Lupine Publishers | Production of Silica from Agricultural Waste

 Lupine Publishers | Journal of Organic and Inorganic Sciences

Abstract

This study aims to produce silica from different material agriculture waste such as sugarcane bagasse, bamboo culm, bamboo leaf, and corncob. The sol-gel method was applied in order to produce silica using 1M NaOH and 1M H2SO4. The sugarcane bagasse ash contains the highest amount of silica, 92.5% followed with bamboo leaf, 62.72%; corncob, 27%; and bamboo culm, 20%.

Keywords: Silica, Agriculture Waste, Sol-Gel

Introduction

The most common generated waste synthesized is rice husk and palm ash, which shown high silica contain as 90-98% and 45- 50%, in respectively [1,2]. Silica produced from these wastes were synthesized mainly using acid leaching treatment. In this study, we focused on the synthesized of other sources silica through sol-gel method. The source such as sugarcane bagasse, corn cob, bamboo stem, and bamboo leaf, till now is still not widely explored, hence become the basis to study the amount of silica that been extracted. Within the scope of study, it shown that several factors play a vital role in determining the silica content of the material, including the species of source material, soil content of source material, maturation etc. Sol-gel synthesis is one of the most common method of converting ash into silica gel. In this process, silica was synthesized from ash through simultaneous hydrolysis and condensation reaction where a sol of sodium silicate, silicon alkoxide or halide gels converted into a polymeric network of gel [3]. The synthesis of silica using this method, lead to silica precipitation under certain conditions like restriction of gel growth that involved coagulation and precipitation step during its preparation [4]. Silica gel synthesize through this method also known as xerogel. The purification and drying produce silica in amorphous powder form that remove any impurities or organic matter that usually contain in waste [1]. Therefore, in this study, herewith, we explore the production of silica from these material waste using sol-gel method.

Experimental

Sugarcane bagasse (SBA), corn cob, bamboo culm(Gigantochloascortechinii), and bamboo leaf were collected from various sources in Melaka, Malaysia. Reagents used are NaoH (HmBg chemical) and sulphuric acid (HmBg chemical). The collected materials were sorted, cleansed and cut to smaller portion. The prepared material was transferred into furnace and combusted at 650⁰C for 3 hours at a heating rate of 10⁰C min-1 to obtain ash. The ash was then collected and labelled accordingly based on the sources material.The silica was prepared by boiling 30g of ash with 1L 1M NaOH for 1 hour with constant stirring until ash dissolved and sodium silicate solution produced. The solution filtered, and the residue washed with distilled water. The filtrate then cooled to room temperature and later adjusted to pH 7 using 1M H2SO4 and IM HCl using titration method. The gel was performed and was let to age for 18 hours. The formed gel then gently broken and centrifuged at 2500 rpm for 10 minutes. The supernatant was discarded, and the gel dried for 11 hours at 80⁰C to form xerogel. It then washed with deionized water to remove minerals and impurities.

Results and Discussion

The aim of this study is to analyse the synthesis of silica from different type of selected silica material. From experimental procedure, 4.7 kg sugarcane bagasse produce 1.3% ash after combustion and this ash contain 92.5% silica. These results are in concordance with previous study that suggested that SBA contain higher silica content from 50%-97% range [5,6]. This higher silica synthesis is due to the higher fibre contain of sugarcane bagasse that made up of lignin (20-30%), cellulose (40-50%) and hemicellulose (30-35%) [7]. Nonetheless, ash produced from the combustion of sugarcane bagasse is quite low, only at 1.3% from total weight used. Based on this result, it shown that sugarcane bagasse ash contains the highest amount of silica, 92.5% and it is almost similar with the amount of silica synthesized from rice husk which stated between 90-98% [1]. This suggesting that sugarcane bagasse is a good source of silica and has wide potential for further study and application. Figure 1 shown the silica % content of the all materials have been studied.

Figure 1: Comparison of silica % synthesized from selected material ash.

Conclusion

In this study, it is confirmed that we successfully extracted silica from different selected materials ashes that usually generated as waste from agricultural. Sugarcane bagasse produce the lowest percentage of ash from all the selected wastes material, 1.3%; however, contain the amount of highest silica, 92.5% which is almost similar with the amount of silica produced from rice husk. Another generated that can synthesise higher silica % is bamboo leaf, 62.7%. Others generated waste such as bamboo culm and corncob ash can synthesise about 20% and 27% respectively.

Acknowledgement

The authors are grateful for the financial support by the University Kuala Lumpur (UniKL MICET) and Majlis Amanah Rakyat (MARA) Malaysia.

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Lupine Publishers | Route evaluation of domestic violence and epileptic seizure (“fit”) experience among recently married women residing inslums communities’pharmaceutical institutions in Pune District, India

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

An attack of an acute disease or the sudden appearance of over symptom, such as coughing and convulsion accepted as ‘’Fit’’. In 2015, epilepsy affected 1.2 percent of the population in the United States, or 3.4 million people, including 3 million adults and 470,000 children. Every function in the human body has triggered by messaging systems in our brain. Epilepsy results when this system has disrupted due to faulty domestic violations. The Centers for Disease Control and Prevention (CDC) describe epilepsy as “a common neurological condition that kept under control and medically care. It has mainly control slowing advance, rather, it must submit their claims to rigorous non-scientific culture.

Opinion

In many cases, the exact cause has not known. Some people have inherited genetic factors that make epilepsy more likely to occur. Other factors that may increase the risk include: head trauma, for instance, during a car crash, stroke infectious diseases, for instance, AIDS and viral encephalitis, developmental disorders, for instance, autism or neurofibromatosis. It has most likely to appear in children under 2 years of age very rare, middle age and adults over 65 years. What a patient with epilepsy experiences during a seizure will depend on which part of the brain has affected, and how widely and quickly it spreads from that area. The incomplete note of medical sciences that the condition “has not well understood.” Often, no specific cause can be identified. Intimate partner violence (IPV), defined as the physical, sexual, psychological abuse, and control perpetrated against an intimate partner, has highly prevalent and cannot ignore for epilepsy epidemic. Approximately one in ten of women reporting physical and abuse by their partner during their lifetime, violation of human rights that often results in physical injury can lead neurological disturbances (trauma). Women who experience IPV have higher odds of depression, anxiety and other mental health disorders, [1] sexually transmitted infections including HIV, [2] chronic pain disorders and gynaecologic morbidity among other chronic disease states lead the epileptic seizure (“fit”). Additionally, their children suffer from greater symptom of epilepsy morbidity and mortality.

In India, although national estimates suggest decreasing frequency, one in three women still report having been abused by their spouses during their lifetime. Further, this figure has likely an underestimate of the abuse women suffer post-epileptic seizer or other members of the husband’s family, hereafter termed domestic violence (DV). Women who reside in India’s slums pharmaceutical institutions are among those at greatest risk of high fever with epilepsy-like symptoms. While the disparate figures between slum- and non-slum residing communities may be in part art efactual due to shame induced underreporting in higher income communities, factors that drive increased DV perpetration and compel women to remain in abusive relationships are likely disproportionately greater in slum to slum communities. Women in slum communities may be more likely to experience DV with periods of extreme muscle weakness because their partners and families into which they marry suffer greater stress (i.e. related to inadequate finances, crowding, limited resources, low update oxygen and poor sanitation), discrimination, and subordination, reside in communities where normalization and acceptance of DV has greater, alcohol use has greater, have weakened immune support systems that do not allow them to develop and exercise positive coping mechanisms, and epileptic disorder use as means of countering feelings of powerlessness.

Further, in Pune district slum communities, at the time of marriage, many women transition from newly enter the slums from surrounding rural areas; thus, the differences in upbringing within the couple may also influence marital expectations and prompt conflict. Further, women residing in slums may be more likely to stay in panic attacks because of poorer knowledge of and access to health support services, on time medicine and increased economic dependence, [3] weaker support systems, stronger perceptions of hopelessness, and residence in environments where DV and other forms of psychogenic seizures occurs with frequency and acceptance willingly [4]. The risk imposed by these factors has compounded by social sanctions that encourage women to weaken ties with (and thus, diminish the social support of) natal family members and their community post-marriage, that limit the time the couple spends together alone to develop their relationship both pre-and post-marriage, and external pressure on the couple (i.e. fertility). Further, women’s financial empowerment through employment, a seemingly logical solution, has counter intuitively been shown to be associated with increased DV experience through challenging traditional gender roles and serving as a threat to male partners. Thus, there are currently cure for most types of correlate Domestic Violation epilepsy. However, surgery can stop some kinds of seizure from occurring, and in many cases, the condition can be managed. An underlying correctable brain condition has causing the seizures, sometimes surgery can stop them. Epilepsy has diagnosed; the doctor will prescribe seizure-preventing drugs or anti-epileptic drugs.

The majority of AEDs are taken orally. The type of seizure the patient has having will decide which drug the doctor may prescribe. Patients do not all react in the same way to drugs, but AEDs appear to help control seizures in 70 percent of cases. Some drugs may stop seizures in one patient, but not in another. Even when the right drug has found, it can take some time to find the ideal dose. Drugs do not work; the next option could be surgery, a special diet or VNS (vagus nerve stimulation).The doctor’s aim has to prevent further seizures from occurring, while at the same time avoiding side effects so that the patient can lead a normal, active, and productive life. A community-tailored approach that recognizes the structural factors of slum environments that shape DV risk reduce. National evidence suggests that almost two-thirds of women who report DV with Fit, state the abuse had begun within the first two years of marriage, [5] underscoring the need for such prevention efforts to occur preor immediately post-marriage. To date, few studies have examined risk factors for DV experience among women residing in slum communities in India. Those who have, identified the following risk factors: age, low educational attainment of self and spouse, young age of marriage, having a love marriage versus arranged marriage, additional dowry request from marital family, employment, changes in her own or her spouse’s employment status, residence in a joint family, renting versus owning one’s residence, fewer rooms in the household and shared bathrooms, accepting attitudes toward wife beating.

Discussion

Epilepsy has neurological condition that can kept under control. Drugs commonly used to treat epilepsy include: sodium valproate and carbamazepine. Consultation authenticated hospitals or government hospitals, indoor treatment at government and empanelled private hospitals and investigations at government and empanelled diagnostic centers.

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Lupine Publishers | Preparation of Morphine Derivatives Using Ionic Liquids

Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

Dextromethorphan, an anti tussive drug belongs to the morphinan family, and is mostly available in the market as a combination therapy. Most of the reported preparation procedures involve the use of racemic starting materials that give lower yields. (S)- Octa base is one of the key starting raw materials used in our process and this easy, convenient and eco-friendly preparation (single step) is reported in this manuscript. This drug, Dextromethorphan is produced in large volumes annually (> 150 tons/year). Most reported synthetic procedures make use of huge amounts of volatile organic solvents which are hazardous for environment. This will be a major issue in the near future. To overcome this problem, we have tried using Ionic liquid as a solvent in the preparation and successfully arrived at best results, thereby decreasing the use of organic volatile solvents.

Keywords: Dextromethorphan, Morphine derivatives, Alkaloids, Formylation, Ionic liquid

Introduction

Dextromethorphan, a drug of the morphinan family, is having tranquilizing, dissociative, and restorative properties (especially at higher doses). It is a cough suppressant (ANTI-TUSSIVE) in several over-the-counter cold and cough medicines including generic labels and store brands, Benylin, Mucinex, Camydex 20 tablets, Robitussin, NyQuil, Vicks, Delsym, TheraFlu, Cheracol D, and others. It has also found plentiful other uses in medication, extending from analgesic effect to psychological submissions useful in the treatment of addiction. It is sold in syrup, capsule, and lozenge forms. In its unadulterated form, Dextromethorphan ensues as a white powder. Currently, Dextromethorphan is not registered in the Schedules of the United Nations 1961 Convention on Narcotic Drug [1].

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It’s IUPAC name is (+)-3-methoxy-17-methyl-9α, 13α, 14α-morphinan. It occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydro bromide salt is water-soluble up to 1.5g/100mL at 25 °C. It is usually accessible as the monohydrated hydro bromide salt. However, some newer extended-release formulations contain Dextromethorphan bound to an ion-exchange resin based on polystyrene sulfonic acid (Picture 1).

Picture 1: Chemical structure of Dextromethorphan Hydro bromide.

Mechanism of Action

Dextromethorphan is a synthetic compound and acts as a dissociative anesthetic when taken in higher doses. Its mechanism of action is via multiple effects, plus actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist [2]. Dextromethorphan and its major metabolite, Dextrorphan, also act as NMDA receptor antagonist at high doses, which produces effects similar to other dissociative anesthetics such as ketamine and phencyclidine [3]. The metabolic pathway continues from dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan (Figure 1) [4].

Figure 1: Explains the metabolic pathway of the drug Dextromethorphan.

In one of the reported processes for the preparation of morphinan alkaloids, racemic hydroxy N- methyl morphinan is used as a starting material, an optically inactive isomer and is treated with tartaric acid for resolution to obtain selective one isomer (+) of morphinan. (PATENT- US2676177 (Roche, 1954, CHprior. 1949)) (Scheme 1).

Scheme 1: This scheme explains the reported procedure that uses a racemic hydroxy N- methyl morphinan as a starting material along with the use of solvents.

In a similar procedure reported in PATENT- CN102977021 A, Method for preparation of Dextromethorphan hydro bromide By Cui, Dapeng et al From Faming Zhuanli Shenqing, 102977021, 20 Mar 2013, Raney Nickel as a reducing agent is replaced by KBH4, thus, reducing the cost. Also, resolution is done with R-ibuprofen for the first time. Another advantage is the use of AlCl3 is adopted to replace H3PO4 to cyclize. Overall, it is a low cost, moderate reaction conditions, easy in operation and suitable for industrial production (Scheme 2).

Further, in the search for better preparation methods, which is easier, lesser preparation steps, cost effective, and also using chemicals that are easy to handle and can provide higher yields as well as purity, it has been found that the critical step of Grewe’s cyclization is reported in a paper titled, ‘A Novel synthesis of substituted 1-benzyloctahydroisoquinolines by acid-catalyzed cyclization of N-[2-(Cyclohex-1-enyl]-N-styryl formamides’ [5] (Scheme 3).

Scheme 2: Explains another reported procedure, where alternate reagents like KBH4, R-ibuprofen and AlCl3 have been used to refine the existing method of preparation of Dextromethorphan.

Scheme 3: Explains a reported procedure involving the preparation of Dextromethorphan that involves Grewe`s cyclization.

Scheme 4: Explains a reported procedure of Dextromethorphan preparation, where formylation was done before the cyclization step to improve the yield.

According to this paper, no cyclization of enamide was observed with Lewis acid catalyst (AlCl3, AlEtCl2, TiCl4), Two equivalents of BF3-Et2O was used, and complete conversion was observed. In all cyclization reactions, a side product is formed that is more polar than the octa hydroisoquinolines and N-formyl octa hydroisoquinolines synthesized from N-formyl- 2-phenylethylamines and benzaldehyde. Also, reduction of N-formaldehyde to N-methylated was done using LiAlH4. While going through literature, it was found that formylation before cyclisation avoids ether cleavage as a side reaction and higher yields were obtained than without N-substitution or N-methylation. In this patent, purification/resolution was done using the formation of Brucine salt (US3634429 (Jan 11, 1972) Morphinan derivatives and preparation there of (Scheme 4).

Experimental and Results

All the above-mentioned processes involve the use of solvents. So, in the existent investigation, an endeavor is explored to develop an alternate process wherein use of solvents can be avoided in the synthesis of Dextromethorphan (Scheme 5).

Scheme 5: Explains a greener preparation of Dextromethorphan using an Ionic Liquid.

Preparation of Dextromethorphan Hydrobromide using 1-butyl-3-methyl imidazolium acetate (Ionic liquid) as a solvent

I-step:

a) Stage-IA: In a flask, charge 1-butyl-3-methyl imidazolium acetate under nitrogen atmosphere. Charge (S)-Octa base under nitrogen atmosphere. Cool if required under nitrogen atmosphere. Charge Sodium methoxide solution in methanol under nitrogen atmosphere. Charge Methyl formate. Raise the temperature of the reaction mass to little reflux by using hot water not more than 55oC. Stir and maintain the reaction mass till reaction complies (2 hours). Concentrate the reaction mass u/v (Capacity of vacuum pump should be > 700 mm/Hg) till almost no solvent distills. To the concentrated reaction mass, charge toluene under nitrogen atmosphere and water extraction is done. The extracted toluene layer was concentrated to give N-Formyl octa base and is used as such.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 1) and (Picture 2).

Table 1: s- singlet, m-multiplet, br-broad.

Picture 2:

b) Stage-IB: In another flask, charge Ortho phosphoric acid (~ 85.0 % w/w). Charge Toluene and Raise the temperature of the reaction mass. Reflux and maintain over Dean stark apparatus to remove water azeotropically. Cool the reaction mass under nitrogen atmosphere and Charge Phosphorus pentoxide under nitrogen atmosphere. Reaction is highly exothermic. Charge 1-butyl-3-methyl imidazolium acetate. Slowly add N-formyl octa base and Raise the temperature of the reaction mass under nitrogen atmosphere. Stir and maintain the reaction mass at 65-70oC under nitrogen atmosphere till reaction complies. Concentrate the reaction mass under vacuum to remove toluene. To the concentrated mass, charge ethyl acetate under nitrogen atmosphere and stir. In another flask, charge water, Cool. Charge ethyl acetate reaction mixture reaction mass in to chilled water. Stir, settle and separate the layers. Repeat for back extraction. Wash the organic layer with water again and then a wash of 7% sodium bicarbonate solution is given. Concentrate the organic layer u/v till almost no solvent distills. Degas the concentrate u/v to remove traces of solvents.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 2) and (Picture 3)

Table 2: s- singlet, m-multiplet, br-broad.

Picture 3:

c) Stage-IC: To the concentrate mass, charge 1-butyl- 3-methyl imidazolium acetate and methanol under nitrogen atmosphere. Stir and slowly add sodium hydroxide solution Pre- Cooled ~15oC (Prepare by using 109 g Sodium hydroxide dissolved in 200ml Water). Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~15 hours). Concentrate the reaction mass u/v. To the concentrate mass, charge toluene under nitrogen atmosphere and water workup is done. The extracted toluene layer was concentrated to give N-Nordextromethorphan (Stage-IC).

m/z (M+H+) - 258

NMR chemical shift values tabulated below (Table 3) and (Picture 4):

Table 3: s- Singlet, m-multiplet, br-broad.

Picture 4:

d) Stage-ID: To the mixture of1-butyl-3-methyl imidazolium acetate and N-Nordextromethorphan (Stage-IC), slowly add Formic acid solution (Prepare by using 32.1g Formic acid diluted with 5.7ml water). Charge Formaldehyde solution. Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~2 hours). After the reaction is complete, Charge water and cool the reaction mass if required and then slowly add sodium hydroxide solution Pre-cool (< 15 oC) (Prepared by using 28.0g Sodium hydroxide dissolved in 140ml water), extracted the product into toluene, again charge water, cool, and slowly add Hydrobromic acid. Raise the temperature of the reaction mass to 70-80 oC and Stir and maintain to get clear solution. The organic and aqueous layers separated. Cool the Aqueous layer under stirring to get precipitate and further cooled to 3-6 oC and wash with pre-chilled water. Dry the solid under vacuum, to get Dextromethorphan hydro bromide.

m/z (M+H+) - 272

NMR chemical shift values tabulated below (Table 4) and (Picture 5):

Table 4: s- Singlet, d- doublet, m-multiplet, br-broad.

Picture 5:

a) 1H-1H coupling constants.

Discussion

As of today, chemical manufacturing process of APIs in pharmaceutical industry is handicapped without the use of chemical solvents. However, it is a scientifically known fact that solvents are dangerously damaging chemical entities, mainly of the following reasons:

a) Volatile nature of solvents.

b) Storage and handling risks.

c) Usage requirements in large scale.

Apart from their handling risks to human beings, they also cause significant saturation in chemical pollution levels in the environment; there has been constant research going-on in academic field as well as industries to find their suitable alternative [6].

Ionic liquids are one such alternative that has been found useful to substitute the commonly used bench solvents. Other than their obvious “solvent” property that have been discussed in various publications [7-10], they have also been found to catalyze certain type of reactions in which they participate [11-13]. Moreover, their complete recovery from the reaction is an easy job when juxtaposed with their volatile solvent counterparts. For this reason, an ionic liquid can be re-cycled for multiple batches of reactions.

Another unique property of ionic liquids is that they can be “tailor-made” to suit specific reaction types by playing around with the cation and anion part of them. They are called as “task-specific ionic liquids”. These tailored [14] and specially synthesized ionic liquids have more scope of their application in a chemical reaction than just acting as a green solvent.

Conclusion

A simple, efficient, eco-friendly synthetic route is developed involving the single-step synthesis of Dextromethorphan Hydrobromide that is high on convenience and also a cost-effective procedure. This process is best suitable for the preparation of Dextromethorphan Hydrobromide and is scalable in plant. This synthetic route using an ionic liquid adapts a cleaner chemistry that assures both risk-free handling and reduced environmental pollution, when scaled-up.

Acknowledgement

Our group would like to thank the Department of Scientific and Industrial Research India, Dr. Hari Babu (COO Mylan), Sanjeev Sethi (Chief Scientific Officer Mylan Inc ); Dr Abhijit Deshmukh (Head of Global OSD Scientific Affairs); Dr Yasir Rawjee {Head-Global API (Active Pharmaceutical Ingredients)}, Dr Sureshbabu Jayachandra (Head of Chemical Research) Mr Manoj Pananchukunnath (Head of Global Injectables Scientific Affairs, Product Development) 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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Lupine Publishers | Preparation of Morphine Derivatives Using Ionic Liquids

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

Dextromethorphan, an anti tussive drug belongs to the morphinan family, and is mostly available in the market as a combination therapy. Most of the reported preparation procedures involve the use of racemic starting materials that give lower yields. (S)- Octa base is one of the key starting raw materials used in our process and this easy, convenient and eco-friendly preparation (single step) is reported in this manuscript. This drug, Dextromethorphan is produced in large volumes annually (> 150 tons/year). Most reported synthetic procedures make use of huge amounts of volatile organic solvents which are hazardous for environment. This will be a major issue in the near future. To overcome this problem, we have tried using Ionic liquid as a solvent in the preparation and successfully arrived at best results, thereby decreasing the use of organic volatile solvents.

Keywords: Dextromethorphan, Morphine derivatives, Alkaloids, Formylation, Ionic liquid

Introduction

Dextromethorphan, a drug of the morphinan family, is having tranquilizing, dissociative, and restorative properties (especially at higher doses). It is a cough suppressant (ANTI-TUSSIVE) in several over-the-counter cold and cough medicines including generic labels and store brands, Benylin, Mucinex, Camydex 20 tablets, Robitussin, NyQuil, Vicks, Delsym, TheraFlu, Cheracol D, and others. It has also found plentiful other uses in medication, extending from analgesic effect to psychological submissions useful in the treatment of addiction. It is sold in syrup, capsule, and lozenge forms. In its unadulterated form, Dextromethorphan ensues as a white powder. Currently, Dextromethorphan is not registered in the Schedules of the United Nations 1961 Convention on Narcotic Drug [1].

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It’s IUPAC name is (+)-3-methoxy-17-methyl-9α, 13α, 14α-morphinan. It occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydro bromide salt is water-soluble up to 1.5g/100mL at 25 °C. It is usually accessible as the monohydrated hydro bromide salt. However, some newer extended-release formulations contain Dextromethorphan bound to an ion-exchange resin based on polystyrene sulfonic acid (Picture 1).

Picture 1: Chemical structure of Dextromethorphan Hydro bromide.

Mechanism of Action

Dextromethorphan is a synthetic compound and acts as a dissociative anesthetic when taken in higher doses. Its mechanism of action is via multiple effects, plus actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist [2]. Dextromethorphan and its major metabolite, Dextrorphan, also act as NMDA receptor antagonist at high doses, which produces effects similar to other dissociative anesthetics such as ketamine and phencyclidine [3]. The metabolic pathway continues from dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan (Figure 1) [4].

Figure 1: Explains the metabolic pathway of the drug Dextromethorphan.

In one of the reported processes for the preparation of morphinan alkaloids, racemic hydroxy N- methyl morphinan is used as a starting material, an optically inactive isomer and is treated with tartaric acid for resolution to obtain selective one isomer (+) of morphinan. (PATENT- US2676177 (Roche, 1954, CHprior. 1949)) (Scheme 1).

Scheme 1: This scheme explains the reported procedure that uses a racemic hydroxy N- methyl morphinan as a starting material along with the use of solvents.

In a similar procedure reported in PATENT- CN102977021 A, Method for preparation of Dextromethorphan hydro bromide By Cui, Dapeng et al From Faming Zhuanli Shenqing, 102977021, 20 Mar 2013, Raney Nickel as a reducing agent is replaced by KBH4, thus, reducing the cost. Also, resolution is done with R-ibuprofen for the first time. Another advantage is the use of AlCl3 is adopted to replace H3PO4 to cyclize. Overall, it is a low cost, moderate reaction conditions, easy in operation and suitable for industrial production (Scheme 2).

Further, in the search for better preparation methods, which is easier, lesser preparation steps, cost effective, and also using chemicals that are easy to handle and can provide higher yields as well as purity, it has been found that the critical step of Grewe’s cyclization is reported in a paper titled, ‘A Novel synthesis of substituted 1-benzyloctahydroisoquinolines by acid-catalyzed cyclization of N-[2-(Cyclohex-1-enyl]-N-styryl formamides’ [5] (Scheme 3).

Scheme 2: Explains another reported procedure, where alternate reagents like KBH4, R-ibuprofen and AlCl3 have been used to refine the existing method of preparation of Dextromethorphan.

Scheme 3: Explains a reported procedure involving the preparation of Dextromethorphan that involves Grewe`s cyclization.

Scheme 4: Explains a reported procedure of Dextromethorphan preparation, where formylation was done before the cyclization step to improve the yield.

According to this paper, no cyclization of enamide was observed with Lewis acid catalyst (AlCl3, AlEtCl2, TiCl4), Two equivalents of BF3-Et2O was used, and complete conversion was observed. In all cyclization reactions, a side product is formed that is more polar than the octa hydroisoquinolines and N-formyl octa hydroisoquinolines synthesized from N-formyl- 2-phenylethylamines and benzaldehyde. Also, reduction of N-formaldehyde to N-methylated was done using LiAlH4. While going through literature, it was found that formylation before cyclisation avoids ether cleavage as a side reaction and higher yields were obtained than without N-substitution or N-methylation. In this patent, purification/resolution was done using the formation of Brucine salt (US3634429 (Jan 11, 1972) Morphinan derivatives and preparation there of (Scheme 4).

Experimental and Results

All the above-mentioned processes involve the use of solvents. So, in the existent investigation, an endeavor is explored to develop an alternate process wherein use of solvents can be avoided in the synthesis of Dextromethorphan (Scheme 5).

Scheme 5: Explains a greener preparation of Dextromethorphan using an Ionic Liquid.

Preparation of Dextromethorphan Hydrobromide using 1-butyl-3-methyl imidazolium acetate (Ionic liquid) as a solvent

I-step:

a) Stage-IA: In a flask, charge 1-butyl-3-methyl imidazolium acetate under nitrogen atmosphere. Charge (S)-Octa base under nitrogen atmosphere. Cool if required under nitrogen atmosphere. Charge Sodium methoxide solution in methanol under nitrogen atmosphere. Charge Methyl formate. Raise the temperature of the reaction mass to little reflux by using hot water not more than 55oC. Stir and maintain the reaction mass till reaction complies (2 hours). Concentrate the reaction mass u/v (Capacity of vacuum pump should be > 700 mm/Hg) till almost no solvent distills. To the concentrated reaction mass, charge toluene under nitrogen atmosphere and water extraction is done. The extracted toluene layer was concentrated to give N-Formyl octa base and is used as such.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 1) and (Picture 2).

Table 1: s- singlet, m-multiplet, br-broad.

Picture 2:

b) Stage-IB: In another flask, charge Ortho phosphoric acid (~ 85.0 % w/w). Charge Toluene and Raise the temperature of the reaction mass. Reflux and maintain over Dean stark apparatus to remove water azeotropically. Cool the reaction mass under nitrogen atmosphere and Charge Phosphorus pentoxide under nitrogen atmosphere. Reaction is highly exothermic. Charge 1-butyl-3-methyl imidazolium acetate. Slowly add N-formyl octa base and Raise the temperature of the reaction mass under nitrogen atmosphere. Stir and maintain the reaction mass at 65-70oC under nitrogen atmosphere till reaction complies. Concentrate the reaction mass under vacuum to remove toluene. To the concentrated mass, charge ethyl acetate under nitrogen atmosphere and stir. In another flask, charge water, Cool. Charge ethyl acetate reaction mixture reaction mass in to chilled water. Stir, settle and separate the layers. Repeat for back extraction. Wash the organic layer with water again and then a wash of 7% sodium bicarbonate solution is given. Concentrate the organic layer u/v till almost no solvent distills. Degas the concentrate u/v to remove traces of solvents.

m/z (M+H+) - 286

NMR chemical shift values tabulated below (Table 2) and (Picture 3)

Table 2: s- singlet, m-multiplet, br-broad.

Picture 3:

c) Stage-IC: To the concentrate mass, charge 1-butyl- 3-methyl imidazolium acetate and methanol under nitrogen atmosphere. Stir and slowly add sodium hydroxide solution Pre- Cooled ~15oC (Prepare by using 109 g Sodium hydroxide dissolved in 200ml Water). Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~15 hours). Concentrate the reaction mass u/v. To the concentrate mass, charge toluene under nitrogen atmosphere and water workup is done. The extracted toluene layer was concentrated to give N-Nordextromethorphan (Stage-IC).

m/z (M+H+) - 258

NMR chemical shift values tabulated below (Table 3) and (Picture 4):

Table 3: s- Singlet, m-multiplet, br-broad.

Picture 4:

d) Stage-ID: To the mixture of1-butyl-3-methyl imidazolium acetate and N-Nordextromethorphan (Stage-IC), slowly add Formic acid solution (Prepare by using 32.1g Formic acid diluted with 5.7ml water). Charge Formaldehyde solution. Raise the temperature of the reaction mass and Stir and maintain the reaction mass till reaction complies (~2 hours). After the reaction is complete, Charge water and cool the reaction mass if required and then slowly add sodium hydroxide solution Pre-cool (< 15 oC) (Prepared by using 28.0g Sodium hydroxide dissolved in 140ml water), extracted the product into toluene, again charge water, cool, and slowly add Hydrobromic acid. Raise the temperature of the reaction mass to 70-80 oC and Stir and maintain to get clear solution. The organic and aqueous layers separated. Cool the Aqueous layer under stirring to get precipitate and further cooled to 3-6 oC and wash with pre-chilled water. Dry the solid under vacuum, to get Dextromethorphan hydro bromide.

m/z (M+H+) - 272

NMR chemical shift values tabulated below (Table 4) and (Picture 5):

Table 4: s- Singlet, d- doublet, m-multiplet, br-broad.

Picture 5:

a) 1H-1H coupling constants.

Discussion

As of today, chemical manufacturing process of APIs in pharmaceutical industry is handicapped without the use of chemical solvents. However, it is a scientifically known fact that solvents are dangerously damaging chemical entities, mainly of the following reasons:

a) Volatile nature of solvents.

b) Storage and handling risks.

c) Usage requirements in large scale.

Apart from their handling risks to human beings, they also cause significant saturation in chemical pollution levels in the environment; there has been constant research going-on in academic field as well as industries to find their suitable alternative [6].

Ionic liquids are one such alternative that has been found useful to substitute the commonly used bench solvents. Other than their obvious “solvent” property that have been discussed in various publications [7-10], they have also been found to catalyze certain type of reactions in which they participate [11-13]. Moreover, their complete recovery from the reaction is an easy job when juxtaposed with their volatile solvent counterparts. For this reason, an ionic liquid can be re-cycled for multiple batches of reactions.

Another unique property of ionic liquids is that they can be “tailor-made” to suit specific reaction types by playing around with the cation and anion part of them. They are called as “task-specific ionic liquids”. These tailored [14] and specially synthesized ionic liquids have more scope of their application in a chemical reaction than just acting as a green solvent.

Conclusion

A simple, efficient, eco-friendly synthetic route is developed involving the single-step synthesis of Dextromethorphan Hydrobromide that is high on convenience and also a cost-effective procedure. This process is best suitable for the preparation of Dextromethorphan Hydrobromide and is scalable in plant. This synthetic route using an ionic liquid adapts a cleaner chemistry that assures both risk-free handling and reduced environmental pollution, when scaled-up.

Acknowledgement

Our group would like to thank the Department of Scientific and Industrial Research India, Dr. Hari Babu (COO Mylan), Sanjeev Sethi (Chief Scientific Officer Mylan Inc ); Dr Abhijit Deshmukh (Head of Global OSD Scientific Affairs); Dr Yasir Rawjee {Head-Global API (Active Pharmaceutical Ingredients)}, Dr Sureshbabu Jayachandra (Head of Chemical Research) Mr Manoj Pananchukunnath (Head of Global Injectables Scientific Affairs, Product Development) 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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Lupine Publishers | Chloride-Induced Highly Active Catalyst for Methyl Esterification of Alcohols

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

In this work, a series of active Au/NiOx catalysts were successful to prepare by tracing the concentrations of chloride in the re-dispersed aqueous solutions. By characterizations, we found that the appropriate amount of residual chloride in Au catalyst would induce Au nanoparticles (Au NPs) to locate on the edges of NiOx particles, which resulted in the active Au/NiOx-9 sample. Fine control of chloride in the aqueous solution provides a new perspective to push for addressing the controllable preparation of active heterogeneous catalysts.

Keywords: Au catalyst, Preparation, Chloride, Esterification

Introduction

In recent decades, Au catalysts have received growing attentions and been widely applied in many important research fields [1], since good performance of Au catalysts was discovered [2]. However, the controllable preparation of highly active heterogeneous catalysts is still a longstanding challenge till now, especially Au catalysts. Many efforts have been devoted to this problem. The active site, structure and the quantum size effect of Au catalyst [3], active oxygen species of the support [4], suitable reducible oxide supports [5],and so on, have been extensively studied. Additionally, catalyst precursors, bases, pH value, aging time, and calcinations temperature are also crucial conditions [2,6]. Nevertheless, the controllable preparation of highly active Au catalyst is still difficult to realize even strictly following all above conditions. Chloride (usually as Cl-) is generally regarded as a poison for Au catalyst, Because of strong interaction of chloride and Au. We realized the reproducible preparation of Au/Fe2O3 catalyst for CO oxidation [7]. It is meaningful to explore whether this method can be applied to other catalysts and reactions or not. In this work, Methyl esterification of alcohols was chosen as model reaction. The controllable preparation of highly active Au/ NiOx catalyst was realized by tracing the concentrations of chloride in the re-dispersed aqueous solutions.

Experimental Details

Au/NiOx catalyst preparation

20ml Ni(NO3)36H2O (0.011 M) and 1.05 ml HAuCl4 (0.24M) were mixed together and were drop wise added into 60 ml Na2CO3 solution (0.31M) under vigorous stirring in 3h. The turbid liquid was divided into four sections and separation by centrifugation. Each section of the recovered precipitate was re-dispersed in different amount of deionised water and ultrasonically washed for 1h. The chloride concentration in the re-dispersed aqueous solution of each section was determined by CHI660D electrochemical workstation. Then, the solid was separated by centrifugation, dried at 80o C for 3h and calcined at 350 oC for 0.5 h to produce the catalyst sample, which was denoted as Au/NiOx-X, in which X suggested the chloride concentration in ppm.

Catalyst activity test

1mmol benzyl alcohol, 30 mg catalyst and 2 ml methanol were added into a glass tube. And then it was exchanged with oxygen and reacted at 60o C (1 atom, O2 balloon). After reaction, it was cooled to room temperature. Biphenyl was used as internal standard and a certain amount of ethanol were added into the reaction mixture up to 10mL for quantitative analysis by GC-FID (Agilent 7890A).

Results and Discussion

The catalytic activities of 15 Au/NiOx samples, which were prepared from the re-dispersed aqueous solutions with chloride concentrations in the range of 2 to 108 ppm, for esterification of benzyl alcohol were studied. According to the results shown in Figure 1, catalytic activity of Au/NiOx varied with the changing of chloride concentration. The yields of methyl benzoate were lower than 21% if the catalysts were prepared from aqueous solutions containing >22ppm chloride. More active catalysts were produced when the chloride concentrations were going down. The Au/ NiOx catalysts with the highest catalytic activity were prepared from aqueous solutions containing 8-13ppm chloride, the yield of methyl benzoate of catalyst Au/NiOx-9 was >99%. Surprisingly, the catalysts turned less active again when the chloride concentrations were < 8ppm. Typically, the yield of methyl benzoate was 20% with catalyst Au/NiOx-3.

Figure 1: The yield of methyl benzoatevs the chlorine concentration of the aqueous solution from which the catalyst samples were prepared.

Figure 2: HR-TEM (left) images and size distributions (right) of Au/NiOx-22 (a), Au/NiOx-9 (c), and Au/NiOx- 3(e).

TEM measurement results of Au/NiOx are shown in Figure 2. Their TEM images were similar and seemed amorphous. For the sample of Au/NiOx-22, the lattice of gold could be observed and wrapped in NiOx particle. For active Au/NiOx-9, the most of Au NPs connected with the edges of NiOx particles or the junctions of several NiOx particles [8]. In consideration of the best catalytic performance of this sample, this observation strongly supported the former results about active site in Au catalyst, i.e. the interface between Au and iron oxide [3]. It suggested that the appropriate amount of chloride might act as the linkage between Au NPs and the edges of NiOx particles to gain the active Au catalyst, For Au/ NiOx-22 and Au/NiOx-3, too much or less chloride was presented, the interaction of Au NPs and NiOx like Au/NiOx-9 decreased significantly. Accordingly, the catalytic activity lost sharply. By metering more than 150Au NPs, the mean diameters of Au NPs in samples Au/NiOx-3, Au/NiOx-9 and Au/NiOx-22were 4.1, 3.8 and 6.6 nm with 1.91, 1.84 and 3.06 standard deviations. The size distributions of Au NPs in Au/NiOx-3 and Au/NiOx-9 samples were extremely similar. The marked difference of catalytic activities of these two catalysts did not come from the size effect of Au particles, but the contact way of Au NPs and NiOx supports.

At present, there is still not sufficient evidence to explain the real role of chloride in the formation of Au catalysts. However, according to the known evidence, we can make some reasonable conjectures. Firstly, as pH value of the mother aqueous solution rises, chlorine in chloroauric acid is substituted by the hydroxyl. Au-Cl bond breaks and then small Au NPs form. Finally, chloride is adsorbed on the support NiOx as well as Au NPs. Due to the stronger interaction of chlorideon the edges than on planes of NiOx crystallites, after the ultrasonication and washing operations, chloride located on the edges of NiOx crystallites remains. As shown in Figure 3, it is this kind of residual chloride that induces Au NPs to anchor on the edges of NiOx crystallites.

Figure 3: The simple scheme of Au/NiOx catalysts.

Conclusion

In summary, by tracing the chloride concentrations in the re-dispersed aqueous solution, we successfully prepared active Au/NiOx catalyst for catalytic methyl esterification of alcohols. If the chloride concentration was not in the range of 8-13ppm, the catalytic activity dropped dramatically. These results indicated that the presence of appropriate amounts of residual chloride was beneficial to obtain highly active heterogeneous catalysts. This work can offer a new perspective to realize the controllable preparation of active heterogeneous catalysts.

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Lupine Publishers | Palauamine and Olympiadane Nano Molecules Incorporation into the Nano Polymeric Matrix (NPM) by Immersion of the Nano Polymeric Modified Electrode (NPME) as Molecular Enzymes and Drug Targets for Human Cancer Cells, Tissues and Tumors Treatment under Synchrotron and Synchrocyclotron Radiations

 Lupine Publishers | Journal of Organic & Inorganic Chemical Sciences

Abbrevations: NPM: Nano Polymeric Matrix; NPME: Nano Polymeric Modified Electrode; CEMs: Chemical Modified Electrodes; MWCNTs: Multi–Walled Carbon Nanotubes; CPE: Carbon Paste Electrode

Editorial

In the current editorial, we study Palau’amine and Olympiadane Nano molecules (Figures 1 & 2) incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations. In this regard, the development of Chemical Modified Electrodes (CEMs) is at present an area of great interest. CEMs can be divided broadly into two main categories; namely, surface modified and bulk modified electrodes. Methods of surface modification include adsorption, covalent bonding, attachment of polymer Nano films, etc. Polymer Nano film coated electrodes can be differentiated from other modification methods such as adsorption and covalent bonding in that they usually involve multilayer as opposed to monolayer frequently encountered for the latter methods. The thicker Nano films imply more active sites which lead to larger analytical signals. This advantage coupled with other, their versatility and wide applicability, makes polymer Nano film modified electrodes particularly suitable for analytical applications [1–27].

Figure 1: Molecular structure of Palau’amine Nano molecules.

Figure 2: Molecular structure of Olympiadane Nano molecules.

Electrochemical polymerization offers the advantage of reproducible deposition in terms of Nano film thickness and loading, making the immobilization procedure of a metal–based electro catalyst very simple and reliable for Palau’ amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations. Also, it must be notice that the nature of working electrode substrate in electro preparation of polymeric Nano film is very important, because properties of polymeric Nano films depend on the working electrode anti–cancer Nano materials. The ease and fast preparation and of obtaining a new reproducible surface, the low residual current, porous surface and low cost of Multi–Walled Carbon Nanotubes (MWCNTs) paste are some advantages of Carbon Paste Electrode (CPE) over all other solid electrodes [28–92].

On the other hand, it has been shown that, macrocyclic complexes of Palau’amine and Olympiadane Nano molecules– encapsulating Carbon nanotubes are interest as modifying agents because in basic media Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes redox centers show high catalytic activity towards the oxidation of small organic anti-cancer Nano compounds. The high–valence species of Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes seem to act as strong oxidizing agents for low-electroactivity organic substrates. 1,2–Dioxetane (1,2– Dioxacyclobutane), 1,3–Dioxetane (1,3– Dioxacyclobutane), DMDM Hydantoin and Sulphobe as the anti–cancer organic intermediate products of methanol oxidation as well as formic acid, is important to investigate its electrochemical oxidation behavior in Palau’ amine and Olympiadane Nano molecules-encapsulating Carbon nanotubes incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations [93–110].

In this editorial, we decided to combine the above mentioned advantageous features for the aim of Palau’ amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes incorporation into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) as molecular enzymes and drug targets for human cancer cells, tissues and tumors treatment under synchrotron and synchrocyclotron radiations. Furthermore, in this editorial, we prepared poly Nano films by electropolymerization at the surface of Multi-Walled Carbon Nanotubes (MWCNTs) paste electrode. Then, Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes were incorporated into the Nano Polymeric Matrix (NPM) by immersion of the Nano Polymeric Modified Electrode (NPME) in a solution. The modifier layer of Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes at the electrode surface acts as a Nano catalyst for the treatment of human cancer cells, tissues and tumors under synchrotron and synchrocyclotron radiations. Suitability of this Palau’amine and Olympiadane Nano molecules–encapsulating Carbon nanotubes–modified polymeric Multi–Walled Carbon Nano tubes (MWCNTs) paste electrode toward the electrocatalytic treatment of human cancer cells, tissues and tumors under synchrotron and synchrocyclotron radiations in alkaline medium at ambient temperature was investigated [111– 153].

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Lupine Publishers | Heterobimetallic Aryloxides of Titanatranes with Aluminum Alkyls for Ring opening polymerization (ROP) of rac-Lactide

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

The titanatrane titanium complexes were treated with Aluminum Alkyls to prepare their bimetallic derivatives (1a-4a). The compounds were confirmed by means of NMR and elemental analysis. The complexes were used as catalysts for ring opening polymerization of racemic lactide. The complexes exhibit high activity and selectivity in the polymerization process.

Abbrevations: ROP: Ring Opening Polymerization; LA: Rac-lactide

Introduction

Olefin polymerization catalysis [1a-1b] continues to be an area of considerable importance to both the academic and industrial communities, and a wide range of reports are appearing on the efficient catalyst designs and application in various catalytic systems. Recently, the work on bimetallic complexes and in particularly bimetallic oxides is gaining considerable attention due to the "cooperativity" or "communication" between neighboring repeating units [2a-2d]. Since heterometallic alkoxides are potential molecular precursors of multicomponent oxides, they are thus of interest for applications in catalysis as well as in material science. Heterometallic alkoxide derivatives have been postulated to act as catalysts in Ziegler-Natta polymerization [3a,3b] or olefin metathesis reactions, [3c] and exhibit high activity and produce polymers with different microstructure. These heterometallic complexes were also found active in nitrogen activation," but detailed characterization is lacking [4].

The main disadvantage of mononuclear catalysts is the need of large amount of MAO or expensive fluorinated borate activators to obtain adequate polymerization activity, which causes concern over the high cost of metallocene catalysts and the high ash content (Al₂O₃) of the product polymers. Consequently, there is a great need to develop new catalyst systems that can provide high catalytic activity with no need for a large amount of expensive cocatalysts. We were thus interested in designing the catalysts which can exhibit high activity in the polymerization without or with very less amount of cocatalysts. For this, we used atrane ligands which have a nitrogen atom that facilitates coordination in a chelate fashion when necessary by providing the metal with additional electronic density [5a-e]. Although there have been many reports on the complexes based on atrane ligands, application of these complexes in polymerization reactions are very limited [6a-c].

We recently reported that heterobimetallic complexes of titanium iso-propoxide and aluminum alkyl containing bis (aryloxo) ethanolamine ligand were effective as catalysts precursor for ethylene polymerization even in the absence of cocatalysts [7]. We then extended the chemistry to tris (aryloxo) amine based ligands [8]. Furthermore, we reported that titanatranes bearing terminal substituted aryloxo ligands exhibit the highest activity in ethylene polymerization [9]. To the best of our knowledge these complexes are the best catalysts for ethylene polymerization among all the titanatranes reported so far. We became interested in isolating the bimetallic complexes of titatnium bearing aryloxo terminal ligands with aluminum alkyls to understand the plausible mechanism of polymerization process and the effect of substituents on the nature of heterobimetallic complexes. In this contribution we report the isolation, structural characterization of the titanatranes bearing aryloxo terminal ligand with the aluminum alkyls and their catalytic activity in ethylene and Ring Opening Polymerization (ROP) of rac- lactide.

Results and Discussion

The titanatranes and their bimetallic derivatives are prepared as reported earlier [8]. The following complexes were confirmed by NMR and elemental analysis. The pure crystalline products were used for the polymerization process (Figure 1). There has been considerable attention on the study of ring-opening polymerization (ROP) of cyclic esters such as rac-lactide (LA) with metal complexes for the past few decades [10a-b]. Various types of metal alkoxides such as tin [11a-e], aluminum, zinc , magnesium, iron [12a-b], lanthanide [13a-c], and lithium [14] organometallic complexes have been found to be active LA polymerization catalysts, and many afford materials with controlled molecular weights and narrow molecular weight distributions. Despite the fact that some excellent initiators have been reported for the polymerization of LA, the search for new catalysts that generate well-defined polylactides remains of keen interest. The roles of the structure of metal alkoxide complexes in determining molecular weights and molecular weight distributions, as well as the polymerization pathway, are significant current research issues.

Figure 1: Bulk Polymerization of rac-Lactide (rac-LA).

Recently, Verkade et al. [15a-b] reported that several titanium alkoxides showed reasonably good catalytic activity in the bulk homopolymerization of rac-LA at 130 °C. Harada et al. [16] also reported the living polymerization of LA by a Ti chloride complex, whose chloride apparently plays the same role as an alkoxide. We thus believed it would be interesting to test heterobimetallic titanium catalysts and compare the activity and control of the molecular and physical properties of the PLA produced by mononuclear and binuclear complexes with well-defined ligand environments. Here, we describe discrete heterobimetallic titanium alkoxide/aryloxide complexes and their bimetallic derivatives for the study of the ROP of LA under bulk polymerization conditions. We also demonstrate the difference in monometallic and bimetallic catalysts towards the ROP of rac-Lactide.

Preliminary results on the use of heterobimetallic catalysts for the bulk polymerization of rac-LA are summarized for 1a-4a, are presented in Table 1. Polymerizations were performed at 130 °C with the [LA]/[Ti] ratio fixed at 300. This table reveals that all the titanium compounds catalyze LA polymerization. Moreover, it appears that chelation aluminium methyl to the tripodal tetradentate ligand significantly decreases the polydispersity index and polymer yield. However, some transesterification probably occurred during the polymerization reaction since the polydispersity indices of both PLA products were somewhat higher than expected for a controlled polymerization. The bimetallic complexes exhibit high activity and produce polylactide with high molecular weight and lower polydispersity compare to their mononuclear precursors [15].

Table 1: Ring opening polymerization (ROP) of rac -Lactide Data for Heterobimetallic complexes.

LA (2.027g) LA/Ti = 300, polymerization temperature = 130 °C, time = 20min.

The weight average molecular weight (M ), the number average molecular weight (M ), and the polydispersity index (PDI) M /M ) were determined by GPC.

Figure 2:

The preference for heterotacticity in our poly (rac-LA) are comparatively stronger for bimetallic complexes than their mononuclear precursor compounds and are similar to the previous reports by Kasperczyk et al. [17]. This may be due to the initiating alkoxide/aryloxide group which dissociate relatively easily from the titanium in bimetallic complexes than their monometallic precursors in the early stage of polymerization so that it can be utilized to initiate LA polymerization and provide a means of controlling the molecular weight by functioning as an end group. It appears that the initiating group is the highly bulky i-Pr alkoxide (in 1 and 3) or i-Pr-phenolate (2 and 4) group in monometallic, similar to the observation made by Verkade et al. [15] But the scenario in bimetallic complexes is complicated. We assume that the initiating group may be similar to the mononuclear complexes, although the insertion of lactide into Ti-O of the aryloxo arm or alkoxo arm cannot be ruled out (Figure 2) and (Table 1).

Concluding remarks

The titanatrane titanium complexes and their bimetallic derivatives exhibit high activity and selectivity in bulk polymerization of rac-Lactide. Bimetallic complexes (Ti-Al) exhibit higher activity and produces high molecular weight compared to their monometallic counterpart [5b]. This may be due to the better electronic and steric environment in bimetallic complexes. The polylactide obtained in this process is heterotactic in nature. Further investigations of mechanism in this process are on in our laboratory.

Experimental Section

General Procedures. All experimental manipulations were carried out under an atmosphere of dry nitrogen using standard Schlenk techniques or using a Vacuum Atmospheres drybox unless otherwise specified. All chemicals used were of reagent grades and were purified by standard purification procedures. Toluene (anhydrous grade, Kanto Kagaku Co., Ltd.) and n-octane (anhydrous grade, Aldrich) for polymerization were stored in a bottle in the drybox in the presence of molecular sieves (a mixture of 3A 1/16, 4A 1/8, and 13X 1/16). Polymerization grade ethylene (purity > 99.9%, Sumitomo Seika Co. Ltd.) was used as received. Toluene and AlMe3 from the commercially available methylaluminoxane [PMAO-S, 9.5wt% (Al) toluene solution, Tosoh Finechem Co.] were removed under reduced pressure (at ca. 50 °C for removing toluene and AlMe3 and then heated at >100 °C for 1 h for completion) in the drybox to give white solids. Bis (2-hydroxy-3,5-dimethylbenzyl) ethanolamine and tris(2-hydroxy-3,5-di-tert-butylbenzyl)amine were prepared according to a published procedure [18]. The titanatranes containing phenoxy terminal ligands Ti(O-2,6- iPr2C6H3){(O-2,4-Me2C6H2-6-CH2)2(OCH2CH2)N} and Ti(O-2,6- iPr2C6H3) [(O-2,4-Me2C6H2-6-CH2)3N] were prepared according to the previous report [9].

Molecular weights and molecular weight distributions for polyethylene were measured by gel permeation chromatography (Tosoh HLC- 8121GPC/HT) with a polystyrene gel column (TSK gel GMHHR-H HT x 2, 30cm *7.8mmΦ, ranging from <102 to <2.8x108 MW) at 140 °C using o-dichlorobenzene containing 0.05 w/v % 2,6-di-tert-butyl-p-cresol as eluent. The molecular weight was calculated by a standard procedure based on the calibration with standard polystyrene samples. All 1H and 13C NMR spectra were recorded on a JEOL JNMLA 400 spectrometer (399.65MHz for 1H, 100.626MHz for 13C). All deuterated NMR solvents were stored over molecular sieves under a nitrogen atmosphere in the drybox, and all chemical shifts are given in ppm and referenced to SiMe4 (TMS). All spectra were obtained in the solvent indicated at 25 °C unless otherwise specified. Elemental analyses were performed by using PE2400II Series (Perkin-Elmer Co.) [19].

Procedure for rac-Lactide Polymerization, LA bulk polymerizations were carried out by charging a stirring bar, 2.00g of LA, and then the appropriate amount of catalyst precursor to a 10ml Schlenk flask. The flask was then immersed in an oil bath at 130 °C, and after the appropriate time, the reaction was terminated by the addition of 5ml of methanol. The precipitated polymers were dissolved in a minimum amount of methylene chloride, and then, excess methanol was added. The resulting reprecipitated polymers were collected, washed with 50ml of methanol, and dried in vacuo at 50 °C for 12h [20a-b].

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Lupine Publishers | 3D Printing of Pharmaceutical Drug Delivery Systems

 Lupine Publishers | Journal of Organic and Inorganic Chemical Sciences

Abstract

Three-dimensional printing (3DP) enables the development of diverse geometries through computer aided design using different techniques and materials for desired applications such as pharmaceutical drug delivery medicine. The FDA approval (2015) of printed-medicine opens up an unprecedented opportunity for the discovery of new compounds and technologies for the pharmaceutical industry development. This report shows some advantages, limitations, challenges and perspectives in concerning to 3DP of pharmaceutical grade formulations and polymers used for drug delivery systems.

Introduction

Drug delivery refers to approaches, systems, technologies and formulations for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect. The concept of drug delivery has greatly evolved over the years from immediate-release oral dosage forms to targeted-release drug delivery systems. Indeed, the necessity of controlling the drug release profile to modulate the absorption, the distribution, the metabolization and the elimination of the drug rapidly appeared as a key factor for improving product efficacy and safety as well as to increase the compliance of the patients [1]. In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer [2].

Three dimensional printing (3DP) technology is a novel technique for rapid prototyping, which constructs solid objects by deposition of several layers in sequence. The introduction and application of 3D printing have promoted enormous innovations in many diverse fields, including aerospace industry, architecture, tissue engineer, biomedical research and pharmacy. It seems that 3D printing technology will lead a new epoch of the next industrial revolution based on its versatility and diversity. Along with development and progress in science and technology, the 3D printing technology gets mature enough so that anyone can apply it with open-source software at a relative lower material cost [3]. The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and it's potential yet to be fully explored [4].

3DP is gaining increasing attention in pharmaceutical formulation development as an effective strategy to overcome some challenges of conventional pharmaceutical unit operations. For instance, the conventional manufacturing unit operation involving milling, mixing, granulation and compression can result in disparate qualities of the final products with respect to drug loading, drug release, drug stability and pharmaceutical dosage form stability [5,6]. 3D printing technology has enabled unprecedented flexibility in the design and manufacturing of complex objects, which can be utilized in personalized and programmable medicine [7]. In this report are shown some advantages, limitations, challenges and perspectives of 3D printing in the elaboration of drug delivery systems.

Advantages and Limitations

Various techniques for 3D printing, such as fused deposition modeling (FDM), binder deposition, inkjet printing, material jetting, powder bed fusion, photopolymerization, pen-based 3D printing and molding, have been reported in the literature [8,9]. Fused Deposition Modeling (FDM) 3D printing has been recently attracted increasing research efforts towards the production of personalized solid oral formulations. However, commercially available FDM printers are extremely limited with regards to the materials that can be processed to few types of thermoplastic polymers, which often may not be pharmaceutically approved materials nor ideal for optimizing dosage form performance of poor soluble compounds [10]. Such a technique holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation. Challenges in this field are mainly related to the paucity of adequate filaments composed of pharmaceutical grade materials, which are needed for feeding the FDM equipment [11] (Figure 1).

Figure 1: Schematic view of the different 3DP techniques used to fabricate drug delivery systems.

Source [12] From the many types of 3DP available, stereolithographic (SLA) printing offers the unique advantage of being able to fabricate objects by cross-linking resins to form networked polymer matrices. Because water can be entrapped in these matrices, it is possible in principle to fabricate pre-wetted, drug-loaded hydrogels and devices [13].

Table 1: Current 3DP technologies and pharmaceutical formulations for drug delivery.

More information in concerning to these technologies and pharmacology is present in the studies of Jassim-Jaboori & Oyewumi (14), Konta et al. [15], and Mauvi et al. [16].

Challenges and Perspectives

The technological advancements in the pharmaceutical field are constantly improving and provide various possibilities for meeting the needs of personalized drug therapy. The three-dimensional (3D) printing technology has endless potential in the fabrication of patient-specific drug delivery devices (DDD) and dosage forms as the technological development is progressing. Moreover, the rapidly evolving research on 3D printed DDD has enabled.com to determine several challenges related to the manufacturing and marketing of personalized drug delivery systems. The 3D printing has enabled the fabrication of prototypes of DDD with varying complexity and shows that customization of drug products is possible. There is potential to improve patient-specific drug therapies of the future using printing technologies. The technological advancements, new scientific concepts, interdisciplinary work and defined regulatory guidelines will continue to support and strengthen the prospects of 3D printing as an option in the manufacture of medical products [17]. Three-dimensional printing (3DP) is a unique prototyping technology that has advanced over the past 35 years and has the great potential to revolutionize the field of drug delivery with its inherent advantages of customizability and the ability to fabricate complex solid dosage forms with high accuracy and precision. 3DP can fabricate solid dosage forms with variable densities and diffusivities, complex internal geometries, multiple drugs and excipients. 3DP can successfully address the issues relating to the drug delivery of poorly water-soluble drugs, peptides, potent drugs and the release of multi-drugs, etc. However, there are some problems that restrict the applications of 3DP in commercial market, such as the selections of suitable binders, excipients and the pharmaco-technical properties of final products. Further advancement in process performance is required to overcome these issues where 3DP technology can be successfully combined with novel drug delivery system (NDDS) [18].

3D printing encompasses a range of differing techniques, each involving advantages and open issues. Particularly, solidification of powder, extrusion, and stereo lithography have been applied to the manufacturing of drug products. The main challenge to their exploitation for personalized pharmacologic therapy is likely to be related to the regulatory issues involved and to implementation of production models that may allow to efficiently turn the therapeutic needs of individual patients into small batches of appropriate drug products meeting preset quality requirements [19].

Three-dimensional printing has become a useful and potential tool for the pharmaceutical sector, leading to personalized medicine focused on the patients' needs. It offers numerous advantages, such as increasing the cost efficiency and the manufacturing speed, since a rapid prototyping (RP) can be done in a matter of minutes. However, there is still a significant barrier to ensure that 3D printed medicines have the same efficacy, safety, and stability as the pharmaceuticals conventionally manufactured by the Pharmaceutical Industry. Regarding the establishment of guidelines, laws, quality systems and safety of use and consumption of 3D printed medicines, it is a great challenge for the regulatory authorities entailing great obstacles, given the traditional requirements by the pharmaceutical sector [13].

The use of various types of printing technologies offer potential solutions for personalized medicine and tailored dosage forms to meet the needs of individual treatments of the future. Many types of scenario for printed dosage form exist and the concepts include, on the simplest level, accurately deposited doses of drug substances. In addition, computer design allows endless opportunities to create suitable geometries with tailored functionality and different levels of complexity to control the release properties of one or multiple drug substances. It will take some time to convert these technological developments in printing to better treatments for patients, because challenges exist. However, printing technologies are developing fast and have the potential to allow the use of versatile materials to manufacture sophisticated drug-delivery systems and bio functional constructs for personalized treatments [20].

3D printing technology can handle complex internal structure such as internal walls, hollow channels, porosity, multiple material regions and multiple drug distributions. This is a feature traditional pharmaceutical manufacturing processes do not share, which ensures feasibility of realizing rapid release, sustained release, controlled release, multiple drug delivery system and personalized medicine based on structure design [21]. Indeed, drug delivery from 3-dimensional (3D) structures is a rapidly growing area of research. It is essential to achieve structures wherein drug stability is ensured, the drug loading capacity is appropriate and the desired controlled release profile can be attained. Attention must also be paid to the development of appropriate fabrication machinery that allows 3D drug delivery systems (DDS) to be produced in a simple, reliable and reproducible manner [22].

Findings

It is evidenced that through its versatility, speed of production and precision, the use of three-dimensional printing for the elaboration and distribution of controlled drugs plays a key role in the current pharmaceutical industry, considering that drugs can be designed according to the patient's need. The fused deposition modeling (FDM) technique and hot melt extrusion (HME) of filaments for 3DP still excels in relation to the other printing techniques, such as binder deposition, inkjet printing, material jetting, powder bed fusion, photopolymerization, pen-based 3D, printing and molding have been gaining more and more space. The use of3DP in pharmaceutical formulation development is an effective strategy to overcome challenges of conventional pharmaceutical unit operations, since the conventional manufacturing operation can result in disparate qualities of the final products with respect to drug loading, drug release, drug stability and pharmaceutical dosage form stability. 3DP offers significant potential benefits in the field of drug delivery and pharmaceutical/medical device manufacture.

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