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Crystalline parecoxib sodium

A parecoxib sodium, crystallization technology, applied in the field of parecoxib sodium crystal form, can solve the problem of weak inhibitory activity in vitro

Inactive Publication Date: 2005-07-20
PHARMACIA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Parecoxib with the following structural formula (I) itself shows weak in vitro inhibitory activity against both COX-1 and COX-2, while valdecoxib (II) has strong anti-COX-2 inhibitory activity, but only COX- Weak inhibitor of 1

Method used

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  • Crystalline parecoxib sodium
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  • Crystalline parecoxib sodium

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0052] Preparation of Parecoxib Sodium

[0053] The parecoxib sodium that can be used in the preparation of any of the above anhydrous, non-solvated crystalline forms or any of the pharmaceutical products of parecoxib sodium can be prepared by any suitable method, including methods known per se. In one such approach, the synthesis of parecoxib sodium (III) involves five chemical steps starting from commercially available starting materials, as shown in Scheme 1 below.

[0054] plan 1

[0055]

[0056]

[0057] In a first step, 210 kg of deoxygenated benzoin (IV), 711 liters of ethanol, and 77 liters of 80% aqueous acetic acid were added to a reaction vessel. Alternatively, glacial acetic acid (63 L) and water (16.5 L) can be used. The mixture was heated to 70°C and 71 liters of 50% aqueous hydroxylamine and 55 liters of water were added. The mixture was kept at 70°C for at least 1 hour. In-process checks were performed to ensure that the a...

Embodiment 1

[0128] Example 1: Preparation of Form A

[0129] Parecoxib sodium Form A was prepared by each of the following methods.

[0130] 1. Lyophilize the aqueous solution of parecoxib sodium. The obtained amorphous parecoxib sodium was placed in the DSC pan in the absence of moisture and the temperature was increased at a rate of 10 °C / min. Crystallization of parecoxib sodium occurs at approximately 125-130°C and is an exothermic event. The crystals were identified as Form A by one or more of PXRD, FTIR, DSC and moisture absorption as described below.

[0131] 2. A total of 10 g of the mixture of parecoxib sodium Form A and ethanol solvate was placed in an oven at 150°C for 3 hours at ambient pressure. The resulting solid was cooled in a desiccant bottle containing Drierite desiccant and confirmed to be Form A by one or more of PXRD, FTIR, DSC and moisture absorption as described below.

[0132] 3. Form E parecoxib sodium was found to convert to Form A at approximately 210° C. ...

Embodiment 2

[0134] Example 2: Preparation of Form B

[0135] Parecoxib sodium Form B was prepared by each of the following methods.

[0136] 1. Expose Parecoxib Sodium Form A to about 75% RH for several days to produce a hydrated crystalline form. This hydrated crystalline form is then dried over a desiccant. The obtained solid was identified as Form B by one or more of PXRD, FTIR, DSC and moisture absorption as described below.

[0137] 2. The ethanol solvate of Parecoxib Sodium was prepared by recrystallizing 11.5 g of Parecoxib Sodium in 100 ml of ethanol by heating to boiling on a hot plate with magnetic stirring, followed by ambient cooling to room temperature. Separately, about 1 g of Form B seeds were added to 450 ml of heptane. The freshly prepared ethanol solvate was collected by vacuum filtration and immediately transferred into a heptane suspension containing Form B seeds. The obtained suspension was heated to reflux for 4 hours with vigorous magnetic stirring. Crystals...

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Abstract

Parecoxib sodium is provided in crystalline form that is substantially anhydrous and substantially unsolvated. A number of such anhydrous, unsolvated crystalline forms have been identified, including Forms A, B and E described herein. Also provided is a pharmaceutical product of parecoxib sodium, wherein at least about 90% of the parecoxib sodium is in one or more anhydrous, unsolvated crystalline forms. Such drug products are storage-stable intermediates that can be further processed, for example, by dissolving or slurrying in an aqueous medium with one or more parenterally acceptable excipients, followed by lyophilization of the resulting solution or slurries to provide reconstitutable injectable compositions suitable for therapeutic use.

Description

field of invention [0001] The present invention relates to crystalline forms of parecoxib sodium, to pharmaceutical compositions comprising such crystalline forms, and to methods of using such compositions for the treatment of cyclooxygenase-2 (COX-2) mediated disorders. Background of the invention [0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and ailments, for example in arthritis and headaches. Such drugs are effective, but their long-term use is limited by gastrointestinal side effects including dyspepsia and abdominal pain and, in severe cases, gastric or duodenal perforation and / or bleeding. By combining the therapeutic efficacy of conventional NSAIDs with a greatly improved gastrointestinal safety profile, the development of selective COX-2 inhibitory drugs has revolutionized the treatment of inflammation and pain. [0003] Inhibition of cyclooxygenase (COX) is believed to be at least the primary m...

Claims

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Application Information

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IPC IPC(8): A61K9/08A61K9/16A61K9/19A61K31/42A61P29/00A61P43/00C07D231/12C07D261/08C07D457/06
CPCA61K31/42C07D457/06C07D261/08A61P29/00A61P43/00
Inventor A·Y·希克T·R·博哈特L·J·费罗G·D·丹泽尔
Owner PHARMACIA CORP
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