolitical issues, conflicts, international monopolies and mining as a by-product of other elements) and those which would have a dramatic impact on business or economy if limited are considered critical [5]. The top 14 metals like tellurium, indium, tin, hafnium, silver, dysprosium, gallium, neodymium, cadmium, nickel, molybdenum, vanadium, niobium and selenium are critical and commonly needed in these emergent low carbon energy technologies [1,6].

Furthermore, industries generate a variety of wastes which contain heavy metals [7]. Electroplating and mining companies generate large amounts of mercury, lead, cadmium, silver, copper, and zinc ions [8,9]. More so, papers, metals, electrical and electronic equipment wastes contain precious metals like Ag, Au [10]. And some of these metals are regarded as technology metals [11,12]. Unfortunately, the reserves of high-grade ores of these metals are depleting [7]. Therefore, there is a need to recycle and recover these metals from the environment. Moreover, some heavy metals can be hazardous even at low concentrations [9,13]. According to Nagajyoti et al. [14] heavy metals such as Cd, Cu, Pb, Cr and Hg are major environmental pollutants, particularly in areas with high anthropogenic activities. Thus, when these metals are in bioavailable forms and at excessive levels, they have the potential to become toxic to plants and consequently the environment [14]. In addition, there are usually trace amounts of iron, copper, manganese, calcium, and other metals found naturally in many raw materials [15,16]. These metal ions are normally found in processing water as well, and may infiltrate processing [15]. Moreso, presence of metal ions in a process or product can bring about scaling, chemical degradation, discoloration, precipitation, emulsion instability, rancidity, and reduce; quality, consumer appeal, shelf-life and ultimate value [15,17,18].

Fortunately, chelating agents have been used to eradicate these problems by binding metal ions via N, O, S atoms as the case may be [19]. When metal ions are bonded to chelant, the metal becomes blocked from undesired interaction [20]. Hence, Chelating agents find use in paper pulp bleaching [21,22], detergents and cleaning [23], water treatment and food industries [24,25]. Chelants have also been used for the extraction of metals [22,26-33]. Other applications where chelating agents are used include fertilisers [22,34-38], photography [39] and pharmaceuticals [40,41]. They are also applied in nuclear industry, soil remediation [42,43] and textile treatment [44]. Additionally, chelators are used in many products to prevent; chemical degradation, discoloration, precipitation, emulsion instability and rancidity; thus increasing consumer appeal, shelf-life, and ultimate value [17]. Chelants are also used for heavy metal detoxification [45], treatment of antitumor [46] and in radioimmuno-diagnostics [47,48]. They are potent agents for solubilising heavy metals from polluted soils [44,49–51] and as root canal lubricants [52]. Sometimes chelating agents are used as precursors of catalysts [53,54]. Chelants are also used to prevent scale [22,55]. They can also enhance the growth of plants by removing toxic metals from the soil [56,57]. Because of their wide needs, the overall chelating agents growth was 4.0% annually during 2009-2014 [58] and the trend is likely to increase..

Incidentally, classical chelating agents such as aminopolycarboxylates, aminophosphonates and phosphates are used to chelate metals with substantial stability [8]. Phosphonates are extensively used as scale inhibitors [20,59]; and as ingredients in detergents for cleaning processes due to their ability to effectively bind Ca(II) [20]. Traditional phosphonate chelating agents include: diethylenetriaminepentakis(methylenephosphonic acid), DTPMP; 1,2 –diaminoethanetetrakis (methylenephosphonic acid), EDTMP; 1-hydroxy ethane (1,1-diylbis-phosphonic acid), HEDP; phosphonobutanetricarboxylic acid, PBTC; nitrilotris (methylenephosphonic acid), NTMP; N-phosphonomethylgycine, PMG. While the aminopolycarboxylates (APCs) chelants mostly used as chelators include ethylenediamine tetraacetic acid, EDTA; nitrilotriacetic acid, NTA; β-alanine diacetic acid, ADA; diethylenetriaminepentaacetic acid, DTPA; ethylenediaminedi(ohydroxyphenylacetic acid, EDDHA; N- (hydroxylethyl) – EDTA, HEDTA [40]. APCs and phosphonates are among the most widely used chelating agents in the world, accounting for 37.8% of consumption in 2009 [8,58]. Figure 1 below presents the percentage distribution of the most consumed chelating agents across different sectors [60].

Aminopolycarboxylates (APCs) chelators (like EDTA and NTA) and phosphonates have strong chelation effects for metals [20,61]. Unfortunately, most of these compounds are not readily biodegradable [20,59,62]. The infiltration of these chelants into the environment could cause dissolution of heavy metals from the sediments and soils, thereby mobilizing them [24,40,49,63] thus leading to increased levels of metals [22], except phosphonates that do not mobilise toxic metals [40,59]. These strong chelants persist in the environment due to their high solubility in water and low biodegradability (except NTA) [22]. It has been stated that 800 μg/L of EDTA has been found in some U.S. industrial and municipal wastewater treatment plants and up to 12 mg/L in European bodies of water [20]. EDTA is now among the EU priority list of substances for risk assessment [16]. According to Sillanpaa [64], ethylenediamine tetraacetic acid (EDTA) contains 10% nitrogen which could harm aquatic organisms. Furthermore, the majority of the traditional chelating agents (APCs and phosphonates) are petroleum derived [65,66]. Therefore, the consumption of traditional APCs chelators is declining (–6% annually), because of the persisting concerns over their toxicity and negative environmental impact [58]. Another concern is that most of these common chelants are produced from toxic substances like cyanide [20,67].

In addition, the EU is regulating the use of phosphates in consumer laundry detergents and consumer dishwasher detergents in order to reduce the eutrophication risks and costs of phosphate removal by wastewater treatment plants [68-71]. Their persistence in the environment is because of their low biodegradability and high water solubility [67,72]. In addition, studies have shown that there is a decline in the high quality phosphorus rock reserves used to produce phosphate chelants which could lead to higher costs associated with obtaining phosphates and phosphonate products. The continuous dependence on phosphates and phosphonate chelators will further accelerate the decline of finite high quality phosphate rocks [73]. Furthermore, phosphates are essential components in fertilisers (used for food production) and therefore the utilisation of phosphates as chelators is in direct competition with the food industry. Therefore, it is essential to look for Greener alternative chelating agents in order to reduce the reliance on these traditional chelants. Hence, this paper gleans for the Greener alternative chelators and their applications, especially in metals recovery.

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Materials and Methods

Aminopolycarboxylic acids chelators are the most widely consumed chelating agents; however, the percentage of the Greener alternative chelators in this category continues to grow [24]. In 2013, these Greener alternative chelants represented approximately 15% of the total aminopolycarboxylic acids demand. This is expected to rise to around 21% by 2018, replacing in particular the EDTA (ethylenediaminetetraacetic acid), NTA (nitrilotriacetic acid) and aminophosphonic acids used in cleaning applications [20,24,58]. This is because of issues like non-biodegradability, toxicity, and mobilization of toxic metals by these traditional chelants [24] as earlier mentioned. In addition, more than 90% of organic chemicals are derived from fossil fuel refineries [74,75] which is not sustainable. The continuous depletion of petroleum resources coupled with a shift to Greener products by consumers means that it is vital to look for alternative Greener chelating agents. Therefore, in order to replace traditional chelants, the alternative chelating agents must have a strong ability to form complexes [16,76], as well as possess low nitrogen content so as to reduce the loading of nitrogen [16]. In addition, they should be readily or at least inherently biodegradable [16,76]. These alternative chelants are well favored by environmental protection policies [62,77]. Examples of some Greener alternative chelating agents include ethylenediamine disuccinic acid ([S, S]-EDDS), polyaspartic acid (PASA), methylglycinediacetic acid (MGDA) [24,25], glutamic diacetic acid (L-GLDA), citrate, gluconic acid, amino acids, plant extracts etc. Asemave [78] and Asemave et al. [79] reported the use of lipophilic β-diketone, 14,16-hentriacontanedione as Greener alternative chelator for metals recovery. These have been proposed to replace the classical EDTA and diethylenetriaminepentaacetic acid (DTPA) chelators in various applications [16,20,80,81]. According to Hyvönen [16], alternative chelants have a lower chelating ability when compared to the traditional chelators, notwithstanding, this will make them less toxic.

Glutamic Acid Diacetic Acid (L-GLDA)

L-glutamic acid diacetic acid is 86% bioderived from foodapproved natural amino acid salt (monosodium L-glutamate or MSG) [66,82]. It’s in turn obtained by fermenting sugar, molasses, corn or rice (renewable feedstock) [66], and is marketed as Dissolvine GL-38 [24]. According to Dixon [24], L-GLDA is produced by a waste-free process and from renewable feedstock, which is in accordance with the 4th principle of green chemistry [24]. Ammonia is generated as a by-product which is collected and re-used in industries. It is a strong chelating agent that is safe, readily biodegradable [61,83] and is considered to be an adequate alternative to phosphates, NTA and EDTA, especially in cleaning applications [20,61,84]. It is readily soluble in water at different pH values, which increases its performance rate [20]. L-GLDA is stable over a different temperature than other APCs. L-GLDA, citrate and carbonate are incorporated in detergent formulations [85]. Aqueous solutions containing L-GLDA can be use as oil field chemicals to dissolve calcium carbonate scale and other subterranean carbonate formations to increase permeability and enhance the withdrawal of oil or gas [86].

Polyaspartic Acid

There are different ways to obtain PASA [87], but the typical method for obtaining it is by heating aspartic acid to 453 K resulting in poly (succinimide) with elimination of water. The sodium hydroxide in the system then reacts with the polymer to partially cleave off the amide bonds, in which the (α and β) bonds are hydrolyzed resulting in a sodium poly (aspartate) copolymer with 30% α-linkages and 70% β-linkages (see Equation 1) [87]. Polyaspartic acid production (PASA) is cost-effective; hence it is available on a large scale. L-aspartic acid derived from plant sugars [88] could be used for the sustainable production of PASA. Poly aspartate is used as a biodegradable anti-scaling agent, corrosion inhibitor and as a metal chelator [87]. Lingua et al. [89] described PASA as a green chelant used in agriculture to supply minerals to crop so as to improve the crop yield.

Ethylenediamine Dissunic Acid ([S, S]-EDDS)

Ethylenediamine disuccinic acid, [S, S]-EDDS is a naturally occurring compound and was first isolated from culture filtrate of the actinomycete, Amycolatopsis orientalis. The biosynthesis of [S, S]-EDDS is from L-aspartate and serine [83,90] or from oxaloacetate and 2,3-diaminopropionic acid [35]. [S, S]-EDDS is also synthesized by the nucleophilic addition of ethylenediamine with sodium maleate affording stereoisomers of ethylenediamine-N,N’-disuccinic acid [90,91]. Alternatively, [S, S]-EDDS is produced from the reaction of maleic anhydride and ethylenediamine to yield a mixture of the 3- isomer of EDDS. The reaction of aspartic acid with 1,2-dibromoethane results in the formation of two isomers ([R, R]-EDDS and [S, S]-EDDS, depending on the isomer of aspartic acid used. Since aspartic acid can be derived from plant sugars it could also enhance the sustainable production of [S, S]-EDDS. It is also produced by fermentation of A. orientalis [35]. [S, S]-EDDS is the structural isomer of EDTA, however it is readily biodegradable than EDTA [61]. Equation 2 describes the synthesis of this compound.

According to Dixon [24], [S, S]-EDDS production is in conformity with the 3rd principle of green chemistry; i.e. designing less hazardous chemical synthesis. It is one of the most promising biodegradable chelating agents [39,49] and has a low nitrogen content [16] making it less toxic [92]. Furthermore, [S, S]-EDDS has zero NTA, formaldehyde or cyanide (toxic chemicals) unlike common traditional APCs chelants [83]. [S, S]- EDDS is effective in chelating several metals from soil [93-95]. Furthermore, it is capable of binding transition metal ions in place of Mg(II) and Ca(II) [24,83]. According to work by Yang et al. [96] [S, S]-EDDS at pH 5.5 is more suitable for Cu(II), Zn(II) and Pb(II) extraction. Ullmann et al. [97] modified [S, S]-EDDS by attaching a lipophilic hydrocarbon chain to its nitrogen atoms in order to make a hydrophobic chelating agent. Such lipophilic chelants are especially good as metals extractants.

In addition to these chelating agents above, in 1998, another greener alternative chelator, sodium iminodisuccinate was introduced [20]. Its production is based on the reaction of maleic anhydride with ammonia and sodium hydroxide [20,98] (see Equation 3). It is readily biodegradable [43,99] and environmentally benign chelator, it is effective in chelating Ca(II), Fe(III), Cu(II). And is used in; cleaning, water softening, photography, agriculture. Thus eliminating the problem of environmental persistence common conventional chelating agents [20]. Moreso, we have methylglycine diacetic acid (MGDA) as greener chelant. In fact, methylglycinediacetic acid (MGDA), L-GLDA and ethylenediamine disuccinic acid [S, S]-EDDS can be used in scale inhibition [100]. Both [S, S]-EDDS and MGDA have demonstrated to be efficient chelating agents with a mobilizing capacity that is comparable with EDTA [43]. MGDA is also considered as a possible replacement for EDTA and DTPA [40]. It is one compound which has been considered as a good substitute for EDTA and DPTA like [S, S]-EDDS [40]. Another biodegradable chelating agent, tetrasodium 3-Hydroxy-2,2’-Iminodisuccinate (HIDS) has also been reported to have high chelating capability [101], which is effective in removing heavy metal ions such as Fe(III), Cu(II), Ca(II) and Mg(II) over wide range of pH. It’s thermally stable, solubility in concentrated alkaline solutions, and is and environmental harmonious chelating agent [101]. HIDs is being found applicable in cleaning processes, textile processing, bleach stabilization, photography, paper and pulp processing, scale removal and prevention, metal treatment working, water treatment, Agriculture [101,102].

Citrates

These are salts of citric acid (2-hydroxy-1, 2, 3-propane tricarboxylic acid). Citric acid is known to be produced by fermentation (using fungi and yeasts) [103], synthesis and extraction from citrus fruits [103,104]. Vegetable wastes of potato, brinjal, cabbage wastes also have been found to as potential sources of citric acid [103]. Citrate fruits are used in the treatment of renal calculi [105]. Citric acid is an excellent chelating agent which is used to remove lime scale from boilers and evaporators [87]. They are used in some cases in place of classical chelating agents. For instance, a 24 h washing of the contaminated soil with 0.5 M citric acid reduces the levels of Cd(II), Cu(II), Zn(II) and Pb(II) from 0.01, 0.04, and 0.42, 41.52 mg g-1 to 0, 0.02, 0.18, and 5.21 mg g-1 respectively [106]. In another development, the ability of citric acid as chelating agents to the removal of lead from contaminated soil was examined both in the soil washing [107]. In the soil washing, the removal efficiency of lead with citric acid was less as [S, S]-EDDS in the pH range from 7-10 [107]. Although citrate is less efficient in terms of coordinating metal ions as compare to some conventional chelants, its activity towards removal of Pb(II) in acid soil is better for its low cost and less harm to crops [42]. It is also used for removing Ca(II) ions [87]. Citric acid is green chelator for removal of heavy metals from contaminated sludge with higher extraction efficiency at mildly acidic pH of about 2.30 [107- 109]. Citric acid was found to highly efficient for the recovery of Cr(III), Zn(II) and Mn(II) from a printed circuit boards (PCBs) [110]. Again mobilization of Pb(II), Zn(II) and Cu(II) from harbor sediments using citric acid as chelating agents has been previously reported [95]. Extraction efficiencies of citric acid for Cr(III), Cu(II), Ni(II), Pb(II) and Zn(II) is significant to lower the heavy metal content in sludge below the legal standards [111].

Gluconates

Gluconic acid (C6H12O7) is found naturally in fruit, honey, kombucha tea, and wine [87]. Gluconic acid is a weak organic acid obtained from glucose by a simple oxidation reaction. The oxidation is done by the enzyme glucose oxidase (fungi) and glucose dehydrogenase (bacteria such as Gluconobacter) [112]. But the microbial production of gluconic acid is the preferred method where the most studied and widely applied fermentation process involves the fungus Aspergillus niger [112]. Gluconic acid has two bonding sites: the ionic acid oxygen (-COO-) and the oxygen on the hydroxyl group (-OH) which can bond with the metal ion [113]. Gluconic acid and its derivatives (such as the sodium gluconates) have wide applications in food and pharmaceutical industries because of their chelating ability [112,113]. Aqueous solutions of the natural chelating agents D-gluconic acid and D-glucaric acid (D[+]-saccharic acid) were used to remove heavy metal ions (Cd(II), Cr(III), Cu(II), Ni(II), Pb(II), Zn(II)) from a soil polluted by long-term application of sewage sludge [114]. They found that, between the pH 12.0 and 13.0, Pb(II) and Cu(II) were selectively extracted [114].

Gallic Acid

Bioconversion studies with Aspergillus niger and Rhizopus oryzae showed that raw substrates like myrobalan fruits can be used as potential substrates instead of extracted tannins for gallic acid production [115]. It was found that Aspergillus niger is better gallic acid producing strain [115]. Gallic and citric acids were reported to induce removal of Cd(II), Zn(II), Cu(II) and Ni(II) from soil without increasing the leaching risk [63]. Net removal of these metals by these acids can be as much as other classical chelators. A major reason for this is the lower phytotoxicity of gallic and citric acids [63]. Other bioderived molecules like cyclodextrins (CDs) have also been identified as molecular chelating agents [116]. Cyclodextrins possess a cage-like supramolecular structure like cryptands, calixarenes, cyclophaneS, Spherands and crown ethers [116]. It can either be in alpha, beta, or gamma form cyclodextrins [80]. Therefore CDs complexes are widely used in many industrial products, technologies and analytical methods [116]. Other applications includes; drug carrier, food and flavors, cosmetics, packing, textileS, Separation processes, environment protection, fermentation and catalysis because of negligible cytotoxic effects of CDs [116]. Also, phytochelatins are oligomers of glutathione, produced by the enzyme phytochelatin synthase. They are found in plants, fungi, nematodes and all groups of algae including cyanobacteria [87]. Phytochelatin are used for heavy metal detoxification [87]. Another natural chelator, phytic acid is an organic acid found in rice bran [117]. It is used as an acidulant for pH adjustment. Phytic acid binds to metals strongly because of strong chelating effect [117]. Moreover, phytic acid shows antioxidant action and prevention of color degradation [117]. The most outstanding feature of phytic acid is its strong metal chelate function, allowing metal ions such as iron (Fe) which often adversely affect the production or storage of food in various forms to be removed or deactivated [117]. Moreso, pectin (found in foods like, apples, bananas, grapes, okra, beets, carrots and all citrus fruits) is useful in removing of heavy metals from the body [118].

Chitosan is a useful polymeric material produced from the shells of crustaceans [119]; it’s a partially deacetylated polymer of acetylglucosamine [119]. Chitosan is a common biodegradable chelating compound [50]. In most cases, chitosan and its derivatives usages is based on their ability to chelate strongly heavy and toxic metal ions [120]. Chelation of copper and nickel by the addition of the biodegradable chelating agent, chitosan, EDTA and citrate was investigated [50]. The experiments showed that the extraction ability for copper and nickel from the contaminated soil decreased as follows: chitosan > EDTA > citrate at pH 3.00 – 3.50. Pimenta et al. [121] also found that, 0.2% chitosan, 15% EDTA and 10% citric acid gave comparable effects in decreasing dentin microhardness. Amino acids and their derivatives have been found use as chelating agents. Amino acid chelants are used to deliver minor elements to plant unlike synthetic chelates [122]. In addition, amino acids complexes of some metals are useful as; anti-inflammatory agents, antibacterial agents (as applied against Escherichia coli and streptococcus pyogenes) and anti-tumor agents (against melanoma) [123]. Furthermore, Fischer [124] investigated the ability of β-thiol group containing amino acids L-cysteine and L-penicillamine to remove heavy metals (Cd(II), Cr(III), Cu(II), Hg(II), Ni(II), Pb(II), Zn(II)) from some soil components (peat, bentonite, illite) at neutral pH. The extractability of metals from peat in the presence of L-penicillamine was slightly higher than L-cysteine in these metals. The recovery of metals from bentonite was higher generally [124]. Riri et al. [125] investigated the use of simple organic acid (oxalic, glycolic and malic acid) to chelate gadolinium (III). Lignosulfonates, proteins, humic or fulvic acids and polyflavonoids are bioderived chemicals that can be used for complexing metals and subsequent application in agricultural foliar [126-128].

Additionally, some plant extracts can also be used as chelators [129,130]. The chelating efficiency of methanolic extracts of Triticum aestivum (wheatgrass) towards iron was investigated to determine the iron chelating activity in iron dextran induced acute iron overload animals. The chelating power or efficacy of the compound was found to be 34.5% to that of desferoxamine (commercial chelant) [131]. Ebrahimzadeh et al. [132] found that the phenolic and flavonoid extract of Mellilotus arvensis has ability to chelate Fe(II) [132]. The chelating ability of aqueous extract of Tetracarpidium conophorum was tested in vitro [133]. The dose (97.38%) showed the highest chelating ability. Therefore, the aqueous extract of Tetracarpidium conophorum could be used in the treatment of iron-overload disorders due to its high chelating ability in vitro at low doses [133]. The tannin fractions isolated from hazelnuts, walnuts and almonds were characterized for chelation of Zn(II), Fe(II), Cu(II) [134]. Copper ions were most chelated by the tannin fractions of hazelnuts, walnuts and almonds. Fe(II) complexation ability of the tannin fractions of walnuts and hazelnuts were lower as compared to the almond tannin fraction [134]. The capacity to chelate Zn(II) was quite varied for the different nut tannin. An in vitro iron chelating properties of 60% ethanolic extracts of some plant parts (Terminalia chebula, Caesalpinia crista, Cajanus cajan, Terminalia belerica, Emblica officinalis, and Tinospora cordifolia) were investigated. The iron chelating property of the plant extracts as reported were; T. chebula > T. belerica > E. officinalis > C. cajan > T. cordifolia > C. crista [135].

Likewise Soya beans extract were found as chelants towards Cu(II) [136]. The binding properties of Pb(II), Cu(II), Ni(II), Cd(II), Zn(II), Cr(III) and Cr(VI) in native and NaOH-modified biomass of Solanum elaeagnifolium were investigated [137]. The result at pH 5.0 revealed that; 20.6 mg Pb(II)/ g, 13.1 mg Cu(II)/ g, 6.5 mg Ni(II)/ g, 18.9 mg Cd(II)/ g, 7.0 mg Zn(II)/ g, 2.8 mg Cr(III)/ g and 2.2 mg Cr(VI)/ g were removed respectively. Better still the NaOH modified material gave higher binding properties in each case [137]. Tsujimoto et al. [138] had observed that anacardic acids from cashew nut can chelate Fe(III). Plant extracts have been used for removal of heavy metals especially Fe [129,131,132,135,136]. They can be used in treatment of iron-overload [133] and recovery of other heavy metals from the environment [134,139]. Column experiments of 14 d and 7 d with partially hydrolyzed wool as chelating agent on a silty-loamy sand agricultural soil was studied. The 14 d wool hydrolysate mobilized 68% of Cu in soil, whereas in the case of Cd it mobilized 5.5%. The plant (Nicotiana tabacum) uptake of Cd(II) and Cu(II), assisted by the application of 6.6 g kg-1 wool hydrolysate was increased by 30% in comparison to the control plants. Phytoextraction has revealed great potential with no leaching detected unlike use of conventional chelating agents [140].

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Materials and Methods

Aqueous solution of the chelant may be directly used to leach metals from spent solid waste into aqueous state. Then recovery process of metals from aqueous system with chelating agents mostly involves liquid – liquid extraction of metal ions with that of chelating agents. Solvent extraction of metals with chelating agents has been considered to be an effective method for purifying metals [141]. Subsequently the resulted complex (chelate) is stripped with strong acid (HCl or HNO3) resulting to the release of the captured metal into another aqueous phase. This is then concentrated to obtain the metal into pure state. From the literature, it has been shown that chelating agents (such APCs) alone or supported on other solids have been used for the recovery of metals [142-145]. Figure 2 is the flow sheet showing the major stages for recovery of metals using chelating agents.

The ability of chelant to bind metal ion is determined by the stability constants [24]. Wuana et al. [146] also reported that extraction of metals with chelating agents depend on stability constants [146]. The larger the stability constant, the stronger the chelation effect and the free metal ion in solution become lesser [147]. Hence, the commonly consumed chelants (APCs) usually have high stability constants with different metal ions [24]. Table 1 gives important information because L-GLDA and [S, S]-EDDS have relatively higher stability constants for most metal ions than most other Greener chelating agents [147,148]. As a matter of fact, they have been considered as replacement for EDTA and NTA in some applications [25]. Although other factors such as temperature, pH and presence of other ions can affect the ability to remove metals by chelants [24]. Whereas, Table 2 gives some of these Greener chelants; their sources and metal chelating functions [149-154]. Again, Table 3 contain some plant extracts which have been used for removal of heavy metals especially Fe.

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Materials and Methods

Classical chelating agents (especially aminopolycarboxylates, APCs and phosphonates) are till date the commonly used in industrial and home processes. This is due to their ability to strongly bind metals, and perhaps their being available in the market over a long time now. Abundant evidences proved that they are not environmentally benign. This has spurred the quest of industrialists and academia, as prompted by environmental policies, towards low toxicological profile and environmentally friendly chelating agents. The desire has resulted into annual rise in formulations and proposals of Greener alternative chelators such as glutamic diacetic acid (L-GLDA), ethylenediamine disuccinic acid [S, S]- EDDS, polyaspartic acid, citrate, gluconic acid, amino acids, lipophilic β-diketone (14,16)-hentriacontanedione, plant extracts etc. to be used in place of the classical chelants. For reasons of environmental compatibility, low toxic profile, biodegradability and sustainability, these Greener chelators are better employed for industrial and home applications. Importantly, they can be applied to recovering metals from wastes to ensure sustainability of metals and their uses.

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                                        Abstract

Glasses with molar composition of (55 - x) molpercentage As2O3 - (25 + x) molpercentage V2O5 - 10 molpercentage Fe2O3 - 10 molpercentage CaO, where x = 0, 5, 10, 15, 20, 25 and 30, have been prepared using the normal melt quench method. The effect of replacement As2O3 by V2O5 on the structure of these glasses have been investigated by Differential scanning calorimetric DSC thermal analysis, Density d measurement and Molar volume Vm calculation. For each sample, DSC showed the presence of a single glass transition temperature Tg in addition to two crystallization peak s. The activation energy for glass transition indicates that the prepared glasses may be of high stability. Both the density and the molar volume changed oppositely with change in composition, indicating significant change of the structural units.

Keywords: Oxide glass; DSC-Glass Transition Temperature; Iron doped glasses; Vanadate glasses; Structure

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Introduction

In recent years glasses biased on V2O5 has attracted attention because of its potential use as cathode in solid-state devices. These glasses electrical properties classified to be similar to the n-type semiconductor. Also it was found that their electronic conduction is caused by a phonon assisted electron hopping between V4+ and V5+ ions [1-2]. Studies, on glasses containing relatively low concentration of V2O5, show that these glasses have a potential application as optical and electrical memory switching, cathode materials for making solid-state devices and optical fiber [1-3]. In the glasses with high percentage of V2O5, it is considered as a glass forming oxide [3-4]. Since the arsenic oxide As2O3 is consider as one of the most efficient fining agent for glass melt because of its ability for removing bubbles from glass mass [5], this article aims to characterize the glassy state of (25+x) mole% V2O5- (55-x) mole% As2O3 -10 mole% Fe2O3-10 mole% CaO glass system.

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Experimental Work

(55 - x) mol% As2O3- (25 + x) mol% V2O5-10 mol% Fe2O3- 10 mol% CaO, glass system have been prepared, by the melt quenching, on the bases of the percentage molecular weights, as shown in Table 1. The start materials were of purity not less than 99.98% while V2O5, As2O3 and Fe2O3 added as such and CaO was introduced as Calcium Carbonate. The finely mixed batches were melted in porcelain crucibles in an electric muffle furnace for 2- Hour, at temperature 750±20 ºC. The melts were stirred several times during melting, and they were then poured between two pre-cooled stainless steel plates in air. The thermal measurements were carried out by using Shimadzu 50-DSC Analyzer with heating rates 5, 10, 20, 30 and 40 K/min in the temperature range (303-1000) K. the calorimetric was calibrated for each heating rate using a material of well known melting temperature and enthalpy.

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Results and Discussion

DSC Thermal Analysis

Differential scanning calorimetric DSC thermal analysis has been used in studying the thermal stability of the prepared glasses. Some parameters have been measured easily and accurately, such as the glass transition Tg and crystallization Tp temperatures, during different heating Processes with different rates. Figure 1 exhibits the DSC traces for sample [1] during different heating rates, β=5, 10, 20, 30 and 40K/min, as a representative Figure, all studied samples were showed the same shapes. For all samples, by inspecting in DSC Spectra only one glass transition temperature in addition to two overlapping exothermic crystallization peaks have been observed, for each heating rate. The crystallization peaks identified and separated by using the de-convolution method, as in Figure 2, as a representative curve, for sample (1). Two crystallization peaks appearance may be indicating that there are two different phases appearing during the crystallization process, as a result to the fact that both V2O5 and Fe2O3 act as nucleating agents [6-8]. For each sample, the appearance of one glass transition temperature may indicate high homogeneity, good glassy stare formation [9]. Table 2 exhibits the obtained thermal parameters of the studied glasses, at different heating rates. By inspecting this table, an increase in the glass transition temperature and glass crystallization temperature have been observed with the heating rate increasing. Such behavior may be indicating an increase in the thermal stability of all investigated glasses as the heating rate increase [6-10]. The dependence of the glass transition temperature (Tg) on the heating rate has been studied by applying Kissinger’s formula Ln(T2g/β) = (Eg/RTg) + constant, Figure 3 Where ΔEg is the activation energy for glass transition, R is the gas constant and β is the heating rate. ΔEg obtained from plotting ln (T2g/β) against (1/Tg) which is a straight line of a slope equal (ΔEg/R), Table 3 exhibits the obtained values of Eg for the studied glass system. Also, Figure 3 exhibits the effect of the V2O5 content increment on the glass transition temperature (Tg), which appears to decrease linearly as V2O5 content increase. Like behavior may be implies a decrease in the glass thermal stability, in other word a decrease in the rigidity of the glass network [11]. Since the unstable glasses have a loose packing, therefore it can predict an increase in the molar volume of the studied glasses as V2O5 content was increased.

Density (ρ) and Molar Volume (Vm)

Density is an important and accurate property, which strongly reflects the fine changes in the glass structure. Therefore, the liquid displacement method used to obtain the room temperature experimental density of the studied glasses and plotted as a function of V2O5 content in Figure 4. It is clear that the measured density decreases approximately linear with As2O3 replacement by V2O5. The molar volume is directly related to the internal spatial structure of glass so it is more suitable to discuss the differences between the structures of the studied glasses in terms of the molar volume [12]. Figure 5 exhibits the calculated molar volume which appeared to increase linearly as V2O5 content was gradually increased, indicating a loose packed structure in an agreement with DSC results. The behavior of both density and molar volume can be attributed to the generally increase in the oxygen atoms, the increase in the non-bridging oxygen (V=O) atoms, in addition to the difference in the atomic weight of V5+ {50} and As3+ {74.9} cations [13]. The inversely variation of both the density and molar volume indicates significant change of the structural units with change in composition.

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Conclusion

(55-x) % As2O3. (25+x)% V2O5. 10% Fe2O3. 10 %CaO, Where 0 ≤ x ≤ 30, glass system have been studied. DSC thermal analysis showed the presence of one glass transition temperature and indicated high homogeneity of the prepared glasses. DSC Also showed the presence of two crystallization peaks indicate the existence of two different crystalline phases. The values of experimental density have found to decrease as V2O5 content was increased. The calculated molar volume values showed an increase, indicating a more open structure, as V2O5 content was increased. The inversely variation was observed for both the density and molar volume indicates significant change of the structural units with change in composition.

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Journal of Chemistry-JuniperPublishers

                                       Abstract

Within the chemical industry oleo-chemicals from Castor beans carry a strong and potential pattern. With some of the old important processes and products are replaced by the new in its constant changes. Some products over the years in contrast that were decline have been revived in accordance with the introduction of new technology and applications. New market demands have mounted heavy pressure on castor chemistry and have responded with great vigor. BSS castor oil is used in wide variety of applications and is the starting material for many other derivatives of castor oil. In pharmaceuticals and cosmetics it is used as an ingredient in formulations. It combines well with styrene and diisocyanates for film forming as well varnish. It is substantially insoluble infusible polymer and is used as lubricant component of coatings for vitamin and mineral tablets. It is also important ingredient for petroleum oil and de emulsification. Ricinoleic acid is also known as castor oil acid and belongs to a family of the unsaturated fatty acid. The Principal Castor Reactions are as follows; pyrolysis, polyamide11, hydrogenation, dehydration, caustic fusion, sebacic acid, undecylenic acid, heptaldehyde, sulfation/sulfonation, alkoxylation, oxidation/polymerization, esterification, dimerization, quaternaries, and engineering resin (interpenetrating networks).

Keywords:Castor Oil; 12-hydroxy Stearic acid; Ricinoleic Acid; Reactions; HCO; DCO

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Introduction

Oleo-chemicals from Castor experience a meaningful pattern within the chemical industry. Its constant changes, with some of the old important processes and products are replaced by the new. Some products over the years in contrast that were decline have been revived in accordance with the Introduction of new technology and applications. New market demands have mounted heavy pressure on castor chemistry and have responded with great vigor. Among all the vegetable oils Castor oil is a most unusual product being more versatile. The concentration of most oils is either one or two applications, such as for edible purposes (cotton seeds, soya, corn, peanut, rapeseed, canola, sunflower, coconut and palm). According to economic factors many of these are interchangeable. Some of these find other uses, such as in coatings, inks lubricants, detergents and soaps. With a wide diversity of commercial applications castor has considerably more uses directly related to the unique hydroxyl fatty acid structure [1].

BSS castor oil is used in wide variety of applications and is the starting material for many other derivatives of castor oil. In pharmaceuticals and cosmetics it is used as an ingredient in formulations. It combines well with styrene and diisocyanates for film forming varnish. It is substantially insoluble infusible polymer and is used as lubricant component of coatings for vitamin and mineral tablets. It is also important ingredient for petroleum oil and de emulsification. It also impregnates capacitor as a sonar transducer fluid and as a dielectric material for electrical condensers. Polyurethane casting resins, fluid for automobiles, trucks and machinery are the other applications of castor oil. It also serves as starting material for other derivatives of castor oil.

12-hydroxy Stearic acid is the mixed fatty acid recovered by hydrolysis of hydrogenated castor oil with high melting point. It is brittle, waxy solid at ambient temperatures. Its deterioration must be protected by storing away from heat. It is insoluble in water and has very negligible solubility in many organic solvents. 12-HSA is non toxic and non hazardous. 12-HSA is utilized in the manufacture of lithium and calcium greases and acrylic polymers. In molding of plastics it finds application as an internal lubricant. It also has applications in aqueous and non aqueous coatings for automotive, equipment, appliances and architecture. Wool is treated with it for its shrink resistance. It is also used as coating liners for the interior of metal food and beverage containers. Aviator and synthetic rubber finds its application as an internal lubricant as well as theology modifier in inks. Specialty chemicals esters as ethoxylates and sulfates also find the use of it beside from plasticizers, textiles, cosmetics and metal working operations [1].

Ricinoleic Acid

Ricinoleic acid is also known as castor oil acid and belongs to a family of the unsaturated fatty acid. It is a viscous yellow liquid having melting point 5.5oC and boiling point 245oC. It is immiscible with water and miscible with most of the organic solvents. Hydrolysis of castor oil yields it. It has uses in textiles finishing, in coating inks and in making soaps. Ricinoleic acid can be reacted with bases like caustic, ammonia, ethanolamines, to prepare soaps. These materials find its applications in cutting oils, industrial lubricants, emulsifiers and metal working compounds and impart lubricity, and rust proof characteristics. Ricinoleic acid is helping aid in making transparent bar soaps and high solids liquid soaps. It also enables the homogenization of phenolic and cresylic ingredients in industrial germicides, disinfectants, and heavy duty detergents. It is also an efficient pigments and dye dispersants that finds uses in inks, coatings, plastics, cosmetics and so on. Its sodium and potassium soaps are emulsifiers and foam stabilizers. It finds very important use in manufacturing poly glycerol poly ricinoleate (PGPR) a key ingredient in chocolates products. The sodium soap is useful as emulsifier, stabilizer, and de foam for emulsion polymerization of resins such as PVC and PVAC. It is also used for the treatment of leather. It provides good wetting, flexibility and softening properties to leather [2].

Properties of Pigments and Dispersing Dyes

Castor oil and many of its derivatives such as esters, hydrogenates and ethoxylates are well understood for their ability to wet surfaces acting as excellent carriers of pigments and dyes. Typical as colors for food stuffs, plastics, lipstick, paints, lacquers, coatings, inks, sealants, adhesives and color concentrates for plastics.

Reactions

As per current commercial practice many castor reactions are utilized as described follow. However there are certain limiting factors that must be recognized. An important illustration is the formation of estolides resulting from a linkage between hydroxyl and carboxyl groups. On storage the hydroxyl in ricinoleic acid forms an ester with the carboxyl. Decline of both hydroxyl value and acid value goes down as reaction proceeds. The change is well known with commercial ricinoleic acid and the two values can change by 5%-10% within 90 days from original production. The subject of castor estolides is reviewed by Modak and Kane which has an important list of references. There are citations where theoretically sound reaction mechanisms cannot be undertaken because of this interference. The ricinoleic acid structure explains why it could not be refined or purified by distillation by the conventional commercial procedure for purifying other fatty acids. Distillation affects the hydroxyl-acid linkage produces an alteration as the product is no longer ricinoleic acid. Factually, the estolide formation becomes one stage in the conversion to dehydrated castor fatty acids, the process for which is explained in this section [2].

In accordance of actual castor tonnage consumption the reactions are presented in order. The comparison of hydrogenated castor with polyamide 11 is difficult to compare. The latter is the larger, producing finished product by one manufacturer. Numerous hydrogenaters, found worldwide. Their product finds applications as an intermediate for several different end products. Polyamide is arbitrarily placed first and the volume of the two is comparable. The Principal Castor Reactions are as follows; Pyrolysis, Polyamide 11, Hydrogenation, Dehydration, Caustic Fusion, Sebacic Acid, Undecylenic Acid, Heptaldehyde, Sulfation/Sulfonation, Alkoxylation, Oxidation/Polymerization, Esterification, Dimerization, Quaternaries and Engineering Resins (Interpenetrating Networks) [2].

Castor Oil and Derivatives in Liquid Carbon Dioxide

Castor oil, Heptaldehyde and heptyl alcohol were included in a study of the mutual solubility of liquid carbon dioxide with each of 261 other substances. The solubility of carbon dioxide in each substance determined as such as was the solubility of each substance in carbon dioxide. 464 ternary systems were prepared with triangular graphs. Advanced research in physical properties of organic chemicals this project was to establish fundamental properties [3].

Process Description for Castor Oil and Its Derivatives

Process Description for Hydrogenated Castor Oil [HCO]:

a) The raw material, bleached castor oil (BSS grade) is processed under vacuum condition at a temperature of around 160oC in presence of nickel catalyst

b) No sooner does the raw material reaches its required temperature, the vacuum is stopped and hydrogen is fed, while the stirrer is still operating.

c) The hydrogen feed is closed as the required degree of hydrogenation is achieved and after this, hydrogenated product is started cooling.

d) As the product temperate reaches around 100°C, the final product gets filtered, cooled and then conveyed to flaking unit for flaking and bagged.

Process Description for Dehydrated Castor Oil (DCO): The reaction vessel is fed with castor oil stock grade through deaerator vessel. The oil gets dried in this vessel and completely freed from air, a higher temperature and vacuum is maintained in the reaction vessel which, continuously re-circulate the oil in the presence of a catalyst. The castor oil dehydrated which increases the un-saturation level and brings down the hydroxyl content of castor oil. The uniform quality of the product by all this process is maintained. The oil is finally passed through heat exchangers for cooling and then catalyst filtration as soon as the required degree of un-saturation and dehydration is met. After the filtration, the product is charged to a decolorizing vessel for removing the excess color from the oil [3].

Process Description for 12-Hydroxy Stearic Acid (12- HSA): The hydrogenated castor oil recovered from HCO plant under set parameters and is converted to soap by mixing it with caustic lye and acidulation vessel is conveyed with the converted HCO soap, in which it is mixed with dilute sulphuric acid which converts the soaps into fatty acids. 8% - 10% of glycerine is left out in the acid water which is then drained out and stored for the recovery of glycerine. 12–hydroxy Stearic acid the acidulated product is fed into drier, from the acidulation vessel, wherein, it gets completely dried up through controlled heating. Pre dried 12–HSA further cooled and taken to flaking unit for flaking [3].

Process Description for Castor Oil Polyols Plant: From the storage tank refined castor oil is taken and pumped into premixing vessel. The catalysts is added and mixed properly in the pre mixing vessel and mixed well through an attached auto feeding system. The material is then flow to the preheating vessel through which it is pumped into high pressure reactor. The propylene oxide is taken in to the reactor through pressure reducing valve at a pressure of about 0.6 MPa. Refined castor oil is mixed with propylene oxide circulating continuously through cooling heat exchanger with a pump. Effective heat and mass transfer resulted due to continuous circulation to produce qualitative product. After the materials have undergone aging it is then pumped to the reactor vessel. Employing dosing pump the acid is then fed into the acid dosing tank and finally fed into the reaction vessel. The material gets neutralized in the reactor and then pumped to the leaf filters to recover solid materials. Finally a clear liquid is recovered which is stored in a separate storage tank. From the storage tank the crude Polyols is taken and fed into the reaction vessel along with the solvent feed. Before it is sent to the drying unit all the materials are well mixed. Post removal of residual impurities, volatiles and purified Polyols, they are stored in a separate storage tank. Vacuum drying unit produce overhead volatile matters are then condensed and collected in separate storage tanks. The solvent distillation reactor is pumped with the volatile matter from which solvent is recovered and recycled in the process [3].

Castor Oil is Non Toxic

It is well established from the extensive historical usage of castor oil for human consumption and topical application which is safe. As an investigation studies by the US Department of Health and Human Services (NIH) established as a measure of safety for castor oil usage. In 1990 the feed studies on rats or mice concluded no adverse side effects of castor oil. Dietary concentrations as high as 10% in 90 days studies, did not affect survival or body weight gains.

Castor Oil, Properties and Characteristics

Particularly alcohol solubility as castor oil characteristics was reported in 1929. As matter of fact, examination also included of bulk oil in 1919 in addition with the comparison of the characteristics of fresh oil against oil under ten months storage. In the same time the examinations also included refractive index, viscosity, acidity, Halphen number, acetyl value, specific gravity, Wijs iodine value and acetic acid solubility all of which have been listed. It is interesting to note from a historical standpoint, the contrast between current test procedures and those used over 60 years ago.

Castor oil has held relatively high purity, (high for a naturally occurring material). Therefore, it could be subjected efficiently to a number of chemical processes to yield high purity chemical derivatives. The chemical bases for such reactions are the three points of functionality existing in ricinoleic acid: (a) The carboxyl or ester group (b) The single point of un-saturation (c) The hydroxyl group castor oil Chemistry [3].

This functionality may be utilized as follows:

A. At the carboxyl position, through a wide range of esterifications.

B. The hydroxyl group can be acetylated or alkoxyllated.

C. The un-saturation can be altered by hydrogenation or epoxidation.

D. The hydroxyl group can be removed by dehydration to increase the un-saturation of the compound thus yielding drying/polymerizing oil.

E. The hydroxyl position is highly reactive and the molecule can be split at that point by high temperature called pyrolysis and by caustic fusion yielding four useful products of shorter chain length.

Castor oil does have an interesting practical thesis on properties and utilization was presented in a review in 1952. Due to technical changes much of the subject matter is now outdated since then. It is recommended however for the clear, concise and practical description of basic properties and characteristics of castor oil and its derivatives. The chemistry of castor oil with this approach refers to good quality oil and frequently identified as “No.1” castor oil with an expression accepted by the major operators in each producing country. No.1 castor oil being an international standard represents quality that is generally usable for the reactions and applications described in this review. An oil of better quality is required in certain instances [3,4].

Castor Oil’s Stability to Oxygen

Castor oil and many of its derivatives are stabilized by the hydroxyl group, which is beta to the double bond. This hydroxyl group protects the double bond by preventing the formation of hyperperoxides sterically and inductively preventing the formation of peroxides, the intermediate chemical species that form the oxidation of double bonds. Peroxide formation is kinetics based and the method by which oxidative stability of a vegetable oil is measured. Oxidative stability data are derived from an American Oil Chemists method and Active Oxygen Method (AOM). A sample of vegetable oil is heated to 97oC while air is bubbled through it. AOM number is the number of hours the sample for each vegetable oil took to reach a peroxide value of 70 meqs. Olive oil mentioned to be the nearest stable vegetable oil after castor oil as, like castor oil, it is predominately mono-unsaturated but is unlike soy and sunflower oils that are polyunsaturated. Olive oil however lacks a stabilizing factor like castor oil’s hydroxyl group. Conclusively castor oil is approximately four times more stable than olive oil [3,4].

Product Applications

The basic derivatives, Heptaldehyde and Undecylenic acid are used to manufacture various perfumery compounds (Table 1), which in turn are used to manufacture perfumes and synthetic flavors.

Market and Growth Drivers

Market: India commands the position of is one of the leading manufacturers of Flavors and fragrances in the world. These all bring natural products, used in developing synthetic flavors and fragrances from castor oil derivatives, India is lagging behind. India, being a world leader in Castor seeds and Castor oil production and processing has edge over other countries like Japan, France and Germany who are importing castor oil and manufacturing these perfumery chemicals for further processing into perfumes and Synthetic flavors. Germany, France, Switzerland and Japan are internationally the leading producers of synthetic flavors and fragrances from many natural ingredients, including castor oil derivatives like Undecylenic acid and Heptaldehyde. Definitely there is large international market for perfumery chemicals and estimated market in India is approx. 5000 MT [3,4]. The Global Demand of Flavors and Fragrances is set to increase (Figure 1). The figure below depicts the region wise Demand Break up of Flavors and Fragrance market, estimated for the year 2008.

Flavors and fragrance as global demand is estimated to increase at a growth rate of around 4% per annum. The demand for flavors and fragrances moreover in the Asia/Pacific region is estimated to be growing at a rate of about 7% per annum through 2008. Growth in the world’s most developed markets will continue to be moderate, restrained by market maturity, consolidation in flavors and fragrances using industries and strong downward pressure on prices. Flavor and fragrance is looking for products from natural sources and prefer to use raw materials which are harmless and bio-degradable. In the light of this fact, there is good scope for castor oil derivatives in the global market. Demand for fragrance blends and essential oils will benefit from increased interest in natural and exotic aromas, which are more expensive than their synthetic counterparts [3,4] (Table 2).

Technology / Process

Subjecting castor oil to pyrolysis or destructive distillation at temperature of above 450°C under vacuum it under goes decomposition to yield mainly Undecylenic acid and Heptaldehyde, in almost equal quantities (28% approx). The yields of both acid and Aldehyde, has been found to enhance in the presence of water vapor. The spongy mass post processing, consisted principally of polymerized Undecylenic acid, which can be used in recovering of some quantity of Undecylenic acid. Undecylenic acid esters are used as ingredients for perfumery chemicals. Heptaldehyde is having characteristic Jasmine flavor in it and typically it is also known as Jasmine Aldehyde, and it can be converted to Heptanoic acid and Heptanol which are used in manufacture of many perfumery compounds. Castor oil’s ingredients’ specifications for proposed perfumery chemicals are listed in the Table 3. Figure 2 explains the flow sheet of Heptaldehyde and Undecylenic acid produce [4,5].

Hydrogenated Castor oil (Flakes/Powder)

Hydrogen is added to Castor Oil in the presence of a nickel catalyst and the oil, called hydrogenated Castor Oil (Figure 3), which is transformed into a hard, brittle wax with a melt point of approximately 85-86 oC. This wax being extremely insoluble, therefore well suited for products requiring resistance to water, oils, petroleum and petroleum derivatives. HCO makes its availability as flakes or powder which melts to a clear transparent liquid. It is being non-toxic and non-hazardous material. Hydrogenated castor oil is used in manufacturing of greases, it may also be used in paper coating for food packaging as well. The product is made to be available with several different melting points, or in beaded or powdered form. Castor oil that is partially hydrogenated found uses in cosmetic formulations such as lipsticks and stick deodorants. Hydrogenated Castor Oil finds an extensive diversified uses due to its unique combination of physicochemical properties [5].

a) In the manufacture of multipurpose Lithium/Calcium grease and high performance aviation grease

b) In the manufacture of soaps & cosmetics

c) As mould release agent in the processing of plastics and rubbers

d) As a component of specialty wax blends like pencils, crayons, lipsticks and anti-deodorant sticks

e) In the manufacture of hot-melt coatings and sealant requiring resistance to water

f) As a coating agent for paper & as anti-foaming agent.

g) Automotive refinish Acrylics manufacture

h) Rheological agent that provides thixotropic in paints, coatings, inks, adhesives, sealants and numerous industrial compositions.

i) Thick film chlorinated rubber, epoxy and vinyl coating

j) Flame Retardant and anti-static agent for fiber

k) Manufacture of Spin finish oil for polyamide fiber

l) In preparation of ointments, emulsified virus vaccines, sustained release capsules, wetting/bodying agent, face paint

m) As plasticizer for cellulosic

n) Processing aid for Color concentrates

o) Surface treatment agents

p) In the manufacture of hot melt adhesives used in packaging books, binding footwear, carpet backing and in product assembly

q) Anti-tack and slip additives for processing plastics

r) In the manufacture of specialty chemicals for applications such as metal working, plasticizers and textile auxiliaries in the form of derivatives such as esters, ethylates, sulfates etc (Figure 3) [5-7].

Poly Glycerol Poly Recinoleate (PGPR)

Polyglycerol Polyricinoleate (PGPR) is a food grade emulsifier consisting of poly-glycerol as the hydrophilic group and interesterified ricinoleic fatty acids as the hydrophobic group (Figure 4). The polyglycerol part of PGPR is mainly found as ditri- or tetra glycerol (min 75%) and max 10% of the polyglycerol part will be found as hepta glycerol or higher.

Properties: PGPR is a strong water-in-oil emulsifier used to manufacture stable pan release agents for the bakery industry and to stabilize low fat margarine systems with high water content. PGPR contributes in the ability to improve the flow properties in chocolate and vegetable fat coatings by lowering the friction between the particles suspended in the liquid fat phase and so-called “Yield Value” will be reduced and the liquid chocolate mass will flow easily even at a low total fat content [5-7].

Manufacture

a) Firstly glycerol is heated to temperatures above 200oC in a reactor. Small percent of alkali is added as catalyst. Condensation of two or more glycerol molecules takes place and water is released and removed over a vacuum pump. Chiefly straight-line polyglycerol units will be created with a smaller amount of cyclic by-products will also be created. In Figure 4 the formation of di- and tri-glycerol is shown, but highly polymerized polyglycerols are also created.

b) Secondly castor oil fatty acids will be heated in a reactor likewise to temperatures above 200oC. The fatty acids from castor oil are found as ricinoleic fatty acids (approx 90%) and the rest fatty acids are found as oleic-, linoleic- Stearicfatty acids. Fatty acids of the ricinoleic react in a simple linear esterifications process to form inter-esterified ricinoleic fatty acid chains. Water is released during the process and removed over vacuum pump.

c) Thirdly the inter-esterified ricinoleic fatty acids are mixed with the polyglycerol to form a complex mixture of polyglycerol-polyricinoleate molecules of different chain length [8-13] (Figure 5).

Application in Foods

PGPR has a dramatic impact on the flow properties of liquid chocolate and compounds based on vegetable fats. Principally it is understood that PGPR functions by lowering the yield value of the chocolate system, whereas the plastic viscosity hardly is influenced. In consideration of the practical implication that PGPR always is added as a co-emulsifier in combination with lecithin or ammonium phosphatide and helps as emulsifiers mainly reduce the plastic viscosity [13-15]. Cocoa butter and specialty vegetable fats are quite expensive raw materials, so the manufactures of chocolate and compounds can benefit from the effect of PGPR and lower the total fat content in the ready to consume products. Also from a health point of view fat reduction in chocolate and compounds are improving the quality in the eyes of the consumers. Due to the strong effect on the yield value in chocolate it is possible to make the chocolate flow during production by use of much less fat. Therefore PGPR is an important tool in manufacturing of various types of chocolatetype products. The effect of PGPR as an ingredient of chocolate is further described by Steven T. Beckett, Schantz, B. and Rohm, H.

Published toxicological studies, with scientific evaluation enables the GRAS determination on polyglycerol poly ricinoleate combined with an evaluation of the consumption pattern of vegetable fat coatings in the US. JECFA has established an accepted daily intake (AD1 value) for polyglycerol poly ricinoleate to 0-7.5 mg/kg body weight per day. The statistical data on consumption of vegetable fat coatings by the US population compared with the established AD1 value on polyglycerol poly ricinoleate clearly support the safety of the use of polyglycerol polyricinoleate at a maximum rate of 0.3% in vegetable fat coatings [14-19].

Undecylenic Acid

The pyrolysis of castor oil at 700oC under reduced pressure has been used to yield Heptaldehyde and Undecylenic acid. (It is the chemical decomposition of organic materials by heating in the absence of oxygen or any other reagents, beside steam). For producing alcohol from Heptaldehyde it can be further hydrogenate for use in the plasticizers. Hydrolysis is another method via the use of Methyl Undecylenate. Methyl Undecylenate is hydrolyzed to give Undecylenic Acid [20-25].

Applications: Undecylenic acid has a long history as antifungal drug. Many types of fungal infections can be treated with its application. Undecylenic acid can be used as a surfactant in hair lotions and as biocide in soaps and deodorants. It goes as a starting material for Nylon 11 [25-27].

Sebacic Acid

Sebacic acid, a 10-carbon di carboxylic acid, can be synthesized from phenols and cresols, but castor oil oxidation is considered a greener‖ process. Manufacture of sebacic acid is done heating castor oil to high temperatures (about 250oC) with the use of alkali. Result of this treatment saponifies the castor oil to ricinoleic acid which is then cleaved to give capryl alcohol (2-octanol) and sebacic acid [20-23].

Applications: One of the many uses of sebacic acid is in the manufacture of Nylon 6-10. Sebacic acid and their derivatives like Azelaic acid finds variety of industrial uses in plasticizers, lubricants, hydraulic fluids, cosmetics, candles, etc. They are used in the synthesis of polyamide and alkyd resins. An isomer, isosebacic acid, has other applications in the manufacture of extrusion plastics, adhesives, polyesters, polyurethane resins and synthetic rubber. Sebacic acid is also used as an intermediate for aromatics, antiseptics and painting materials. Thousands of potential starting materials can be obtained from esters. It is used as a corrosion inhibitor in metalworking fluids and as a complexion agent in greases. Sebacic acid when mixed with amines yields a very effective water soluble works as corrosion inhibitor for metal working fluids. Lithium hydroxyl stearate complex greases often utilize dibasic acids such as sebacic acid for the more unusual performance parameters. These greases are prepared from the esters of sebacic acid, and are being developed for specific performance criteria under varying conditions. Sebacic acid esters are used as plasticizers also for vinyl resins and in the manufacture of dioctyl sebacate; a jet lubricant and lubricant in air cooled combustion motors [24-30] (Table 4).

Notations for Demand

a) 1, 2 Very High: 50,000 T and above per ear

b) High: 30,000 - 50,000 T per year

c) Medium-High: 15,000-30,000 T per year

d) Medium: 5,000-15,000 T per year

e) Low-Medium: 1,000-5,000 T per year

f) Low: Less than 1,000 T per year

Notations for Demand-Supply Gap

a) Medium: There exists some demand over and above supply, but there has not been a significant amount of demand that has gone unmet

b) Medium-High: There have been some instances where a significant demand has gone unmet

d) Low: There have been very few instances when a significant demand has gone unmet

e) NA: denotes that information on demand supply gap is not available owing to the negligible demand volume

Transesterification of Castor Oil

Deshpande DP have studied the Transesterification of castor oil in a batch reactor employing KOH as a catalyst. They have chosen the variables such as residence time, oil to methanol ratio, catalyst concentration and reaction time. Mohammed H. et al. in their studies of transesterification of castor oil with methanolic KOH, the authors varied operating conditions; KOH catalyst concentration 2.1-3g for 250ml feedstock; temperature 30- 70oC; reaction time 30-360 minutes. The authors have reported ester (biodiesel) content 48% which is highest and glycerine 52%. They carried the reaction with 65 ml methanol and 2.4 g KOH catalyst, reaction time of 360 minutes at a temperature of 70oC and converting 250 ml castor oil feedstock. They also exercised parallel experiments involving two stage process viz esterification by acid followed by normal transesterification. Recommendation of this procedure was proposed by Marchetti. Esterifications process comprised of two stages by Mohammed et al reported the ester content up to 85%. The authors confirmed castor biodiesel viscosity of 13.75 mm2 sec-1 and density 0.9279 at 150C. The castor oil used by the authors having viscosity of 239.39 mm2 sec-1 [30-34].

The fatty acids consist of approximately 80–90% ricinoleic acid, 3-6% linoleic acid, 2-4% oleic acid and 1-5% saturated fatty acids. The high content of ricinoleic acid is the reason for the versatile value of castor oil in technology (Table 5). In Comparison with other vegetable oils, castor oil has a very high proportion of simply unsaturated fatty acids (18:1). A high proportion of those acids can be comparatively found only in the oil of the high oleic (HO) sunflower, appearing, however, as oleic acid. In castor oil it is ricinoleic acid, the only unsaturated fatty acid occurring in natural vegetable oils with a hydroxyl function of the carbon atom 12. The extraordinarily high viscosity of castor oil is attributed to the presence of the hydroxyl group. The variation of specific gravity with residence time in their study appeared in a similar trend as that of viscosity. Decrease in the Specific gravity was observed from 0.9096 to 0.882 as residence time is increased from 30 to 45 minutes, further increase in residence time from 60 to 90 minutes the specific gravity increased 0.882 to 0.9026 while acid value of biodiesel product decreased with increasing reaction time and saponification value decreased with increasing reaction time and further increases [34-36].

Table 6 presents their data of variation in viscosity with time. The authors observed increase in specific gravity with increasing temperature, the same changes were observed in acid value. They also observed that at lower temperature of 30oC the biodiesel product gave lower viscosity and they further increased the temperature up to 50oC. Acid value had shown similar trend as that of viscosity. Sap value too shown similar trend as that of specific gravity (Table 7) [35-37].

According to their observation the specific gravity of the product was lowest at 1wt % catalyst concentration and increased with increasing catalyst concentration up to 2wt%. The specific gravity of product was increased at lowest concentration at 0.5wt%. Specific gravity was higher due to probably of lower catalyst concentration of 0.5wt % conversions were very low. Therefore with referring to above data, 1wt% catalyst concentration may be optimum in the range of operating condition studied. The viscosity decreased with initially up to 1wt. % catalyst concentration and then increased up to 2wt% of catalyst concentration. Initially specific gravity decreased up to 1wt. % of catalyst concentration and further found to increased and acid value shown similar trend as that of viscosity. Sap value was found practically constant post 1wt% catalyst concentration. The authors have supported their data with the plot of figures as presented by Figures 6-11 [35,36].

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Materials and Methods

Global demand is estimated to increase at a growth rate of around 4% of flavors and fragrance from castor oil per annum. Much above the demand for flavors and fragrances in the Asia/ Pacific region is estimated to be growing at a rate of about 7% per annum through 2008. Growth in the world’s most developed markets will continue to be moderate, restrained by market maturity, consolidation in flavors and fragrances using industries and strong downward pressure on prices. Flavor and fragrance is looking for products from natural sources and prefer to use raw materials which are harmless and bio-degradable. In the light of this fact, there is good scope for castor oil derivatives in the global market. Fragrance blends and essential oils’ demand will benefit from increased interest in natural and exotic aromas, which are known to be more expensive than their synthetic counterparts.

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                                       Abstract

Within the chemical industry oleo-chemicals from Castor beans carry a strong and potential pattern. With some of the old important processes and products are replaced by the new in its constant changes. Some products over the years in contrast that were decline have been revived in accordance with the introduction of new technology and applications. New market demands have mounted heavy pressure on castor chemistry and have responded with great vigor. BSS castor oil is used in wide variety of applications and is the starting material for many other derivatives of castor oil. In pharmaceuticals and cosmetics it is used as an ingredient in formulations. It combines well with styrene and diisocyanates for film forming as well varnish. It is substantially insoluble infusible polymer and is used as lubricant component of coatings for vitamin and mineral tablets. It is also important ingredient for petroleum oil and de emulsification. Ricinoleic acid is also known as castor oil acid and belongs to a family of the unsaturated fatty acid. The Principal Castor Reactions are as follows; pyrolysis, polyamide11, hydrogenation, dehydration, caustic fusion, sebacic acid, undecylenic acid, heptaldehyde, sulfation/sulfonation, alkoxylation, oxidation/polymerization, esterification, dimerization, quaternaries, and engineering resin (interpenetrating networks).

Keywords:Castor Oil; 12-hydroxy Stearic acid; Ricinoleic Acid; Reactions; HCO; DCO

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Introduction

Oleo-chemicals from Castor experience a meaningful pattern within the chemical industry. Its constant changes, with some of the old important processes and products are replaced by the new. Some products over the years in contrast that were decline have been revived in accordance with the Introduction of new technology and applications. New market demands have mounted heavy pressure on castor chemistry and have responded with great vigor. Among all the vegetable oils Castor oil is a most unusual product being more versatile. The concentration of most oils is either one or two applications, such as for edible purposes (cotton seeds, soya, corn, peanut, rapeseed, canola, sunflower, coconut and palm). According to economic factors many of these are interchangeable. Some of these find other uses, such as in coatings, inks lubricants, detergents and soaps. With a wide diversity of commercial applications castor has considerably more uses directly related to the unique hydroxyl fatty acid structure [1].

BSS castor oil is used in wide variety of applications and is the starting material for many other derivatives of castor oil. In pharmaceuticals and cosmetics it is used as an ingredient in formulations. It combines well with styrene and diisocyanates for film forming varnish. It is substantially insoluble infusible polymer and is used as lubricant component of coatings for vitamin and mineral tablets. It is also important ingredient for petroleum oil and de emulsification. It also impregnates capacitor as a sonar transducer fluid and as a dielectric material for electrical condensers. Polyurethane casting resins, fluid for automobiles, trucks and machinery are the other applications of castor oil. It also serves as starting material for other derivatives of castor oil.

12-hydroxy Stearic acid is the mixed fatty acid recovered by hydrolysis of hydrogenated castor oil with high melting point. It is brittle, waxy solid at ambient temperatures. Its deterioration must be protected by storing away from heat. It is insoluble in water and has very negligible solubility in many organic solvents. 12-HSA is non toxic and non hazardous. 12-HSA is utilized in the manufacture of lithium and calcium greases and acrylic polymers. In molding of plastics it finds application as an internal lubricant. It also has applications in aqueous and non aqueous coatings for automotive, equipment, appliances and architecture. Wool is treated with it for its shrink resistance. It is also used as coating liners for the interior of metal food and beverage containers. Aviator and synthetic rubber finds its application as an internal lubricant as well as theology modifier in inks. Specialty chemicals esters as ethoxylates and sulfates also find the use of it beside from plasticizers, textiles, cosmetics and metal working operations [1].

Ricinoleic Acid

Ricinoleic acid is also known as castor oil acid and belongs to a family of the unsaturated fatty acid. It is a viscous yellow liquid having melting point 5.5oC and boiling point 245oC. It is immiscible with water and miscible with most of the organic solvents. Hydrolysis of castor oil yields it. It has uses in textiles finishing, in coating inks and in making soaps. Ricinoleic acid can be reacted with bases like caustic, ammonia, ethanolamines, to prepare soaps. These materials find its applications in cutting oils, industrial lubricants, emulsifiers and metal working compounds and impart lubricity, and rust proof characteristics. Ricinoleic acid is helping aid in making transparent bar soaps and high solids liquid soaps. It also enables the homogenization of phenolic and cresylic ingredients in industrial germicides, disinfectants, and heavy duty detergents. It is also an efficient pigments and dye dispersants that finds uses in inks, coatings, plastics, cosmetics and so on. Its sodium and potassium soaps are emulsifiers and foam stabilizers. It finds very important use in manufacturing poly glycerol poly ricinoleate (PGPR) a key ingredient in chocolates products. The sodium soap is useful as emulsifier, stabilizer, and de foam for emulsion polymerization of resins such as PVC and PVAC. It is also used for the treatment of leather. It provides good wetting, flexibility and softening properties to leather [2].

Properties of Pigments and Dispersing Dyes

Castor oil and many of its derivatives such as esters, hydrogenates and ethoxylates are well understood for their ability to wet surfaces acting as excellent carriers of pigments and dyes. Typical as colors for food stuffs, plastics, lipstick, paints, lacquers, coatings, inks, sealants, adhesives and color concentrates for plastics.

Reactions

As per current commercial practice many castor reactions are utilized as described follow. However there are certain limiting factors that must be recognized. An important illustration is the formation of estolides resulting from a linkage between hydroxyl and carboxyl groups. On storage the hydroxyl in ricinoleic acid forms an ester with the carboxyl. Decline of both hydroxyl value and acid value goes down as reaction proceeds. The change is well known with commercial ricinoleic acid and the two values can change by 5%-10% within 90 days from original production. The subject of castor estolides is reviewed by Modak and Kane which has an important list of references. There are citations where theoretically sound reaction mechanisms cannot be undertaken because of this interference. The ricinoleic acid structure explains why it could not be refined or purified by distillation by the conventional commercial procedure for purifying other fatty acids. Distillation affects the hydroxyl-acid linkage produces an alteration as the product is no longer ricinoleic acid. Factually, the estolide formation becomes one stage in the conversion to dehydrated castor fatty acids, the process for which is explained in this section [2].

In accordance of actual castor tonnage consumption the reactions are presented in order. The comparison of hydrogenated castor with polyamide 11 is difficult to compare. The latter is the larger, producing finished product by one manufacturer. Numerous hydrogenaters, found worldwide. Their product finds applications as an intermediate for several different end products. Polyamide is arbitrarily placed first and the volume of the two is comparable. The Principal Castor Reactions are as follows; Pyrolysis, Polyamide 11, Hydrogenation, Dehydration, Caustic Fusion, Sebacic Acid, Undecylenic Acid, Heptaldehyde, Sulfation/Sulfonation, Alkoxylation, Oxidation/Polymerization, Esterification, Dimerization, Quaternaries and Engineering Resins (Interpenetrating Networks) [2].

Castor Oil and Derivatives in Liquid Carbon Dioxide

Castor oil, Heptaldehyde and heptyl alcohol were included in a study of the mutual solubility of liquid carbon dioxide with each of 261 other substances. The solubility of carbon dioxide in each substance determined as such as was the solubility of each substance in carbon dioxide. 464 ternary systems were prepared with triangular graphs. Advanced research in physical properties of organic chemicals this project was to establish fundamental properties [3].

Process Description for Castor Oil and Its Derivatives

Process Description for Hydrogenated Castor Oil [HCO]:

a) The raw material, bleached castor oil (BSS grade) is processed under vacuum condition at a temperature of around 160oC in presence of nickel catalyst

b) No sooner does the raw material reaches its required temperature, the vacuum is stopped and hydrogen is fed, while the stirrer is still operating.

c) The hydrogen feed is closed as the required degree of hydrogenation is achieved and after this, hydrogenated product is started cooling.

d) As the product temperate reaches around 100°C, the final product gets filtered, cooled and then conveyed to flaking unit for flaking and bagged.

Process Description for Dehydrated Castor Oil (DCO): The reaction vessel is fed with castor oil stock grade through deaerator vessel. The oil gets dried in this vessel and completely freed from air, a higher temperature and vacuum is maintained in the reaction vessel which, continuously re-circulate the oil in the presence of a catalyst. The castor oil dehydrated which increases the un-saturation level and brings down the hydroxyl content of castor oil. The uniform quality of the product by all this process is maintained. The oil is finally passed through heat exchangers for cooling and then catalyst filtration as soon as the required degree of un-saturation and dehydration is met. After the filtration, the product is charged to a decolorizing vessel for removing the excess color from the oil [3].

Process Description for 12-Hydroxy Stearic Acid (12- HSA): The hydrogenated castor oil recovered from HCO plant under set parameters and is converted to soap by mixing it with caustic lye and acidulation vessel is conveyed with the converted HCO soap, in which it is mixed with dilute sulphuric acid which converts the soaps into fatty acids. 8% - 10% of glycerine is left out in the acid water which is then drained out and stored for the recovery of glycerine. 12–hydroxy Stearic acid the acidulated product is fed into drier, from the acidulation vessel, wherein, it gets completely dried up through controlled heating. Pre dried 12–HSA further cooled and taken to flaking unit for flaking [3].

Process Description for Castor Oil Polyols Plant: From the storage tank refined castor oil is taken and pumped into premixing vessel. The catalysts is added and mixed properly in the pre mixing vessel and mixed well through an attached auto feeding system. The material is then flow to the preheating vessel through which it is pumped into high pressure reactor. The propylene oxide is taken in to the reactor through pressure reducing valve at a pressure of about 0.6 MPa. Refined castor oil is mixed with propylene oxide circulating continuously through cooling heat exchanger with a pump. Effective heat and mass transfer resulted due to continuous circulation to produce qualitative product. After the materials have undergone aging it is then pumped to the reactor vessel. Employing dosing pump the acid is then fed into the acid dosing tank and finally fed into the reaction vessel. The material gets neutralized in the reactor and then pumped to the leaf filters to recover solid materials. Finally a clear liquid is recovered which is stored in a separate storage tank. From the storage tank the crude Polyols is taken and fed into the reaction vessel along with the solvent feed. Before it is sent to the drying unit all the materials are well mixed. Post removal of residual impurities, volatiles and purified Polyols, they are stored in a separate storage tank. Vacuum drying unit produce overhead volatile matters are then condensed and collected in separate storage tanks. The solvent distillation reactor is pumped with the volatile matter from which solvent is recovered and recycled in the process [3].

Castor Oil is Non Toxic

It is well established from the extensive historical usage of castor oil for human consumption and topical application which is safe. As an investigation studies by the US Department of Health and Human Services (NIH) established as a measure of safety for castor oil usage. In 1990 the feed studies on rats or mice concluded no adverse side effects of castor oil. Dietary concentrations as high as 10% in 90 days studies, did not affect survival or body weight gains.

Castor Oil, Properties and Characteristics

Particularly alcohol solubility as castor oil characteristics was reported in 1929. As matter of fact, examination also included of bulk oil in 1919 in addition with the comparison of the characteristics of fresh oil against oil under ten months storage. In the same time the examinations also included refractive index, viscosity, acidity, Halphen number, acetyl value, specific gravity, Wijs iodine value and acetic acid solubility all of which have been listed. It is interesting to note from a historical standpoint, the contrast between current test procedures and those used over 60 years ago.

Castor oil has held relatively high purity, (high for a naturally occurring material). Therefore, it could be subjected efficiently to a number of chemical processes to yield high purity chemical derivatives. The chemical bases for such reactions are the three points of functionality existing in ricinoleic acid: (a) The carboxyl or ester group (b) The single point of un-saturation (c) The hydroxyl group castor oil Chemistry [3].

This functionality may be utilized as follows:

A. At the carboxyl position, through a wide range of esterifications.

B. The hydroxyl group can be acetylated or alkoxyllated.

C. The un-saturation can be altered by hydrogenation or epoxidation.

D. The hydroxyl group can be removed by dehydration to increase the un-saturation of the compound thus yielding drying/polymerizing oil.

E. The hydroxyl position is highly reactive and the molecule can be split at that point by high temperature called pyrolysis and by caustic fusion yielding four useful products of shorter chain length.

Castor oil does have an interesting practical thesis on properties and utilization was presented in a review in 1952. Due to technical changes much of the subject matter is now outdated since then. It is recommended however for the clear, concise and practical description of basic properties and characteristics of castor oil and its derivatives. The chemistry of castor oil with this approach refers to good quality oil and frequently identified as “No.1” castor oil with an expression accepted by the major operators in each producing country. No.1 castor oil being an international standard represents quality that is generally usable for the reactions and applications described in this review. An oil of better quality is required in certain instances [3,4].

Castor Oil’s Stability to Oxygen

Castor oil and many of its derivatives are stabilized by the hydroxyl group, which is beta to the double bond. This hydroxyl group protects the double bond by preventing the formation of hyperperoxides sterically and inductively preventing the formation of peroxides, the intermediate chemical species that form the oxidation of double bonds. Peroxide formation is kinetics based and the method by which oxidative stability of a vegetable oil is measured. Oxidative stability data are derived from an American Oil Chemists method and Active Oxygen Method (AOM). A sample of vegetable oil is heated to 97oC while air is bubbled through it. AOM number is the number of hours the sample for each vegetable oil took to reach a peroxide value of 70 meqs. Olive oil mentioned to be the nearest stable vegetable oil after castor oil as, like castor oil, it is predominately mono-unsaturated but is unlike soy and sunflower oils that are polyunsaturated. Olive oil however lacks a stabilizing factor like castor oil’s hydroxyl group. Conclusively castor oil is approximately four times more stable than olive oil [3,4].

Product Applications

The basic derivatives, Heptaldehyde and Undecylenic acid are used to manufacture various perfumery compounds (Table 1), which in turn are used to manufacture perfumes and synthetic flavors.

Market and Growth Drivers

Market: India commands the position of is one of the leading manufacturers of Flavors and fragrances in the world. These all bring natural products, used in developing synthetic flavors and fragrances from castor oil derivatives, India is lagging behind. India, being a world leader in Castor seeds and Castor oil production and processing has edge over other countries like Japan, France and Germany who are importing castor oil and manufacturing these perfumery chemicals for further processing into perfumes and Synthetic flavors. Germany, France, Switzerland and Japan are internationally the leading producers of synthetic flavors and fragrances from many natural ingredients, including castor oil derivatives like Undecylenic acid and Heptaldehyde. Definitely there is large international market for perfumery chemicals and estimated market in India is approx. 5000 MT [3,4]. The Global Demand of Flavors and Fragrances is set to increase (Figure 1). The figure below depicts the region wise Demand Break up of Flavors and Fragrance market, estimated for the year 2008.

Flavors and fragrance as global demand is estimated to increase at a growth rate of around 4% per annum. The demand for flavors and fragrances moreover in the Asia/Pacific region is estimated to be growing at a rate of about 7% per annum through 2008. Growth in the world’s most developed markets will continue to be moderate, restrained by market maturity, consolidation in flavors and fragrances using industries and strong downward pressure on prices. Flavor and fragrance is looking for products from natural sources and prefer to use raw materials which are harmless and bio-degradable. In the light of this fact, there is good scope for castor oil derivatives in the global market. Demand for fragrance blends and essential oils will benefit from increased interest in natural and exotic aromas, which are more expensive than their synthetic counterparts [3,4] (Table 2).

Technology / Process

Subjecting castor oil to pyrolysis or destructive distillation at temperature of above 450°C under vacuum it under goes decomposition to yield mainly Undecylenic acid and Heptaldehyde, in almost equal quantities (28% approx). The yields of both acid and Aldehyde, has been found to enhance in the presence of water vapor. The spongy mass post processing, consisted principally of polymerized Undecylenic acid, which can be used in recovering of some quantity of Undecylenic acid. Undecylenic acid esters are used as ingredients for perfumery chemicals. Heptaldehyde is having characteristic Jasmine flavor in it and typically it is also known as Jasmine Aldehyde, and it can be converted to Heptanoic acid and Heptanol which are used in manufacture of many perfumery compounds. Castor oil’s ingredients’ specifications for proposed perfumery chemicals are listed in the Table 3. Figure 2 explains the flow sheet of Heptaldehyde and Undecylenic acid produce [4,5].

Hydrogenated Castor oil (Flakes/Powder)

Hydrogen is added to Castor Oil in the presence of a nickel catalyst and the oil, called hydrogenated Castor Oil (Figure 3), which is transformed into a hard, brittle wax with a melt point of approximately 85-86 oC. This wax being extremely insoluble, therefore well suited for products requiring resistance to water, oils, petroleum and petroleum derivatives. HCO makes its availability as flakes or powder which melts to a clear transparent liquid. It is being non-toxic and non-hazardous material. Hydrogenated castor oil is used in manufacturing of greases, it may also be used in paper coating for food packaging as well. The product is made to be available with several different melting points, or in beaded or powdered form. Castor oil that is partially hydrogenated found uses in cosmetic formulations such as lipsticks and stick deodorants. Hydrogenated Castor Oil finds an extensive diversified uses due to its unique combination of physicochemical properties [5].

a) In the manufacture of multipurpose Lithium/Calcium grease and high performance aviation grease

b) In the manufacture of soaps & cosmetics

c) As mould release agent in the processing of plastics and rubbers

d) As a component of specialty wax blends like pencils, crayons, lipsticks and anti-deodorant sticks

e) In the manufacture of hot-melt coatings and sealant requiring resistance to water

f) As a coating agent for paper & as anti-foaming agent.

g) Automotive refinish Acrylics manufacture

h) Rheological agent that provides thixotropic in paints, coatings, inks, adhesives, sealants and numerous industrial compositions.

i) Thick film chlorinated rubber, epoxy and vinyl coating

j) Flame Retardant and anti-static agent for fiber

k) Manufacture of Spin finish oil for polyamide fiber

l) In preparation of ointments, emulsified virus vaccines, sustained release capsules, wetting/bodying agent, face paint

m) As plasticizer for cellulosic

n) Processing aid for Color concentrates

o) Surface treatment agents

p) In the manufacture of hot melt adhesives used in packaging books, binding footwear, carpet backing and in product assembly

q) Anti-tack and slip additives for processing plastics

r) In the manufacture of specialty chemicals for applications such as metal working, plasticizers and textile auxiliaries in the form of derivatives such as esters, ethylates, sulfates etc (Figure 3) [5-7].

Poly Glycerol Poly Recinoleate (PGPR)

Polyglycerol Polyricinoleate (PGPR) is a food grade emulsifier consisting of poly-glycerol as the hydrophilic group and interesterified ricinoleic fatty acids as the hydrophobic group (Figure 4). The polyglycerol part of PGPR is mainly found as ditri- or tetra glycerol (min 75%) and max 10% of the polyglycerol part will be found as hepta glycerol or higher.

Properties: PGPR is a strong water-in-oil emulsifier used to manufacture stable pan release agents for the bakery industry and to stabilize low fat margarine systems with high water content. PGPR contributes in the ability to improve the flow properties in chocolate and vegetable fat coatings by lowering the friction between the particles suspended in the liquid fat phase and so-called “Yield Value” will be reduced and the liquid chocolate mass will flow easily even at a low total fat content [5-7].

Manufacture

a) Firstly glycerol is heated to temperatures above 200oC in a reactor. Small percent of alkali is added as catalyst. Condensation of two or more glycerol molecules takes place and water is released and removed over a vacuum pump. Chiefly straight-line polyglycerol units will be created with a smaller amount of cyclic by-products will also be created. In Figure 4 the formation of di- and tri-glycerol is shown, but highly polymerized polyglycerols are also created.

b) Secondly castor oil fatty acids will be heated in a reactor likewise to temperatures above 200oC. The fatty acids from castor oil are found as ricinoleic fatty acids (approx 90%) and the rest fatty acids are found as oleic-, linoleic- Stearicfatty acids. Fatty acids of the ricinoleic react in a simple linear esterifications process to form inter-esterified ricinoleic fatty acid chains. Water is released during the process and removed over vacuum pump.

c) Thirdly the inter-esterified ricinoleic fatty acids are mixed with the polyglycerol to form a complex mixture of polyglycerol-polyricinoleate molecules of different chain length [8-13] (Figure 5).

Application in Foods

PGPR has a dramatic impact on the flow properties of liquid chocolate and compounds based on vegetable fats. Principally it is understood that PGPR functions by lowering the yield value of the chocolate system, whereas the plastic viscosity hardly is influenced. In consideration of the practical implication that PGPR always is added as a co-emulsifier in combination with lecithin or ammonium phosphatide and helps as emulsifiers mainly reduce the plastic viscosity [13-15]. Cocoa butter and specialty vegetable fats are quite expensive raw materials, so the manufactures of chocolate and compounds can benefit from the effect of PGPR and lower the total fat content in the ready to consume products. Also from a health point of view fat reduction in chocolate and compounds are improving the quality in the eyes of the consumers. Due to the strong effect on the yield value in chocolate it is possible to make the chocolate flow during production by use of much less fat. Therefore PGPR is an important tool in manufacturing of various types of chocolatetype products. The effect of PGPR as an ingredient of chocolate is further described by Steven T. Beckett, Schantz, B. and Rohm, H.

Published toxicological studies, with scientific evaluation enables the GRAS determination on polyglycerol poly ricinoleate combined with an evaluation of the consumption pattern of vegetable fat coatings in the US. JECFA has established an accepted daily intake (AD1 value) for polyglycerol poly ricinoleate to 0-7.5 mg/kg body weight per day. The statistical data on consumption of vegetable fat coatings by the US population compared with the established AD1 value on polyglycerol poly ricinoleate clearly support the safety of the use of polyglycerol polyricinoleate at a maximum rate of 0.3% in vegetable fat coatings [14-19].

Undecylenic Acid

The pyrolysis of castor oil at 700oC under reduced pressure has been used to yield Heptaldehyde and Undecylenic acid. (It is the chemical decomposition of organic materials by heating in the absence of oxygen or any other reagents, beside steam). For producing alcohol from Heptaldehyde it can be further hydrogenate for use in the plasticizers. Hydrolysis is another method via the use of Methyl Undecylenate. Methyl Undecylenate is hydrolyzed to give Undecylenic Acid [20-25].

Applications: Undecylenic acid has a long history as antifungal drug. Many types of fungal infections can be treated with its application. Undecylenic acid can be used as a surfactant in hair lotions and as biocide in soaps and deodorants. It goes as a starting material for Nylon 11 [25-27].

Sebacic Acid

Sebacic acid, a 10-carbon di carboxylic acid, can be synthesized from phenols and cresols, but castor oil oxidation is considered a greener‖ process. Manufacture of sebacic acid is done heating castor oil to high temperatures (about 250oC) with the use of alkali. Result of this treatment saponifies the castor oil to ricinoleic acid which is then cleaved to give capryl alcohol (2-octanol) and sebacic acid [20-23].

Applications: One of the many uses of sebacic acid is in the manufacture of Nylon 6-10. Sebacic acid and their derivatives like Azelaic acid finds variety of industrial uses in plasticizers, lubricants, hydraulic fluids, cosmetics, candles, etc. They are used in the synthesis of polyamide and alkyd resins. An isomer, isosebacic acid, has other applications in the manufacture of extrusion plastics, adhesives, polyesters, polyurethane resins and synthetic rubber. Sebacic acid is also used as an intermediate for aromatics, antiseptics and painting materials. Thousands of potential starting materials can be obtained from esters. It is used as a corrosion inhibitor in metalworking fluids and as a complexion agent in greases. Sebacic acid when mixed with amines yields a very effective water soluble works as corrosion inhibitor for metal working fluids. Lithium hydroxyl stearate complex greases often utilize dibasic acids such as sebacic acid for the more unusual performance parameters. These greases are prepared from the esters of sebacic acid, and are being developed for specific performance criteria under varying conditions. Sebacic acid esters are used as plasticizers also for vinyl resins and in the manufacture of dioctyl sebacate; a jet lubricant and lubricant in air cooled combustion motors [24-30] (Table 4).

Notations for Demand

a) 1, 2 Very High: 50,000 T and above per ear

b) High: 30,000 - 50,000 T per year

c) Medium-High: 15,000-30,000 T per year

d) Medium: 5,000-15,000 T per year

e) Low-Medium: 1,000-5,000 T per year

f) Low: Less than 1,000 T per year

Notations for Demand-Supply Gap

a) Medium: There exists some demand over and above supply, but there has not been a significant amount of demand that has gone unmet

b) Medium-High: There have been some instances where a significant demand has gone unmet

d) Low: There have been very few instances when a significant demand has gone unmet

e) NA: denotes that information on demand supply gap is not available owing to the negligible demand volume

Transesterification of Castor Oil

Deshpande DP have studied the Transesterification of castor oil in a batch reactor employing KOH as a catalyst. They have chosen the variables such as residence time, oil to methanol ratio, catalyst concentration and reaction time. Mohammed H. et al. in their studies of transesterification of castor oil with methanolic KOH, the authors varied operating conditions; KOH catalyst concentration 2.1-3g for 250ml feedstock; temperature 30- 70oC; reaction time 30-360 minutes. The authors have reported ester (biodiesel) content 48% which is highest and glycerine 52%. They carried the reaction with 65 ml methanol and 2.4 g KOH catalyst, reaction time of 360 minutes at a temperature of 70oC and converting 250 ml castor oil feedstock. They also exercised parallel experiments involving two stage process viz esterification by acid followed by normal transesterification. Recommendation of this procedure was proposed by Marchetti. Esterifications process comprised of two stages by Mohammed et al reported the ester content up to 85%. The authors confirmed castor biodiesel viscosity of 13.75 mm2 sec-1 and density 0.9279 at 150C. The castor oil used by the authors having viscosity of 239.39 mm2 sec-1 [30-34].

The fatty acids consist of approximately 80–90% ricinoleic acid, 3-6% linoleic acid, 2-4% oleic acid and 1-5% saturated fatty acids. The high content of ricinoleic acid is the reason for the versatile value of castor oil in technology (Table 5). In Comparison with other vegetable oils, castor oil has a very high proportion of simply unsaturated fatty acids (18:1). A high proportion of those acids can be comparatively found only in the oil of the high oleic (HO) sunflower, appearing, however, as oleic acid. In castor oil it is ricinoleic acid, the only unsaturated fatty acid occurring in natural vegetable oils with a hydroxyl function of the carbon atom 12. The extraordinarily high viscosity of castor oil is attributed to the presence of the hydroxyl group. The variation of specific gravity with residence time in their study appeared in a similar trend as that of viscosity. Decrease in the Specific gravity was observed from 0.9096 to 0.882 as residence time is increased from 30 to 45 minutes, further increase in residence time from 60 to 90 minutes the specific gravity increased 0.882 to 0.9026 while acid value of biodiesel product decreased with increasing reaction time and saponification value decreased with increasing reaction time and further increases [34-36].

Table 6 presents their data of variation in viscosity with time. The authors observed increase in specific gravity with increasing temperature, the same changes were observed in acid value. They also observed that at lower temperature of 30oC the biodiesel product gave lower viscosity and they further increased the temperature up to 50oC. Acid value had shown similar trend as that of viscosity. Sap value too shown similar trend as that of specific gravity (Table 7) [35-37].

According to their observation the specific gravity of the product was lowest at 1wt % catalyst concentration and increased with increasing catalyst concentration up to 2wt%. The specific gravity of product was increased at lowest concentration at 0.5wt%. Specific gravity was higher due to probably of lower catalyst concentration of 0.5wt % conversions were very low. Therefore with referring to above data, 1wt% catalyst concentration may be optimum in the range of operating condition studied. The viscosity decreased with initially up to 1wt. % catalyst concentration and then increased up to 2wt% of catalyst concentration. Initially specific gravity decreased up to 1wt. % of catalyst concentration and further found to increased and acid value shown similar trend as that of viscosity. Sap value was found practically constant post 1wt% catalyst concentration. The authors have supported their data with the plot of figures as presented by Figures 6-11 [35,36].

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Materials and Methods

Global demand is estimated to increase at a growth rate of around 4% of flavors and fragrance from castor oil per annum. Much above the demand for flavors and fragrances in the Asia/ Pacific region is estimated to be growing at a rate of about 7% per annum through 2008. Growth in the world’s most developed markets will continue to be moderate, restrained by market maturity, consolidation in flavors and fragrances using industries and strong downward pressure on prices. Flavor and fragrance is looking for products from natural sources and prefer to use raw materials which are harmless and bio-degradable. In the light of this fact, there is good scope for castor oil derivatives in the global market. Fragrance blends and essential oils’ demand will benefit from increased interest in natural and exotic aromas, which are known to be more expensive than their synthetic counterparts.

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                                           Abstract

We describe an efficient synthesis of (3S, 4R)-5-Phenylpentane-1, 3, 4-triol (1) from commercially available 3-phenylpropanal for the first time. The key reactions involved in this synthesis are proline catalyzed hydroxylation, followed by (Z)-selective Wittig olefination, and Sharpless asymmetric epoxidation (Figure 1).

Keywords: Natural product; Triol; Wittig olefination; Total synthesis; Alzheimers; Parkinsons

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Introduction

Polyhydroxylated compounds are ubiquitous structural motifs found in a multitude of naturally occurring compounds, pharmaceuticals and material interest [1-5]. In addition to this their synthetic analogues are important as lead structures or drug candidates for the discovery of novel drugs [6-9]. These compounds have explicitly exhibited a broad spectrum of biological activities including antibacterial, antitumoral, antimicrobial, antifeedant, herbicidal, plant growth inhibition and the inhibition of cholesterol biosynthesis properties [10-14]. Recently Hirokazu Kawagishi et al. isolated the triol compound named (3S,4R)-5-Phenylpentane-1,3,4-triol (1, Scheme 1) from the EtOH extract of edible mushroom Mycoleptodonoides aitchisonii [15]. It exhibits protective activity against endoplasmic reticulum (ER) stress-dependent cell death. ER stress is caused by abnormalities in cell function such as changes in calcium channel functioning or accumulation of misfolded protein and this may be responsible for Parkinson’s, Alzheimer’s and prion type of human neuronal diseases, and also other diseases (diabetes, atherosclerosis, and heart & liver disease) [16,17]. Therefore, development of efficient strategies for the preparation of natural and unnatural products, which exhibits protective activity against endoplasmic reticulum stress-dependent cell death, is of great significance. Due to its interesting structural features and evident pharmacological potential, the synthesis of 1 has attracted much attention for the synthetic and medicinal chemists. In continuation of our research on the synthesis of biologically significant natural products from simple starting materials [18,19]. We herein, report a first total synthesis of 1, starting from 3-phenylpropanal (2) in a six steps with 45% overall yield.

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Results and Discussions

Our approach to the asymmetric synthesis of (3S, 4R)- 5-Phenylpentane-1, 3, 4-triol (1) is shown in scheme 1. We envisioned that the target molecule can be derived from allyl alcohol 5 via Sharpless asymmetric epoxidation protocol. The allylic alcohol 5 from 3-phenylpropanal (2) using proline catalyzed sequential -aminooxylation and Horner-Wadsworth- Emmons olefination. The synthetic sequence began with the preparation of ester fragment 3 from commercially available 3-phenylpropanal (2, scheme 2). Thus, phenylpropanal (2) was subjected to aminooxylation process by using nitrosobenzene as an oxygen source and L-proline as a catalyst at -20C, followed by in situ (Z)-selective Wittig olefination reaction with the triethyl phosphonoacetate, LiCl and DBU to furnish crude -aminooxy ester [20]. Subsequent reduction of the -aminooxy compound with 30 mol % CuSO4.5H2O in methanol provided the hydroxy unsaturated ester 3 in 69% yield. The enantiomeric purity of the hydroxyl ester 3 was determined as 99% by using chiral HPLC analysis. The protection of the hydroxy group in compound 3 with TBS-Cl, imidazole in THF gave silyl ether compound 4 in 96% yield [21]. The reduction of ester functionality in compound 4 was carried out with Dibal-H in THF at room temperature to afford allylic alcohol 5 in 92% yield [22]. Next, installation of chiral epoxide on intermediate 5, has been achieved using Sharpless asymmetric epoxidation protocol with (-)-di-isopropyl tartrate, tert-butyl hydroperaxide and titanium tetra (isopropaxide) in tert-butanol and water at -20C for 12h, gave the chiral epoxide 6 in 91% yield [23]. Opening of the epoxide in a compound 6 with Red-Al provided diol 7 in 86% yield [24]. Finally, deprotection of the silyl group in 1, 3-diol 7 with TBAF in THF yielded the title compound, (3S, 4R)-5-Phenylpentane-1, 3, 4-triol (1) in 95% yield.

In conclusion, the first asymmetric synthesis of (3S, 4R)- 5-phenylpentane-1, 3, 4-triol (1) starting from commercially available 2-phenylpropioal has been achieved in a six steps with 45% overall yield. The key reactions include, a proline-catalyzed -aminooxylation, followed by (Z)-selective Wittig olefination and Sharpless asymmetric epoxidation.

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Experimental

Synthesis of ((3S)-3-((R)-1-((tert-butyldimethylsilyl) oxy)-2-phenylethyl)oxiran-2-yl)methanol (6)

To a stirred mixture of powdered molecular sieves (4Å, 4.0g) and titanium tetraisopropoxide (1.37mL, 1.37mmol, 1M solution in CH2Cl2, 0.2equiv.) in (20mL) cooled at -20°C was added a (-)-di-isopropyl tartrate in CH2Cl2 (0.64g, 2.74mmol, 0.4equiv.). The mixture was stirred at -20°C for 10min, and a solution of allylic alcohol 5(2.00g, 6.84mmol, 1equiv.) in CH2Cl2(15mL) and a 5M solution (1,2-dichloroethane) of tert-butylhydroperoxide (2.46g, 5.47mL, 27.40mmol, 4equiv.) were added, successively. The resulting mixture was stirred at -20°C for 12h and quenched with 3mL H2O and 0.8ml 20% NaOH. After the mixture was stirred at rt for 45min, the organic layer was separated, and filtered the reaction mixture. The aqueous layer was extracted with CH2Cl2 (2 x 30mL). The organic layer and the extracts were combined, washed with brine, dried over Na2SO4, and concentrated. The residual oil was purified by column chromatography over silica gel using hexanes/ethyl acetate (80:20) to give 6(1.92g, 91%) as a colorless oil.

Synthesis of target molecule 1

To an ice cold solution of silyl ether 7 (0.50 g, 1.61 mmol, 1 equiv.) in THF (20mL) was added TBAF (2.41 mL, 1.0 M solution in THF, 2.41 mmol, 1.5 equiv.). The solution was stirred at room temperature for 5 h and diluted with saturated NH4Cl (20 mL) and ethyl acetate (20mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 30mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain an oily residue, which was purified by chromatography over silica gel using hexanes/ethyl acetate (70:30) to afford 1 (300mg, 95% yield); [α]D20 +63.9 (c 0.12, MeOH); 1H NMR (300 MHz, CDCl3): δ 7.27- 7.32 (m, 2H), 7.19-7.24 (m, 3H), 3.77-3.87 (m, 4H), 2.83 (dd, J = 14.0, 3.7 Hz, 1H), 2.69 (dd, J = 13.9, 9.0 Hz, 1H), 1.75-1.81 (m, 2H); 13CNMR (75 MHz, CDCl3): δ 138.3, 129.3, 128.5, 126.4, 75.3, 73.4, 60.7, 38.4, 33.0; IR (KBr): νmax = 3351, 2924, 1464, 1224, 1171, 725 cm-1; MS (ESI): m/z 219 (M+Na)+; HRMS (ESI):m/z calcd for C11H16NaO3 (M+Na)+: 219.0992, found: 219.0995.

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Acknowledgement

R Venkateshwarlu thankful to the Director, CSIR-IICT, Hyderabad, for their support to provide NMRs.

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Abstract

Model speeds drug discovery a series of novel, twenty 1,3,5-tri substituted-lH- indole 2,3-dione scaffold on a putative "U shape" molecular recognition of novel HIV-1 inhibitors were designed and synthesized using a parallel synthesis unit processes technology. Among synthesized and tested compounds 1A, 1B, 1C, 1D, 1E, 1F, 1G and 1H found good quality of IC50 ranges from 4.91 to 32.01μg. One among those, compound 1C is the most potent inhibitor as a target compound against HIV-1. Target compound N-[(3Z) 5-methoxy-1-(morpholin-4-ylmethyl)-2-oxo-1,2-dihydro- 3H-indol-3ylidene]amino}benzene sulfamethaxazole (1C) tactically very low cytotoxicity (CC50>1mM). It is reported 7.15 μg/ml to engineered cell lines, TZM- l (JC53BL-13).

Keywords: N-[(3Z) 5-methoxy-1-(morpholin-4-ylmethyl)-2-oxo-1,2-dihydro-3H-indol-3ylidene]amino

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Introduction

A human immunodeficiency virus strains is sloppy in its reproduction. However, due to the infidelity of HIV-1 during replication, the emergences of mutations (especially K103N and Y181C) rapidly develop resistance and high cytotoxicity rate to the first-generation with rigid structures, such as Nevirapine (NVP) and Efavirenz (EFV) [1-3]. In an effort to address the low resistance barrier issue, next generations have been designed with the structural feature of smaller building blocks, representative second generation improved drug resistance profiles are the recently marketed diarylpyrimidine analogues rilpivirine (TMC278, RPV) and etravirine (TMC125, ETR) [46]. At this moment, doing up about untapped chemical space in inhibitors binding pocket, also explore unresolved chemical modification obtaining more potent, quality, efficacy and safety back -up extraordinary series of unique 1,3,5 tri substituted- 1H-indole-2,3-dione connected by flexible linkers have been investigated.

Compounds and Reagents

Compounds were authorized from Sigma-Aldrich Company (MO,USA) and structure, compounds, HIV activity were amplified using Biqualys offers accurate analyses combining LC-SPE-NMR- MS and Agilent Cary 630 FTIR spectrometer, Luminometer for virus counts and ELISA analyzer.

Cells and Viruses

Engineered TZM-bl indicator cell line was provided by the TZM-bl NIH AIDS Reagent Program USA. This is a CXCR4-positive HeLa cell clone that was engineered to express CD4 and CCR5. Laboratory adapted strains, including HIV-1UG070, 7th PID dated 05/12/14 was obtained from the Department of Molecular Virology, Bio safety Laboratory -II NARI Pune. An automated, 96-well parallel array synthesizer for solid-phase organic synthesis has been designed and constructed. The instrument employs a unique reagent array delivery format, in which N-morpholinomethyl-indole-2, 3-dione utilized has a dedicated plumbing system. An inert atmosphere is maintained during all phases of a synthesis, and temperature can be controlled via a thermal transfer plate which holds the injection moulded reaction block. The reaction plate assembly slides in the X-axis direction, while eight nozzle blocks holding the glacial acetic acid reagent lines slide in the Y-axis direction, allowing for the extremely rapid delivery of sulphonamide reagents to 96 wells. In addition, there are six banks of fixed nozzle blocks, which deliver the same reagent or solvent to eight wells at once, for a total of 72 possible reagents. The system described herein is an efficient means for the parallel synthesis of compounds for lead.

Interpretation of Gold Dock

A computer program designed to screen rapidly by performed using Gold Dock Suite. The coordinates for X-ray crystal structure of HIV-1 (PDB code: 3M8Q) was downloaded from the Protein Data Bank (PDB) at the Research Collaboration for Structural Bioinformatics (http://www.rcsb.org/pdb/home/ home.do) and Shanghai small molecular database (SSMD) has been utilized. Gasteiger charges were assigned to both protein and ligands. A grid with spacing of 0.375 A and 60x60x60 points in the x, y, and z axes was built and centred on the centre of mass of the bound ligand in the crystal structure. Energy grid maps for all ligand atom types were calculated, while keeping the protein structure rigid, we selected Lamarckian genetic algorithm (LGA) to search the conformational and orientation space of the ligands. Each small molecule, 100 separate docking calculations were performed with the breakpoint settings of parameters: population size of individuals at 350, a maximum number of 25 million energy evaluations, a maximum number of generations of at 27,000, a mutation rate of 0.02, a crossover rate of 0.8, and an elitism value of 1. Docking, cluster analysis was performed on the results with the root-mean-square (RMS) deviations less than1.0 A. The breakthrough docked conformation was then selected as the lowest energy stance in the most populated cluster.

Thus, the lowest binding energy complex of more populated cluster depicts more specific and highly reliable, greater efficacy binding conformation of the compound. Insertion of the hydrogen bonding with K101 was constraints for the specificity of binding of compounds in active site of strain as reported in previously. The computational simulation of active compounds showing higher inhibition was compared with that of etravirine, next generation drug. In docking study standard etravirine [a and b ]and compound [1C] showed the hydrogen bonding with K101 residue because the second position C= O group in ring brought to form hydrogen bonding with in hydrophobic pocket of enzyme, in this context C=O is a oxygen isolated in the active compound 1C they formed hydrogen bond with back bone of K101 residue which is crucial for drug resistance and thus compromised the untapped chemical space in IBP and this increase the affinity of compound toward strain inhibition. It is further conclude that region having OCH3, Br, CH3, Cl of C-5 and distance between interaction 2.44 and combined K103, prone to mutation at the IBP entrance. Like pyrrole ring substitution on C-1 by morpholine showed higher activity as it has made vander walls force that are acting upon TYR 188 with distance 3.307 between residue atom and ligand atom which going to stabilized the inhibitor binding pocket and it should be prevent the inhibitor from leaving the binding pocket. Vander walls force interaction act on TYR 188 which made flexible clamp, however mutation resulting in looses or any changes interaction (Figure 1).

Most important in this research and finding substitution at C-3 by sulphonamide based substituent�s may be lead pi-pi stacking interaction between compound and aromatic amino acid residue TYR 181 with interaction distance 5.9 which is prone to mutation resulting loss or change of interaction. This clearly indicates that the inhibitor binding process and residues must facilitate to enter the binding pocket and adopt an appropriate conformation is the optimal interaction with the surrounding residue. This lead to change due to conformation of U, shoes horse like structure, made sites feedback inhibitor to regulate the activities and showed higher activity. Legend: black dashed line-hydrogen bond, salt bridge, metal interaction, green solid line- hydrophobic interaction, green dashed line-pi-pi, pi-cation interaction. Note: Covalent bonds to protein are not displayed. Image generated using pose view software. By downloading this image you confirm to follow citation rule (Figure 2).

3D structure of the docked conformation of target compound, N-[(3Z) 5-methoxy-1 (morpholin-4-ylmethyl) -2-oxo-1,2- dihydro- 3H-indol-3ylidene]amino} benzene sulfamethaxazole (1C) and BP of K103N/Y181C mutant HIV-1 strain, (PDB code:3M8Q),showed interaction of target compound in purple colour and 3M8Q in green and blue colour. Predicted Figure 2C showed the hydrogen bonding with K101 residue, Figure 2D hydrophobic interaction, pi-pi interaction, hydrogen bonds formed between target compound and K101 were maintained which is crucial for drug resistance and (d) merged molecule insertions position in inhibitor-binding pocket (IBP) (PDB:3M8Q) cavity endorsed lock form in open position and stop the transcription.

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Conclusion

A comparison of the designed, synthesized and evaluated novel 1, 3, 5- tri- substituted-1H-indole 2,3-dione which showed nano molar activity against HIV-1. Taste compounds 1A, 1B, 1C, 1D, 1E, 1F, 1G and 1H possess inhibitory activity. Target compound N-[(3Z) 5-methoxy-1-(morpholin-4-ylmethyl)- 2-oxo-1,2-dihydro-3H-indol-3ylidene]amino} benzene sulfamethaxazole (1C) displays potency (IC50 at micro molar level) and detect low cytotoxicity (CC50s > 1mM) against HIV- 1 UG070 7th PID. In this study and model of binding energy complexes determination, characterized and examined selected new series of resistance mutation (refence protein 3M8Q PDB) and noted changes in interaction between target compound and HIV-1 mutant. At best, binding energy could be related to IC50 in assay, more negative of the binding energy results in the formation of stronger complexes belonging therefore when a ligand have a low binding energy its affinity towards the HIV- 1 target is bigger also points to the fact that target compound belonging to adaptable are circulating and giving rise to new. The detection of binding energy value of refence protein and reference ligand complexes shows -12.43 kcal/mol and average of experimental binding energy values of new ligands and refence protein complexes were shows -11.60 kcal/mol. Target compound [1C] has been shown binding energy -8.69 kcal/ mol, which was show its affinity towards the protein 3M8Q is sizeable in comparison with other lead ligands with higher binding energy. IC 50 of target compound N-[(3Z) 5-methoxy-1- (morpholin-4-ylmethyl)-2-oxo-1, 2-dihydro-3H-indol 3ylidene] amino} benzene sulfamethaxazole (1C) was found to be 4.91 μg/ ml. Also it has been clearly indicates strain- target compound inhibitor binding energy values highly correlated which is less than two reported determined binding energy values, which is high degree to cover all edges and outskirt in IBP and reduce the frequency of chemical space creation.

The differences in these correlations may reflect good ground of biological features of the interactions of HIV-1 inhibitor and its complexes. A thorough study was carried out over twenty computationally designed 1,3 5- tri substituted- 1H-2,3-dione analogs using gold dock suite and program with the goal of identifying potential lead molecules that bind to the HIV -1 mutant protein respectively. The comparatively higher interaction scores of lead compounds compared to Etravirine when docked with HIV-1 mutant protein at the IBP active site residue suggest these novel leads would potentially bind more strongly to the pockets of HIV -1 3M8Q proteins. Further, the leads are docked with Lys101, Val106, Leu234 and His235 this proteins residue to predict their binding efficiencies with HIV-1 protein. All the twenty designed 1,3,5- substituted-2,3-dione and its analogs with chemical substitutions at the X1,X3,X5 showing better interactive scores respectively than reference ligand ( Interactive score = -152.57), as a result of docking of among twenty analogs eight lead compounds 1A,1B,1C,1D,1E,1F,1G and 1H were shows interactive score -81.69, -88.28, -80.98, -55.92, -85.35, -74.04, -67.87 and -78.17 and in-vitro experiment IC 50 were found 25.65μg/ml, 31.18μg/ml, 4.91μg/ml, 32.01μg/ml, 4.59 μg/ml, 3.96 μg/ml, 5.02 μg/ml and 25.34 μg/ml. To date the target molecule 1C, when docked with 3M8Q, have shown better dock scores (Interaction Score -80.98 compared to reference ligand (Interaction Score -152.57). Hence these are expected to bind strongly onto inhibitor binding pockets and have suggested that above is highly functional novel lead has very low cytotoxicity (CC50>1mM) and it has been displays 7.15 μg/ml to cell lines, TZM-bl and displayed potent anti-HIV-1 activity found 4.91 μg/ ml against laboratory adapted strains UG070, 7th PID. Ethics statement, the study was conducted in accordance with basic principal and study of the Bio safety Laboratory II and Bio safety Laboratory III, National AIDS Research Institute (ICMR) Pune. This study and the informed consent processes were approved by the Indian Council of Medical Research Government of India.

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Acknowledgment

I would like to express deep gratitude to my post-doctoral guide Renowned Scientist, Respected Dr. Ramesh S. Paranjape Retired Director & Scientist 'G' National AIDS Research Institute, India.

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Abstract

In health care, the contemporary dentistry is starting to utilize, realize, and understand the biotechnology's advantages. For metal dental implants, the material scien ces' study along with the material and design concepts' bio-mechanical sciences supports to implant investigation. By using multi-criteria decision making method, the goal of this paper is to choose the most convenient metal dental implant material in human health. Among metal dental implant materials, the problem of choosing the most proper materials is evaluated, using important criteria related properties. In this article, the main properties of diverse metal dental implant materials have been investigated and their material strength properties have been evaluated by experts at medical, dentist and material area.

Keywords: Implant; Multi-Criteria Decision Making; Ahp; Strength; Dental

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Introduction

The dental implants' utilize has increased obviously in the recent years, driven by populations' ageing, and the patients' desire to sustain the same activity level and life's quality. For this reason, the requisition for high-effectiveness dental implant materials that can address challenges in spine, vascular therapy, cardiology, orthopedics, trauma, wound and dental maintenance has also been rising continuous. As a dental implant, in an attempt to change missing teeth numerous diverse materials have been tested. In the technology and science with all the developments and advancements, the materials suitable for implants also developed [1]. (Table 1) is displayed to the materials developed as a dental implant [2]. The available biomaterials' functionality and diversity, as well as the techniques for their assembly and processing into implacable apparatus, have also experienced important development, with the hybrid, natural, and synthetic materials' wide variety right now on the market [3-6].This variety allows for material's better choice to fulfill the treatment's specific goals. Lately, there has been an important emphasis on the selected dental implant materials' multi-functionality. (Figure 1) is shown the application of dental implant material [2]. The implant material's right choice is an important factor for implants' long term performance. In terms of strength, this paper determines the most convenient among different metal dental implant materials which were used in the recently.

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Method and Materials

In this paper, The Analytic Hierarchy Process (AHP) is used. It is developed by Saaty [7]. For dealing with complex decision making, this method is an influential tool and obtains the most accurate decision and may support the decision-maker to determine true priorities. By decreasing decisions complicated to pair wise comparisons' a series, and then synthesizing the conclusions, AHP method aims to obtain both objective and subjective views of the decision. Besides, AHP technique in corporate a utilize method for assessing the decision-makers evaluations' consistency, therefore decreasing the preconception in the decision-making procedure. By using AHP technique, the choice of the best metal dental implant material is obtained in this study. The conclusions are important both from dentist and material science perspective as the implemented method is practically applicable.

In the study, the metal dental implant materials assessed are stated as below

a) Ti6Al4V (casted)

b) Ti6Al4V (wrought)

c) Stainless steel 316L

d) Co Cr Mo Alloy

e) Mg (%99, 9, casted)

f) Mg (%99, 9, wrought)

Four different criteria have been identified for the evaluation of implant materials in the study. These criteria are;

a) Young's Modulus (G Pa)

b) Yield Strength (M Pa)

c) Compression Strength (M Pa)

d) Tensile Strength (M Pa)

Technical properties of implant materials according to the respective criteria are shown in Table 2 (Figure 2) [8].

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Conclusion

In this paper, the AHP method is used to solve the problem and it is benefited from the Expert Choice program. The priority values of the criteria according to the AHP method are presented in (Figure 3). Furthermore, since the consistency of the matrix is 0.02 and this value is smaller than 0.1, the matrix is consistent. According to (Figure 4), the most important criterion is the compression strength and the least important criterion is the young's modulus and tensile strength. The result obtained from the analysis. According to Table 2 while the most suitable implant material is the Ti6Al4V (wrought) in terms of mechanical properties, the lowest priority material is the Mg (%99, casted). In addition, it is determined that all the matrices in the method are consistent.

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                                      Abstract

Cancer diagnosis begins with a thorough physical examination and a complete medical history. Laboratory studies of blood, urine, and stool can detect abnormalities that may indicate cancer. Normal ranges of Indoline-2,3-dione scaffolds have been studied. We report here one, two, three novels anticancer target compounds 5-Flouro-1-benzyl isatin -2, 3-b-quinoxaline and 5 -Methyl-1-benzyl isatin -2,3-b- quinoxaline and display good quality of molecular arrangement towards cancerous cells.

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Introduction

Cancer has a variety of forms this definition still holds secrete even today and selection removes variation. Cancer comes homologous proteins can differ in their specificities, specific activities, level of expression or some other basic property. However homologous will have some residual similarity in their form and function. Cancer is a biological event has brought some useful innovations in practice to the study of treatment. It was felt there should not be separate drug discovery standard for reduce the dose frequency and reduce adverse effect and shorten time treatment. The natural history of drug discovery could illustrate the complexity in selecting a baseline. Cancer drug discovery is a relatively slow growing chemical agent with an incubation period said to range from a few year to a life time. If any other anatomical symptoms will see during the laboratory trial, it must be treated thoroughly Indoline-2,3-dione scaffolds is multifunctional expressed by drug discovery series of novel 97 compounds were synthesized for anticancer and cytotoxic activity against different 60 cell line cultures [1]. 07 compounds were selected on molecular recognition and screened for anticancer study [2]. Among those is screened compounds RH8, RH 42, RH84, RH89, RH90, RH 94, RH97 found good quality of anticancer activity against most of the cancer cell line with ranges from -77.23 to 55.85% growth. Target compound 5-Flouro-1-benzyl isatin -2, 3-b-quinoxaline (RH-89) display -77.23 to 7.31% growth & another target compound RH 94 display -64.78 to 65.14% growth against most of the leukemic cell lines, while RH-08 has shown very good activity against CCRF-CEM cell line with -31.85% growths and weak anticancer activity against breast cancer cell line with 53.47% growth, but failed to respond against other leukemic cell lines. RH-89 has also shown moderate activity against nonsmall cell-lung cancer (HOP-62) with 34.69% growth. RH-90 has shown good anticancer activity against leukemic cell line SR with 18.70% growth and weak activity against Non small cell lung cancer HOP-92 and NCL-H322M with 57.14 and 57.20% growth respectively. The cytotoxic property [3] of Indoline-2,3-dione scaffolds, among 3-benzohydrazide (RH 06-64) series, RH-22 and 28 were found to be most cytotoxic against L-1210 cell line (9 and 6μg/ml). RH-33 was found to be cytotoxic against CEM/0 cell line (6.9μg/ml). Among 3-isonicotinohydrazide derivatives (RH 65-72), RH-70 was found to have better cytotoxic property against all three types of cell lines (6.1-6.7μg/ml). From 3-quinazolin-4(3H)-one series (RH 74-82), RH-75 was found to be better cytotoxic against Molt4/8 cell line (6.0μg/ml) and RH-77 was found to have better cytotoxicity against L1210 cell line (9μg/ml) remaining compounds RH-79, 80, 82 have shown moderate to weak cytotoxic property. Among 6H-indolo [2,3-b] quinoxaline derivatives (RH 83-96), RH-92 have shown better cytotoxic property against L1210 cell line (7.2μg/ml).

Compounds and Reagents

All chemicals used were procured from Sigma-Aldrich. The purity of chemicals was checked before use and purified. Melting points were recorded by open capillary tube method and uncorrected. Purity of all the synthesized compounds was assessed by thin layer chromatography on silica Gel-G'(100-200 mesh) plates. Structures of compounds were confirmed by FTIR, 1HNMR and Mass spectra. IR spectra were recorded in KBr disk on Nicolate IR-Instrument and reported in cm-1. Mass spectra were recorded on Shimadzu-LCMS 2010 EV-single quadrapole instrument. 1HNMR spectra were recorded on the BRUKER-300 instrument with TMS as the internal standard in CDCl3/DMSO as a solvent. Total 97 derivatives of Indoline-2,3-dione scaffolds have been synthesized by Sandmeyer process methodology using N-methyl morpholine, substituted benzylchlorides, isoniazid, substituted benzoylhydrazide, quinazoline, orthophenylenediamine, halogens and alkyl groups as substituent and compounds were recrystallized by using ethanol-chloroform mixture. Synthesized compounds and melphalan as a standard were also evaluated for their in vitro cytostatic activity against human Molt 4/C8 and CEM T-lymphocytes as well as murine leukemia L1210 and anticancer activity against Leukemia, Non-Small Cell-Lung Cancer, Colon Cancer, and Breast Cancer. Synthesized compounds were screened for anticancer activity at National Cancer Institute, Maryland, USA and Rega Institute, Belgium respectively (Figure 1).

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Result and Discussion (Tables 1 &2).

Chemistry

RH8; MF C15H10N3O2Cl, Yellowish fluffy mass, MW 299.71, MP 280-82,% Yield 49, IR 3226 (-NH), 3044 (-CH, ar.), 1701 (>CO), 1678 (>CO). NMR 14.03 (d, 1H, NH.), 11.28 (s, 1H, NH), 7.88-7.84 (m 2H, ar.), 7.59-7.42 (m, 4H, ar.), 7.25-7.23 (m, 1H, ar.), 6.87-6.84 (m, 1H, ar.). m/s 299 (299.29)

RH 42; MF C22H16N3O2C., Yellowish-fibrous mass, MW 389.83,'22 16 3O Cl MP 170-72, % Yield 81, IR 3363 (-NH), 3196 (-CH, ar.), 3028 (CH, alip.), 1750 (>CO), 1682 (>CO). NMR 14.04 (s, 1H, NH.), 7.97(d, 2H, ar.), 7.82 (s, 1H, ar.), 7.46 (t, 2H, ar.), 7.48 (t, 1H, ar.), 7.257.04 (m, 5H, ar.), 6.76 (d, 1H, ar.), 4.87 (s, 2H, CH2), 2.25 (s, 3H, CH3). m/s 389 (389.42)

RH84: MF C21H14FN3, Reddish Fluffy Mass, MW 327.35,MP 162-13,% Yield 72,IR 3045-3013 (-CH, ar.), 2954-2849 (-CH,

alip.), 1610, (>C=C), 1580 (>C=N).,NMR 8.51 (d, 1H, ar.), 8.348.32 (m, 1H, ar.), 8.16 (d, 1H, ar.), 7.80-7.76 (m, 1H, ar.), 7.737.69 (m, 1H, ar.), 7.63 (t, 1H, ar.), 7.41-7.31(m, 4H, ar.), 7.00 (t, 2H, ar.), 5.69 (s, 2H, -CH2).,

RH89, MF C21H14FN3, Orange Mass, MW 327.35,MP 220-22,% Yield 68, IR 30(56-3004 (CH, ar.), 2904-2849 (CH, alip.), 1618 (>C=C), 1582 (>C=N)., NMR 8.38 (d, 1H, ar.), 8.24-8.19 (m, 2H, ar.), 7.86-7.82 (m, 1H, ar.), 7.79-7.74 (m, 1H, ar.), 7.42 (d, 1H, ar.), 7.39-7.32 (m, 2H, ar.), 7.31-7.28 (m, 4H, ar.), 5.77 (s, 2H, -CH2).

RH90; MF C22H16FN3, Yellowish Mass, MW 341.38,MP 17722 16 380,% Yield 71,IR 3054-3029 (CH, ar.), 2917-2849 (-CH, alip.), 1613 (>C=C), 1585 (>C=N). NMR 8.33 (d, 1H, ar.), 8.18-8.15 (m, 1H, ar.), 7.81-7.77 (m, 1H, ar.), 7.73-7.69 (m,1H, ar.), 7.37-7.29 (m, 3H, ar.), 7.22 (d, 2H, ar.), 7.12 (d, 2H, ar.), 5.68 (s, 2H, -CH2), 2.30 (s, 3H, -CH3).

RH 94; MF C22H17N3, Reddish Fluffy Mass, MW 323.39, MP 215-18, % Yield 75, IR 3059-3024 (CH, ar.), 2966-2850 (-CHalip.), 1616 (>C=C), 1578 (>C=N).NMR 8.38-8.36 (m, 2H, ar.), 8.20-8.18 (m, 1H, ar.), 7.83-7.79 (m, 1H, ar.), 7.76-7.72 (m, 1H, ar.), 7.49 (d, 1H, ar.), 7.38-7.29 (m, 6H, ar.), 5.67(s, 2H, -CH2), 2.59 (s, 3H, -CH3).

RH97: MF C21H15FN3, Yellowish Mass, MW 309.36,MP 173-75,% Yield 6(3 IR 3048-3030 (CH, ar.), 2908-2856 (-CH, alip.),1610 (>C=C), 1562(>C=N).NMR 8.32 (d, 2H, ar.), 8.14 (d, 1H, ar.) 7.79-7.75 (m, 1H, ar.), 7.71-7.68 (m, 1H, ar.), 7.45 (d, 1H, ar.), 7.32-7.23 (m, 3H, ar.) 6.98-6.95 (m, 2H, ar.), 5.66, (s, 2H, -CH2), 2.55 (s, 3H, CH3).

RH-22; MF C15H9BrFN3O2, Orange gritty powder, MW 362.15, MP >310, % Yield 57, IR 3229 (-NH), 3056 (-CH, ar.), 1681 (>CO), 1620 (>C=C), 1552 (C=N), 1463 (C-H). NMR

RH28; Yellowish fluffy mass, MW 423.06, MP >310, % Yield 84,IR 3263 (-NH), 3035 (-CH, ar.), 2783 (-CH, alip), 1672 (>CO), 1665 (>C=C), 1529 (C=N), 1467 (C-H).

RH65;MF C21H8N4O2Cl, Yellowish fluffy mass, MW 390.82, MP 197-99, % Yield 76 IR3252 (-NH), 3073 (-CH, ar.), 2918, (CH, alip.), 2850 (CH, alip.) 1691 (>CO). 13.87 (s, 1H, -NHCO), 8.873 (d, 2H, ar.) 7.813 (d, 2H, ar.), 7.765 (s, 1H, ar.), 7.611 (d, 1H, ar.), 7.339 (m, 4H, ar.), 7.05 (d, 1H, ar.), 5.018 (s, 2H,-CH2)

RH 72; MF C14H2N4O2ClF, Orange gritty powder, MW 318.69, MP299-300, % Yield 70, IR 3249 (-NH), 3070 (-CH, ar.), 29312849 (-CH, alip.), 1700-1691 (>CO), 1613 (>C=C), 1520 (C=N), 1472 (C H). NMR13.95 (s, 1H, - NHCO), 8.86 (d, 2H, ar.), 7.80 (d, 2H, ar.), 7.5 (s, 1H, ar.), 7.305 (m, 6H, ar.), 6.9685 (d, 1H, ar.), 4.987 (s, 2H, -CH2 -), 2.296 (s, 3H, -CH3).

*50% inhibitory concentration (IC50) value, expressed in uM

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Conclusion

A comparison of the synthesized and evaluated novel Indoline-2,3-dione scaffolds and its series which showed nanomolar activity against most of the leukemia cell line and other cancers cell line. Taste compounds RH8, RH 42, RH84, RH89, RH90, RH 94, and RH97 possess inhibitory activity. Target compound RH89 and RH 94 displays -77.23 to 7.31% and another target compound - 64.78% to 65.14% growth respectively. All the 97 compounds designed analogs with chemical substitutions at the various position confirmed by analytical model showing better interactive scores respectively Molecular recognition studies in the series removal of alky group from 4'-position of N-benzyl ring causes loss in activity (RH-71) and replacement of benzyl group by -H makes the compound inactive (RH-72), while RH-08 has shown very good activity against CCRF-CEM cell line with -31.85% growths and weak anticancer activity against breast cancer cell line with 53.47% growth, but failed to respond against other leukemic cell lines. RH-89 has also shown moderate activity against non-small cell- lung cancer (HOP-62) with 34.69% growth. RH-90 has shown good anticancer activity against leukemic cell line SR with 18.70% growth and weak activity against Non small cell lung cancer HOP-92 and NCL-H322M with 57.14 and 57.20% growth respectively. The comparison of activity with structure similarity and differences in substitution reveals that compounds with quinoxaline moiety are more active than benzohydrazide moiety (RH-89 & 94> RH-08). Further, 5-fluoro or 5-methyl substituted compounds (RH-89 & 94) were more active than un-substituted analogues (RH-97). It was also observed that any substitution on the 4' position of N-benzyl ring causes loss in activity (RH-90 & 97). Similarly among benzohydrazide series compounds with chlorine substitution at 5th position is active (RH-08), however N-benzylation reduces the activity (RH-42). However role of N-benzyl group has mixed effect on the activity. The cytotoxic results of benzohydrazide series show that RH-22 and RH-28 were most cytotoxic against L-1210 cell line (9 and 6μg/ml). RH- 33 was found to be cytotoxic against CEM/0 cell line (6.9μg/ml). The activity report shows that presence of halogen increases the cytotoxic property. Replacement of halogen from 4' position of benzohydrazide causes loss in activity as in case of RH-06, 25, 26, 28 and 31. Among 3-isonicotinohydrazide derivatives RH-70 was found to have better cytotoxic property against all three types of cell lines (6.1-6.7μg/ml). Removal of alky group from 4'-position of N-benzyl ring causes loss in activity (RH-71) and replacement of benzyl group by -H makes the compound inactive (RH-72). It shows that halogen at 5th position and alkyl group at 4' position of N-benzyl ring is essential for activity. From 3-quinazolin- 4(3H)-one series RH-75 was found to be better cytotoxic against Molt4/8 cell line (6.0μg/ml) and RH-77 was found to have better cytotoxicity against L1210 cell line (9μg/ml). Among 6H-indolo [2,3-b]quinoxaline derivatives RH-92 has shown better cytotoxic property against L1210 cell line (7.2 μg/ml) which shows the importance of halogen at 5th position and presence of N-benzyl moiety in the compound. Alteration in the combination leads to loss in activity (RH-84, 87, 88, 89, 90, 91, 93-96). Based on the results without any halogen has either very weak activity or inactive and none of them are close to the standard Malphalan (2.1-3.2μg/ml) [4-11].

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Acknowledgment

This study has been guided under the guidance of Renowned Laboratory Scientist Respected Dr. Ramesh Paranjape, Founder National AIDS Research Institute India. I express my sincere gratitude towards Respected Sir for motivation and being great knowledge source for this work.

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Abstract

The kinetics of erythromycin with 2, 3 dichloro-5,6-dicyano -1,4- benzoquinone (DDQ) is described for the determination of erythromycin. It was carried in aqueous HC1O4 (2M) medium at ionic strength of 0.01moldm-3, Kinetics of the reactions infer that the rate of formation of the charge transfer complex did not vary significantly with increase in concentration of erythromycin indicating likely zeroth order dependence of the rate with respect to concentration of the drug. However, the linearity of the pseudo-first order plot points to first order dependence of rate on [DDQ].The overall rate equation for the reactions can be given as

Keywords: Kinetic studies; Erythromycin; Charge transfer; DDQ

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Introduction

The kinetic methods of analysis are highly sensitive, selective, simple, accurate and less expensive [1]. Erythromycin, 3R, 45 55, 6R, 7R, 9R, 11R, 12R, 13R, 14R - 4-[(2,6-didiocy -3-c-methy 1-3-0-methy 1 -a-l-ribo -hexopy- ransyi) oxy]- 14 ethy 1-7, 12,13-trihydroxy- 3, 5,7,9,11,13-hexamethy 1-6-[(3,4,6-trideoxy -3-dimethy kmiro - P-D-xylo-hexopy ransoyl) -oxy] oxa - cydofetradecare -2, 10-dione is a macrolide antibiotic used for the treatment of urinary tract infection. It targets at the ribosome and inhibits the protein synthesis of gram positive bacteria such as mycoplasma and Chlamydia [2]. In recent years, several kinetic catalytic techniques have been reported for the detection of biomolecules [3,4]. Literature revealed different techniques for the analysis of erythromycin as follows: spectrofluorimetry [5]. Capillary electrophoresis [6], HPLC [7], microbiological method [8] spectrophotometry [9,10]. Therefore, the aim of this research is to determine a kinetic method based on formation of charge transfer complex between erythromycin and DDQ that is simple, fast, economical and less laborious.

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Materials and Methods

Equipment

All kinetic measurements were carried out using a UV- 1800 Shidmazu and 752w UV - Vis grating with a silica glass cell of l cm thickness. All chemicals were of analytical grade and were used as such. Erythromycin powder was supplied by AC pharmaceutical limited, Enugu, Nigeria. The commercial erythromycin tablet (500mg per tablet) was purchased from the local market (Syncom formulations limited, India) 2,3 dichloro - 5, 6- dicyano-1,4-benzoquinone (98% purity) was supplied by sigma Aldrich, Germany.

Kinetic Measurements

Kinetics of the reactions of DDQ with erythromycin was followed spectrophotometrically under pseudo-first order condition with one of the reactants (donor) in at least 10 fold in excess over the reactant (acceptor) at 290C. The pseudofirst order rate constants were determined by using various concentrations of erythromycin (0.001 M to 0.0035 M) with fixed concentration of acceptor (2.5 x10-4 M). Effects of ionic strength, pH and hydrogen ion on the rates of reaction were also determined.

The pseudo-first order rates constant were obtained from a plot of log versus time following equation 1.

Where Aα and A 0are the final and initial absorbencies respectively, is absorbance at time t and is pseudo-first order rate constant.

Effect of Hydrogen Ion Concentration on the Rate of Erythromycin and DDQ Reaction

Within the hydrogen ion concentration range 1.0 x10- 2 to 1.0mol dm-3, kinetic runs were carried out keeping the concentrations of the drug and reagent constant at I =1.02mol dm-3 and T= 30.0± 0.20C.

Effect of Ionic Strength on the Rate of Erythromycin- DDQ Reaction

Within the range of ionic strength of the media 0.001- 0.03mol dm-3, the variation of rate of reaction with ionic strength was investigated for the reaction of erythromycin and DDQ, At T = 280C and keeping the concentrations of drug and reagent constant, the ionic strength was varied and the rate of plot isreseprented in Figure 1. reaction monitored.

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Results and Discussion

Reaction of Erythromycin with DDQ

The wavelength of maximum absorption spectrum was found to be 464nm with a stoiochiometric ratio of 1:1 of erythromycin - DDQ complex [11].

Kinetic Studies

The rate of the charge transfer reaction of erythromycin and DDQ was followed spectrophotometrically under pseudo - first order conditions by monitoring the rate of consumption of DDQ at 464nm. Erythromycin was at least 10 fold in excess of DDQ and the reaction was carried out at pH 8.Kinetic decays were exponential and pseudo first rate constants were determined from the plots of log versus time according to equation 1. The plots were linear for more than 90 % extent of reaction. Typical plot is represented in Figure 1.

NaClO4 = 1.02M, [Erythromycin] = 2.0x10-5 M, [DDQ] = 1 x 10-6 M

The second order rate constants were determined by dividing Kobs with [erythromycin]. The values of Kobs and k2 are represented in Table 1. The result from table 1 shows that as concentration of erythromycin increased from 0.001M to 0.0035M, the Kobs values did not vary significantly indicating a zero order dependence on reaction rate with respect to the concentration of erythromycin. However, the linearity of the pseudo - first order plot points to first - order dependence of rate with respect to [DDQ].

Effect of Hydrogen Ion Concentration on Erythromycin - DDQ Complex

The H+ concentration was varied from 0.08M to 1M while keeping other variables constant. Table 2 shows that Kobs increase from 0.08M to 1M. This infers that within this acid concentration range, protonation of the reactants played significant role in the charge transfer reaction. The Second order rate constants were determined by dividing Kobs with[erythromycin]. Table 2 is a display of pseudo-first order and second order rate constants.

Effect of Ionic Strength on Erythromycin - DDQ Complex

In addition, ionic strength medium was varied from 0.001M to 0.03M. Table 3 shows that Kobs did not vary significantly at 0.001M-0.01M but increased from 0.015M to 0.025M of the varied ionic strength which indicates primary salt effect and likely involvement of charged partners at the rate determining step.

Effect of Temperature on Erythromycin - DDQ Complex

Effect of temperature was studied between 303k- 333k. Result in (Table 4) shows a drop in Kobs from 313k to 333k, this shows that as the temperature increases, the rate of reaction decreased. Also, Table 4 reveals a negative entropy, negative enthalpy change and positive Gibb's free energy change which means that the reaction does not occur spontaneously

Least square fit of log K_obs/T 1/Tvs based on the Eyring - Polanyi (equation 2) is represented in figure 2.

Where, kr = rate constant, k = Boltzmann's constant, h = Planck's constant, ΔS# = entropy of activation ΔH# = enthalpy of activation, T = absolute temperature, R = gas constant.

The rate determining steps of erythromycin-DDQ complex are as follows:

ΔS# (kJk-1/mol) = -2391; ΔH# (kJ mol-1) = -11

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Conclusion

The proposed kinetic method infer that the rate of formation of charge transfer complexes did not vary significantly with increase in concentration of erythromycin indicating a likely zeroth order dependence of the rate with respect to the concentration of erythromycin. However, the linearity of the pseudo - first order plot points to first order dependence of rate on [DDQ].To know more about Journal of chemistry,

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                                           Abstract

The anti-fungal activities of the pure ligands, pure soaps and their four corresponding complexes have been evaluated by testing these against Alternaría alternata at different concentration by Agar plate technique. All complexes show higher activity than pure soaps and ligands suggesting that complexes are more powerful anti-fungal agents further N, S, O etc containing compounds like benzothiazole are able to enhance the performance of copper soaps. These results show that the complexes of ligands (-Cl and -CH3 substituted benzothiazole) are much more toxic than the ligands themselves. Their efficiency increases with their concentration.

Keywords: Surfactants; Caprylate; Caprate; 2-amino; 6-chloro benzothiazole; 6-methyl benzothiazole; Benzene; Methanol

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Introduction

Recently, the deeper understanding of the role of metal ion in bio-system has led to the awareness that metal complexing is useful in the treatment of bacterial, fungicidal and viral diseases. Most of the antimicrobial agents are obviously organic compounds, which behave as good chelating agent. Their pathogenic activity is enhanced on complexing with various transition, inner transition and toxic metals. The biological effect of these derivatives depends on the nature and structure of ligands and their metal complexes and also on the presence of particular element [1,2].

Nitrogenous ligands have been found to be effective against many metal enzymes, bacteria and number of fungi. Large number of compounds containing nitrogen and sulpher atoms in the heterocyclic ring shows different types of activities. Some examples are given here possessing benzothizaole or similar type of structure containing nitrogen and sulpher atoms in the aromatic cyclic ring. Recently, Wood has developed metabolic antagonist theory of drug action and Fields led to the synthesis of several co-ordination compounds, which have been used for antibacterial and anti-tubercular activity [3,4].

Synthesized and evaluated biological activities of some new 2-arylamino-4-fluoroaryl thiazoles, were found to possess fungicidal, herbicidal and anti-arthritic activities. Thus on the basis of the foregoing studies, it becomes very clear that benzothiazole and their substituted derivatives have been found to be very active against variety of bacteria, fungi, herbs and insects [5,6]. It has also been established by several workers that chelation of the benzothiazole and their substituted derivatives enhances the biological and fungicidal activity [7,8]. The ligands used during the present investigation viz. 2-amino-6-substituted (-Cl and -CH3) benzothiazole have been very well reported to possess biocidal activity. Our continuing interest in the search for better fungicides and bactericides has led us to synthesise some new complexes derived from Cu-caprylate and caprate soaps with the above mentioned ligands and screen them for their fungicidal activities [9,10].

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Experimental

The general laboratory techniques followed in the course of this investigation are as suggested by Booth and Hawks worth [11].

Sterilisation of Glasswares

Glasswares used in our present study were of Pyrex brand. The glassware viz. test tubes, conical flasks, pipettes (micro and macro), glass rods and petridishes were thoroughly washed after rinsing with chromic acid each time before sampling. The petriplates and other glassware were then sterilised in hot air oven at 1600C for 24 hours before use.

Culture Media Used

The culture medium used for the growth of the organism of the present study was P.D.A. The following media were used in the present study [12] (Table 1).

200gm of potatoes were cleaned, cut into pieces and boiled in about 1000ml of tap water for 2 hours. Then the contents were strained using muslin cloth. To this extract 20gm of dextrose, 20gm of agar were added and made upto 1000ml in graduated flask, before sterilising the medium.

Preparation of Sample Solutions

The four complexes were prepared by Copper (II) caprylate and caprate soaps with 2-amino-6-chloro benzothiazole and 2-amino-6-methyl benzothiazole. They were designated as CCpl ,ACB, CCpr ACB, CCpl .AMB and CCpr AMB. All chemicals used were of reagent grade. The calculated amount of the complex was weighed in a standard flask and the solution containing different concentration of complex in methanol-benzene mixtures of varying compositions were prepared.

Test Organism

The test organism used in the present study was Alternaria alternata which was isolated from its natural habitat [plants, (debris)]. Purified, characterised and identified [13].

Fungicidal Testing

1 ml of the diluted solution [complex dissolve in 40% methanol-benzene solvent mixture and 80% methanol- benzene solvent mixture] was aseptically transferred into sterile petriplates. Into these plates, 20 ml of P.D.A was poured and was mixed with complex solution by rotating the petriplates in clockwise and anti clock wise direction 3-4 times and was allowed to solidify. After the solidification of the above medium, single hypha / spore of Alternaria alternata were aseptically transferred in the centre of the petriplates. The plats were incubated at 28 + 10C for 7 days. After the period of incubation the plats were observed for the growth of fungus in different concentration of the complex solution used in the present study The data were statistically analysed according to the following formula [14]:

% Inhibition= (C-T)/C*100

C = diameter of fungal colony in control plate after 7 days;

T = diameter of fungal colony in test plate after 7 days

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Results and Discussion

The antifungal activities of the pure ligands, pure soaps and their corresponding complexes have been evaluated by testing against Alternaria-alternata at different concentration by Agar plate technique [15]. A perusal of results reveals that all complexes show higher activity than pure soaps and ligands suggesting that complexes are more powerful anti-fungal agents and benzothiazole and other N, S, O etc. containing compounds are able to enhance the performance of copper soaps. These results show that the Cu (II) soap-complexes of ligands [-Cl and -CH3 substituted benzothiazole] are much more toxic than the ligands themselves. The enhanced activity of newly synthesized complexes as compared to those of the ligand can possibly be explained on the basis of chelate formation, presence of donor atoms, basicity as well as the structural compatibility with molecular nature of the toxic moiety. Enhanced biological activity of complexes is in accordance with the chelation theory [16].

In final conclusion, that the appearance of enhanced activity may be due to synergistic mechanism i.e. the free ligands are less active but on complexation show more activity in combination with copper (II) soaps. The studies suggest that the copper (II) ions in soaps may be responsible for enhancement of the activity against fungi [17]. The evaluation of anti-fungal studies further revealed that fungi toxicity of the complexes also depends on the nature of metal ions. Their efficiency increases with their concentration [18,19]. Thus it is evident that concentration plays a vital role in increasing the degree of inhibition. So fungicidal screening data revealed that at lower concentration the inhibition of growth is less as compared to higher concentration (Figures 1-3).

CCplAMB, CCprAMB complexes are more active than CCplACB, CC ACB complexes. Their activities also enhanced with thepr increase in chain length of the soap segment in the complex [CCpr ACB, CCpr AMB complexes are more effective in all cases]. In all complexes toxicity increases with the domination of methanol in the solvent mixture of methanol and benzene [40% methanol- benzene and 80% methanolbenzene], suggesting that complexes are more effectively playing there role to check the growth of fungi in the domination of polar solvent in the ternary system: complex + methanol + benzene. Some recent studies about antimicrobial activities of newly synthesised 1, 4-benzothiazines possessing thiazolyl/imidazolyl moieties also support our studies [20].

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Conclusion

CCplAMB, CCprAMB complexes are more active than CCplACB, CC ACB. Their activities also enhanced with the increase inCCpr Their actives also enhanced with the in chain length of complex. In all complexes toxicity increase with the domination of methanol in the solvent mixture of benzene and methanol suggesting that complexes are more effectively playing their role to check the growth of fungi in the presence of polar solvent.

All the above studies made by us leads to the conclusion that copper soaps having many fungicidal, herbicidal and other biological activities possessing a tendency to make complexes with donor atom containing ligands. Their performance enhanced by the presence of the other biologically active segment in the complex. Their micellar features and other physical properties analyzed and reported in the above studies will play a significant role in their applications in various fields of industries, wood preservation and agriculture etc.

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Acknowledgment

The authors pay their sincere gratitude to Principal, S. P. C. Govt. College, Ajmer, S.D. Govt. College Beawar, Rajasthan (India) for providing necessary research facilities to accomplish this study.

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