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Co-crystals of tramadol and nsaids

A technology of tramadol and heterocycle, applied in the field of co-crystal of tramadol and NSAID, can solve the problems such as little known

Active Publication Date: 2011-09-14
ESTEVE PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While it has been generally recognized for several years that APIs (active pharmaceutical ingredients) like tramadol can form crystalline polymorphs, solvates, hydrates and amorphous forms, little is known about which APIs form co-crystals little

Method used

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  • Co-crystals of tramadol and nsaids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0300] Example 1a: Method for obtaining (-)-tramadol-(S)-naproxen (1:2) co-crystal

[0301]A solution of (S)-naproxen (2.14 g, 9.3 mmol) in 20 mL of methanol was added to (-)-tramadol (2.45 g, 9.3 mmol) in 10 mL of methanol over 10 minutes with stirring in solution. The resulting solution was stirred at room temperature for 30 minutes, and the solvent was evaporated in vacuo to a pale yellow oil. The oil was cooled to -197°C and then warmed to room temperature to afford amorphous (-)-tramadol-(S)-naproxen salt as a white solid (4.59 g, 100%).

[0302] Procedure: Suspend the amorphous (-)-tramadol-(S)-naproxen salt (1:1) (2.2 g, 4.46 mmol) obtained above in 10 mL of diisopropyl ether and heat at room temperature Under stirring for 7 days. The resulting suspension was filtered off. The filtrate was washed with about 2 mL of diisopropyl ether and dried under vacuum (10 mm Hg) at 40 °C for 24 hours to obtain a 1:2 ratio of (-)-tramadol-(S)-naproxen co- crystalline as a crys...

Embodiment 1b

[0303] Example 1b: Method for obtaining (-)-tramadol-(S)-naproxen co-crystal (1:2) co-crystal:

[0304] A solution of (-)-tramadol (0.58 g, 2.20 mmol) in 2 mL of isopropanol was added to (S)-naproxen (1.02 g, 4.43 mmol, 2 eq) in 2 mL of Stir the suspension in isopropanol. The resulting solution was cooled to room temperature and one-third of the solvent was evaporated. 5-10 mg of crystalline (-)-tramadol-(S)-naproxen co-crystal (1:2) was added as a seed crystal to the solution, and it was mixed at room temperature without stirring. Let stand for 48 hours. The resulting suspension was filtered off and the filtrate was washed with about 1 mL of isopropanol and dried under vacuum (10 mm Hg) at 60°C for 24 hours to obtain a co-crystal (-)-tramadol-(S) in a 1:2 ratio - Naproxen as a white solid (1.31 g, 81%).

[0305] Characterization of the cocrystal:

[0306] The (-)-tramadol-(S)-naproxen (1:2) co-crystal obtained according to Example 1 was tested by 1H-NMR, FTIR, powder...

Embodiment 2

[0328] Example 2: (+)-Tramadol-(R)-Naproxen (1:2) Cocrystal

[0329] Method for obtaining (+)-tramadol-(R)-naproxen (1:2) co-crystal

[0330] A solution of (R)-naproxen (751 mg, 3.26 mmol) in 4 mL of methanol was added to a solution of (+)-tramadol (430 mg, 1.63 mmol) in 1 mL of methanol. The mixture was stirred for 30 minutes and the solvent was evaporated in vacuo to an oil which solidified by cooling to -197°C. The resulting solid was suspended in 10 mL of diisopropyl ether and stirred at room temperature for 7 days. The resulting suspension was filtered off. The filtrate was washed with 5 mL of diisopropyl ether and dried under vacuum (10 mm Hg) at 40° C. for 16 hours to obtain a cocrystal of (+)-tramadol-(R)-naproxen in a 1:2 ratio, It was a crystalline white solid (620 mg, 53%).

[0331] Characterization of the cocrystal:

[0332] The (+)-tramadol-(R)-naproxen (1:2) cocrystal obtained according to Example 2 passed 1 H-NMR, FTIR, powder X-ray diffraction, DSC ...

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Abstract

The present invention relates to co-crystals of tramadol and co-crystal formers selected from NSAIDs, processes for preparation of the same and their uses as medicaments or in pharmaceutical formulations, more particularly for the treatment of pain. In a preferred embodiment, the co-crystal is a co-crystal of (-) -tramadol and (S) -naproxen (1:2); (+) -tramadol and (R) -naproxen (1:2) or (rac) -tramadol-Hcl-celecoxib (1:1).

Description

technical field [0001] The present invention relates to the co-crystal of tramadol (tramadol, tramadol) and NSAID (non-steroidal anti-inflammatory drug), its preparation method and its use as medicine or in pharmaceutical preparations, more particularly in the treatment of pain use in . Background technique [0002] Pain is a complex response that is functionally divided into sensory, autonomic, motor, and affective components. The sensory aspect includes information about the site and intensity of the stimulus, while the adaptive component is thought to be endogenous pain-modified activity and motor planning for the escape response. The affective component appears to include ratings of painful discomfort, stimulus threat, and negative emotions evoked by the memory and environment of the painful stimulus. [0003] In general, pain states can be divided into chronic pain and acute pain. Chronic pain includes neuropathic pain and chronic inflammatory pain such as arthritis,...

Claims

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Application Information

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IPC IPC(8): A61K31/135A61K31/192A61P25/04A61P29/00C07C59/64C07C217/74
CPCA61K31/192A61K31/137A61K31/635C07C2101/14A61K31/135C07C217/74C07C59/64C07C2601/14A61K45/06C07D231/12A61P19/00A61P19/02A61P21/00A61P25/00A61P25/04A61P29/00A61P43/00A61P3/10A61K2300/00C07C2602/10C07B2200/13A61K9/16
Inventor 赫尔穆特·海因里希·布施曼利易斯·索拉卡兰戴尔乔迪·比奈特布赫雷尔茨乔迪·卡尔斯·西隆贝特朗卡洛斯·拉蒙·布拉塔萨拉曼尼古拉斯·特松
Owner ESTEVE PHARMA SA
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