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OLANZEPINE VISITED PART 2/3

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PART 1…..https://newdrugapprovals.org/2015/04/08/olanzepine/

PART 2….https://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-22/

PART 3…….https://newdrugapprovals.org/2015/04/09/olanzepine-visited-part-33/

WATCHOUT………..

 

…………………….

PATENT

 http://www.google.com/patents/US7459449

Olanzapine is a pharmaceutically active compound that can be represented by formula (1).

Figure US07459449-20081202-C00001

It was disclosed in EP 454436 and corresponding U.S. Pat. No. 5,229,382 as a useful antipsychotic agent. Olanzapine acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. In commercially available final forms, the active substance is marketed as a free base, which is a white to yellow crystalline solid that is insoluble in water; i.e., solubility at pH 6.8=0.02 mg/ml.

The olanzapine base is known to exist in various crystalline modifications and in various hydrated forms that are generally stable at ambient conditions; see for example EP 733635 and corresponding U.S. Pat. No. 5,736,541; WO 98-11893; and EP 831098. Having so many different forms is considered to be a disadvantage as repeated production of olanzapine substance may give rise to unpredictable amounts of the respective modifications in the product, which in turn can influence the properties of the product such as in tabletting and/or releasing of the active from the tablets after ingestion.

WO 99-16313 discloses olanzapine pamoate as a pharmaceutical agent. It is a compound that is also insoluble in water and is useful particularly in intramuscular depot forms. However, like the free base, the pamoate salt exists in several forms including hydrates, solvates, and in different counter ion ratios.

WO 03-007912 discloses an amorphous lyophilized olanzapine in a reconstitutable parenteral formulation. The olanzapine is “intimately mixed” with a stabilizer and a solubilizer. The stabilizer is preferably lactose and the solubilizer includes organic acids and most preferably tartaric acid. The composition is formed by lyophilizing, i.e. a type of freeze drying, a solution of olanzapine, the stabilizer and the solubilizer to form the intimate mixture. The resulting lyophilized amorphous product can be reconstituted with parenteral diluents to make an injectable composition. Whether the tartaric acid salt of olanzapine is present in the lyophilized product is unclear.

For instance, the “des-methyl olanzapine” (2) may be methylated by formic acid/formaldehyde (Chinese Journal of Pharmaceuticals 2001, 32, 391-393) to form an olanzapine reaction mixture.

Figure US07459449-20081202-C00002

Similarly, the “des-piperazine olanzapine” (3) can be treated with N-methylpiperazine in DMSO under conditions of olanzapine formation to produce a reaction mixture containing olanzapine.

Figure US07459449-20081202-C00003

In a third process, the “formyl-olanzapine” (4) is reduced by a reducing agent, for instance by a borohydride agent (WO 2004/000847) or by hydrogen under the presence of a hydrogenation catalyst.

Figure US07459449-20081202-C00004

The starting compounds (2), (3), and (4) are known compounds and may be obtained by procedures known in the art.

EXAMPLE 16A

Olanzapine Benzoate by Methylation of Desmethyl Olanzapine

Figure US07459449-20081202-C00005

In a 100 ml flask, equipped with a magnetic stirrer, 0.5 g desmethyl olanzapine was dissolved in 5 ml DMSO. Then, 0.142 g formic acid (37% in water) and 0.082 g formic acid (98%) were added and the resulting mixture was heated at 80° C. for 2 hours. After cooling to room temperature, 20 ml ethyl acetate and 20 ml water were added. The organic layer was washed with 2*20 ml water and 20 ml saturated aqueous NaCl, dried (Na2SO4) and concentrated at reduced pressure to a volume of about 10 ml. Then, 0.200 g benzoic acid dissolved in 2 ml ethyl acetate was added dropwise to the crude olanzapine solution. An off-white/yellow solid formed which was isolated by filtration and dried over weekend at 40° C. in vacuo. Isolated yield: 0.58 gram (80%). 1H-NMR: expected compound; trace of ethyl acetate present.

EXAMPLE 16B

Synthesis of Olanzapine and Isolation of Olanzapine as the Benzoate Salt

Figure US07459449-20081202-C00006

In a 250 ml flask, equipped with a magnetic stirrer, 4.3 g of N-desmethylpiperazine-olanzapine was refluxed in a mixture of 15 ml N-methylpiperazine, 20 ml DMSO, and 20 ml toluene under a nitrogen atmosphere for 20 hours. The mixture was cooled and 50 ml water was added. The aqueous layer was extracted three times with 150 ml ethyl acetate and the combined organic layers were washed 3 times with 100 ml water and once with 100 ml aqueous saturated sodium chloride. After drying over Na2SO4, the organic layer was concentrated to about 100 ml and 1.6 g benzoic acid was added. After a few minutes, a yellow solid was formed. Stirring was continued at 4° C. for 1 hour. The solid material was isolated by filtration, washed with 5 ml ethyl acetate and 10 ml diethyl ether, and dried overnight at 40° C. in vacuum. Isolated yield: 4.61 g (80%; based on benzoic acid).

EXAMPLE 16C

Synthesis of Olanzapine and Isolation of Olanzapine as the Benzoate Salt

Figure US07459449-20081202-C00007

In a 2000 ml flask, 50 g of desmethyl olanzapine was dissolved in 450 ml of DMSO. Then, 13.04 g of formaldehyde (37% in water) and 7.59 g of formic acid (98%) were added and the resulting mixture was heated at 80° C. for 2 hours. The crude reaction mixture was poured into a mixture of 1000 ml of ethyl acetate and 1000 ml of ice-cooled water. The aqueous layer was separated and extracted with 2×500 ml of ethyl acetate. The combined organic layers were washed with 3×500 ml of water and 500 ml of saturated aqueous NaCl, dried (Na2SO4) and concentrated at reduced pressure to a volume of about 1000 ml. To the warm solution, 20.4 g of benzoic acid was added in one portion under stirring. An off-white/yellow solid was formed. Stirring was continued overnight at room temperature and subsequently for 2 hours at 4 C. The yellow solid was isolated by filtration, washed with 30 ml of cold ethyl acetate and 100 ml of diethyl ether and dried overnight at 60° C. in vacuo. Isolated yield: 60.25 g. Assay (HPLC): 99.1%.

EXAMPLE 16D

Synthesis of Olanzapine and Isolation of Olanzapine as the Benzoate Salt

Figure US07459449-20081202-C00008

In a 3000 ml flask, 86 g of desmethylpiperazine-olanzapine hydrochloride was refluxed in a mixture of 300 ml of N-methylpiperazine, 400 ml of DMSO, and 400 ml of toluene under a nitrogen atmosphere for 5 hours. The mixture was cooled to 50° C. and poured into a mixture of 2000 ml of ethyl acetate and 2000 ml of ice-cooled water. The aqueous layer was extracted with 2×500 ml of ethyl acetate and the combined organic layers were washed with 3×500 ml of water and with 500 ml of aqueous saturated sodium chloride. After drying over Na2SO4, the organic layer was concentrated to about 1500 ml and 39.6 g of benzoic acid was added in one portion. After a few minutes, a yellowish solid was formed. Stirring was continued overnight at room temperature. The solid material was isolated by filtration, washed with 50 ml of ethyl acetate and 200 ml of diethyl ether, and dried overnight at 60° C. in vacuum. Yield: 86.35 gram.

EXAMPLE 16E

Olanzapine Benzoate from Formyl Olanzapine

Figure US07459449-20081202-C00009

In a 250 ml flask, 3.0 g of N-formyl olanzapine precursor (compound (4)) was suspended in 45 ml of dry toluene and cooled to 0C. Under nitrogen atmosphere, 5.4 ml of Red-Al™ solution (70 wt % solution of sodium dihydrido-bis(2-methoxyethoxy) aluminate in toluene) was added dropwise under stirring. The resulting mixture was allowed to warm up to room temperature. Then 5.0 ml of Red-Al solution was added dropwise at this temperature. After stirring for 5 hours at room temperature, the reaction mixture was poured into 100 ml of water and immediately 100 ml of ethyl acetate was added. The mixture was filtered over a P3-filter to remove insoluble material. The biphasic filtrate was allowed to stand for separating the layers and the aqueous layer was removed and washed with 2×50 ml of ethyl acetate. The combined organic layers were washed with 2×50 ml of water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a volume of about 50-60 ml. Then, 1.12 g of benzoic acid was added in one portion and the resulting mixture was stirred at 4° C. for 4 hours. The formed solid was isolated by filtration, washed with 5 ml of cold ethyl acetate and 10 ml of cold diethyl ether, and dried overnight at 40 C under vacuum. Yield: 2.75 gram, purity (HPLC): 94.8%.

………………

PATENT

http://www.google.com/patents/WO2003101997A1?cl=en

EXAMPLE 1 ULTRA-PURE OLANZAPINE FORM I

Figure imgf000004_0001

A three necked flask, fitted with a nitrogen gas inlet and a water condenser with calcium chloride guard tube, is charged with 4-amino-2-methyl-10H-theino[2,3-b][1 ,5] benzodiazepine HCI (5.0 g, 0.0188 mol), 1-methylpiperazine (13.0 mL, 0.11 mol, 99.0%, Aldrich Chemicals, USA) and anhydrous dimethyl sulfoxide (30.0 mL, Aldrich Chemicals, USA, water< 0.1%). The reaction mixture is stirred at 112-115°C (oil bath temperature 115°C) for 16 hours under continuous flow of nitrogen to drive away the ammonia gas generated during the reaction. The reaction is monitored by HPLC and it is found that within 16 hours 97% product is formed. The reaction mixture is cooled to room temperature (24- 25°C) and added dropwise to a mixture of dichloromethane.water-methanol (190:190:15, 395 mL). After addition, the reaction mixture is stirred for 30 minutes at room temperature. The resulting mixture is yellowish hazy with a dark brown organic layer settled at the bottom of the flask. The dark brown colored dichloromethane layer is separated from the aqueous hazy phase.

After separating the organic layer, the aqueous hazy phase is again extracted with dichloromethane (1×100.0 mL). The combined dichloromethane phases (total volume 290.0 mL) are extracted twice with 50 % aqueous acetic acid solution (1×100 mL, 1×75.0 mL). A dark orange color acetic acid layer is separated. The pH of the acetic acid solution is found to be around 3.0-3.5 when tested by litmus paper. Combined aqueous acetic acid solution is basified, to pH 7.5-8.5, using 40% aqueous sodium hydroxide solution under cold conditions (0-10°C). After attaining the desired pH of the solution, 200 mL dichloromethane is added and stirred. The content is transferred to a separating funnel and is vigorously shaken. The dichloromethane layer is separated and the aqueous phase is again extracted with dichloromethane (1×75.0 mL). The combined dichloromethane extracts are washed with cold saturated sodium chloride solution (1×30.0 mL) and dried over anhydrous sodium sulfate. Removal of solvent on a rotary evaporator with a water bath temperature of 45°C, gives a dark orange brown viscous liquid. To this viscous liquid, 80-85.0 mL dry toluene is added.

The toluene containing crude olanzapine is transferred into a dry 250 mL single necked round bottom flask. Methanolic sodium hydroxide solution (0.32 g sodium hydroxide dissolved in 3.0-4.0 mL methanol by sonication) is added and the mixture is heated in an oil bath at 60°C for 2 hours. After the stipulated time, 20-25 % of the total volume of solvent is evaporated on a rotary evaporator, with a 55-60°C water bath, to ensure the complete removal of dichloromethane and trace amounts of water, resulting in a final volume of between 55-60 mL. The hot solution is removed from the water bath and cooled in an ice bath with stirring. Within 2-3 minutes, the solution is quickly seeded with previously prepared ultra pure olanzapine Form I, as determined by X-Ray and IR, with stirring. Stirring is continued for 40-45 minutes. The yellowish solid obtained in the solution is filtered off, washed with 1.5-2.0 mL dichloromethane and dried on a vacuum pump for 50-60 minutes to give 4.85 g ( 82.4 % yield) of olanzapine Form I. The solid obtained is crushed to a fine powder and air dried to remove traces of dichloromethane. Karl Fisher analysis indicates 5000-8000 ppm water content. The material is dried in an oven at 65°C for 1.5-2.0 hours and analyzed for water (670-860 ppm water). The weight of the title product is 4.80 g (82 % yield), HPLC purity = 99.83%, polymorphic purity is 100% as no detectable polymorph II is observed by X-ray and IR, as shown in Example 3.

The HPLC conditions are as follows: Column: SymmetryC18 , 4.6 x 250 mm λmax 254 nm

Flowrate : 1.0 mL/min. Run Time: 70 minutes

The buffer comprises 5.4 g potassium phosphate; 0.5 g heptanesulfonic acid sodium salt and 0.5 g 1-octanesulfonic acid sodium salt dissolved in 500 mL Dl water and adjusted the pH to 2.6 using cone, phosphoric acid. The mobile phase was 500 mL buffer/300 mL acetonitrile/200 mL methanol. The final pH of the mobile phase is about 3.6. The concentration of the standard is 100μg/mL; the injection volume is 15 μl; and RT = 4.6—4.7 min.

EXAMPLE 2 RECRYSTALLIZATION

From the dried yellowish solid prepared according to Example 1 , 2.0 g (0.0064 mol) is transferred into a single necked round bottom flask provided with a magnetic stirrer. To the solid, 40.0 mL dry toluene and methanolic sodium hydroxide solution (0.052 g sodium hydroxide pellets dissolved in 2.0 L methanol by sonication) are added. To this mixture 3.5-4.0 mL dichloromethane is added.

The mixture is heated for 5-10 minutes in an oil-bath at 60-65°C until a clear solution is obtained. After heating, the solution is transferred into an ice bath and seeded with previously prepared ultra-pure olanzapine Form I. The solution is stirred for 30-35 minutes at 0-10°C. The yellowish solid obtained is filtered on vacuum pump and washed with 2.0-2.5 mL dichloromethane. The solid is dried on a vacuum pump for 40-45 minutes. The solid obtained is crushed into a fine powder and air dried to remove traces of dichloromethane. The air dried material is further dried in the oven at 65°C for 1.5-2.0 hours and analyzed for water content. Karl Fisher study shows 670-860 ppm water content. The weight of olanzapine Forml is 1.93 g (95.0 % crystallization yield) of 99.96 % HPLC purity. EXAMPLE 3 X-RAY POWDER DIFFRACTOMETRY STUDY

Olanzapine Form I prepared according to Example 1 is analyzed by X-ray, IR, and DSC and found to conform to a commercially available reference standard olanzapine Form I. DSC of the olanzapine Form I prepared according to the present invention shows an endotherm peak at 195°C.

…………………

http://www.google.com/patents/CN102268010A?cl=en

Currently, the preparation of olanzapine, mainly in the following three ways:

1.4-amino-2-methyl–10H- thieno [2,3-b] [1,5] – benzodiazepine hydrochloride and N- methylpiperazine, in a nitrogen atmosphere Toluene and DMSO as solvent at reflux for 20h, after-treatment to give the product, recrystallized from acetonitrile to give crystals of olanzapine, a yield of 33% (US5229382).

 

Figure CN102268010AD00041

[0013] The process route fewer steps, simple process, raw materials, but a long reaction time, the use of toxic solvents, pollution, low yield, industrial production adversely.

[0014] CN1906201A discloses the use of no solvent or low boiling organic solvent method for preparing olanzapine, pointed N- methylpiperazine with 4-amino-2-methyl -10H- thieno [2,3-b] [l, 5] molar ratio _ benzodiazepine hydrochloride of 3: 1~8: 1,110~145 ° C after the reaction at least polonium, water was added, at least two organic solvents, or water and at least one organic solvent precipitation olanzapine. This improved process reaction time is shortened, reducing energy consumption and cost, but an excess of starting material N- methylpiperazine unrecovered, resource waste problems still exist.

[0015] 2. 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride, to generate demethylolanzapine piperazine is reacted with level, and then obtained by methylation of olanzapine, recrystallized from ethanol to obtain refined product yield of 68% (CN1420117A).

[0016]

Figure CN102268010AD00042

[0017] The method for preparing olanzapine via a two-step process is relatively complicated and the reaction time is still long; Further, more by-products: The first step is easy to form dimeric product, a second step Iddo methylation.

[0018] 3. 4-amino-2-methyl -10H- thieno [2,3-b] [1,5] – benzodiazepine and N, N- two – (2_ haloethyl ) _ methylamine in alkaline catalyst, solvent reflux 3~IOh obtained crude olanzapine, yield 75% to 92%. Wherein, X = Br or Cl, the catalyst is sodium alkoxide, sodium hydroxide, sodium amide, sodium hydroxide, inorganic bases (CN101168544A).

[0019]

Figure CN102268010AD00051

[0020] This method is simple, shorten the reaction time and therefore reduce energy consumption, but the raw material N, N- two – (2-halo-ethyl) _ methylamine not easy, if more raw material preparation is bound to increase the cost of production.

The present invention is olanzapine preparation method:

[0024]

Figure CN102268010AD00052

 

Example 1 olanzapine [0030] Implementation

[0031] To a 250ml three-necked flask of 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 20. OOg (0 075mol.) , N_-methylpiperazine 75. 30g (0. 75mol), nitrogen and stirred and heated to reflux the reaction cell. Under stirring, the reaction mixture was poured into 200ml of water to precipitate a pale yellow solid powder, stirring was continued for lh, filtered and dried to give olanzapine product 23. 30g, yield 99.4%, purity 99. 0% (HPLC).

2 olanzapine refined example [0032] Implementation

[0033] Example 1 was 23. 30g olanzapine product was transferred into 250ml single neck flask was added MOml ethanol, stirred and heated to reflux to make the product the whole solution. 0. 20g of activated carbon was added to the system, reflow bleaching treatment 30min, filtered, and the filtrate cooled to room temperature and crystallization, filtration and dried to give a yellow crystalline powder 16. 32g, yield 70.0%, the purity of 99. 8% (HPLC), high performance liquid phase chromatogram, see photos.

Olanzapine Preparation Example 3 [0034] Implementation

[0035] To a three-necked flask IOOOml 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 150. 03g (. 0 56mol) , N- methylpiperazine 339. 29g (3. 39mol), nitrogen and stirred and heated to reflux the reaction cell. Cooling, vacuum distillation recovery more than 70% excess N- methylpiperazine to give Olanzapine crude solid.

[0036] 400ml of ethanol was added to the three-necked flask and heated to reflux for solid all dissolved. Then dissolved under stirring in ethanol olanzapine solution was poured IOOOml water to precipitate a pale yellow solid powder was filtered and dried to give olanzapine product 173. 87g, yield 99.4%, purity 98. 9% (HPLC).

Preparation 4 olanzapine [0037] Implementation

[0038] To a 250ml three-necked flask of 4-amino-2-methyl -10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 10. OOg (0 038mol.) , N_-methylpiperazine 39. 63g (0. 40mol) and diethylene glycol dimethyl ether 30ml, nitrogen and stirred and heated to reflux the reaction cell. Cooling, vacuum distillation recovery more than 80% excess of N- methylpiperazine and diethylene glycol dimethyl ether mixture to give solid crude olanzapine.

[0039] 40ml of ethanol was added to the three-necked flask and heated to reflux all dissolved solids. Then under stirring to dissolve olanzapine solution was poured into 200ml of water in ethanol, a yellow powder precipitated solid was filtered and dried to give olanzapine product 11.79g, yield 99.3%, purity 98. 7% (HPLC).

Olanzapine Preparation Example 5 [0040] Implementation

[0041] To a 250ml bottle of three 4-amino-2-methyl–10H- thieno [2,3_b] [1,5] – benzodiazepine hydrochloride 20. OOg (0. 075mol) , N_-methylpiperazine 62. 34g (0. 62mol), nitrogen and stirred and heated to reflux the reaction cell. Cooling, vacuum distillation recovery more than 75% excess N- methylpiperazine to give Olanzapine crude solid.

[0042] 60ml of ethanol was added to the three-necked flask and heated to reflux all dissolved solids. Then under stirring to dissolve olanzapine solution was poured into 600ml of ethanol in water to precipitate a pale yellow solid powder was filtered and dried to give olanzapine product 23. 37g, yield 99.7%, purity 99. 0% (HPLC). [0043] Example 6 olanzapine refined

[0044] Example 5 was 23. 37g olanzapine product was transferred into 250ml single neck flask was added ^ Oml ethanol, stirred and heated to reflux to make the product the whole solution. 0. 03g of activated carbon is added to the system and 0. 03g diatomite, reflow bleaching treatment 15min, filtered, and the filtrate cooled to room temperature and crystallization, filtration and dried to give a yellow crystalline powder 16. 76g, yield 71.7%, purity 99.7% ( HPLC).

 

………………….

http://www.google.com/patents/EP0733635B1?cl=en

 

Example 1

      Technical Grade olanzapine

    • Figure 00100001
    • In a suitable three neck flask the following was added:
      Dimethylsulfoxide (analytical):
      6 volumes
      Intermediate 1 :
      75 g
      N-Methylpiperazine (reagent) :
      6 equivalents

      Intermediate 1 can be prepared using methods known to the skilled artisan. For example, the preparation of the Intermediate 1 is taught in the ‘382 patent.

    • A sub-surface nitrogen sparge line was added to remove the ammonia formed during the reaction. The reaction was heated to 120°C and maintained at that temperature throughout the duration of the reaction. The reactions were followed by HPLC until ≤ 5% of the intermediate 1 was left unreacted.
    • After the reaction was complete, the mixture was allowed to cool slowly to 20°C (about 2 hours). The reaction mixture was then transferred to an appropriate three neck round bottom flask and water bath. To this solution with agitation was added 10 volumes reagent grade methanol and the reaction was stirred at 20°C for 30 minutes. Three volumes of water was added slowly over about 30 minutes. The reaction slurry was cooled to zero to 5°C and stirred for 30 minutes. The product was filtered and the wet cake was washed with chilled methanol. The wet cake was dried in vacuo at 45°C overnight. The product was identified as technical olanzapine.
      Yield: 76.7%; Potency: 98.1%

Example 2

    Form II

  • A 270 g sample of technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was suspended in anhydrous ethyl acetate (2.7 L) . The mixture was heated to 76°C and maintained at 76°C for 30 minutes. The mixture was allowed to cool to 25°C. The resulting product was isolated using vacuum filtration. The product was identified as Form II using x-ray powder analysis. Yield: 197 g.
  • The process described above for preparing Form II provides a pharmaceutically elegant product having potency > 97%, total related substances < 0.5% and an isolated yield of > 73%.

………………….

Impurities

Olanzapine N-oxide (Olanzapine Impurity D)

…………..

Synthesis and characterization of impurities of an anti-psychotic drug substance, Olanzapine (08-3022UP)
Poornachander Thatipalli, Ramesh Kumar, Chandrasekhar Bulusu, Ramesh Chakka, Pratap R. Padi, Anjaneyulu Yerra and Satyanarayana Bollikonda
Full Text: PDF (226K)
pp. 195 – 201

 

 

 

 

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Citing Patent Filing date Publication date Applicant Title
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P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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2 Comments

  1. […] OLANZEPINE VISITED PART 2/2 April 9, 2015 […]

  2. […] OLANZEPINE VISITED PART 2/3 April 9, 2015 […]

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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