Crystalline and non-crystalline forms of tofacitinib, and a pharmaceutical composition comprising tofacitinib and a penetration enhancer

A composition and form technology for drug combination, drug delivery, non-central analgesics, etc., capable of solving problems such as unpredictable, daunting results

Inactive Publication Date: 2013-12-18
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The study of the most stable form and such other forms is arduous and the results unpredictable

Method used

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  • Crystalline and non-crystalline forms of tofacitinib, and a pharmaceutical composition comprising tofacitinib and a penetration enhancer
  • Crystalline and non-crystalline forms of tofacitinib, and a pharmaceutical composition comprising tofacitinib and a penetration enhancer
  • Crystalline and non-crystalline forms of tofacitinib, and a pharmaceutical composition comprising tofacitinib and a penetration enhancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0242] 2-propanolate (method 1): by adding 750 g of 3-((3R,4R)-4-methyl-3-[methyl- (7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile citrate to prepare a crystalline form. The resulting mixture was stirred at 20°C for about 1 hour. Then 4 L of 1M aqueous sodium hydroxide solution was added to the mixture over 40 minutes. The mixture was then stirred at 20°C for about 17 hours. The solid was isolated by vacuum filtration, washed twice with 1.9 L of water, and dried under reduced pressure at 65°C for about 30 hours. The resulting crystalline solid contained 1.0 wt% water by Karl-Fischer analysis and 2.6 wt% 2-propanol by residual solvent analysis.

Embodiment 2

[0244] 2-propanolate (method 2): 271 g of 3-((3R,4R) -4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile citric acid salts to prepare crystalline forms. Mixing was facilitated with an overhead stirrer throughout the experiment. While providing high speed agitation to the slurry, 1.88 L of 1.0 N aqueous sodium hydroxide solution was slowly added at 20°C. The reactor was then seeded with 1 wt% crystalline form and stirred at ambient temperature for several hours to obtain a slurry. The solid was isolated by vacuum filtration, washed with water and dried under reduced pressure at 60-70°C. The resulting crystalline solid contained 0.9% by weight water and 2.8% by weight 2-propanol as determined by Karl-Fischer analysis and residual solvent analysis, respectively.

Embodiment 3

[0246]2-propanolate (method 3): by adding 218 mg of non-crystalline 3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile to prepare a crystalline form. The mixture was stirred at room temperature for about 5 days, isolated by vacuum filtration and dried under reduced pressure at 70 °C for 1 day. The resulting crystalline solid contained 4.7% by weight 2-propanol by residual solvent analysis.

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PUM

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Abstract

The present invention discloses novel crystalline and non-crystalline forms of 3-((3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile, pharmaceutical composition containing the same, preparations thereof and the uses thereof.

Description

【Technical field】 [0001] The present invention relates to 3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino in crystalline or non-crystalline form ]-piperidin-1-yl)-3-oxopropionitrile. The invention also relates to pharmaceutical compositions comprising crystalline or non-crystalline forms, and methods of preparing such forms. The invention further relates to the use of crystalline or non-crystalline forms for topical treatment of various diseases. 【Background technique】 [0002] 3-((3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)- 3-oxopropionitrile has the formula C 16 h 20 N 6 O and the following structural formula: [0003] [0004] 3-((3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-amino]-piperidin-1-yl) - The synthesis of 3-oxopropionitrile is described in WO 2001 / 42246 and WO 2002 / 096909, commonly assigned to the assignee of the present invention and incorporated herein by reference in thei...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P17/06
CPCC07D487/04A61K9/0014A61K47/10A61P1/00A61P1/04A61P11/06A61P17/00A61P17/02A61P17/06A61P19/02A61P25/00A61P25/28A61P29/00A61P35/00A61P35/02A61P37/06A61P37/08A61P43/00A61P5/14A61P3/10A61K31/519
Inventor B·J·墨菲T·D·怀特B·P·切卡尔P·J·约翰逊C·J·福蒂L·A·马古利斯
Owner PFIZER INC
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