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Method for preparing pharmaceutical cocrystals through suspension crystallization

A technology for preparing drugs and crystallization, which is applied in the field of preparation of drug co-crystals by suspension crystallization, can solve problems such as insufficient understanding of process mechanism and product impurity, and achieve the effects of reducing solvent recycling, reducing energy consumption, and saving costs

Inactive Publication Date: 2014-08-20
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

People do not know enough about the mechanism of the process of preparing pharmaceutical co-crystals by grinding, and the problem of product impurity often occurs in large-scale preparations

Method used

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  • Method for preparing pharmaceutical cocrystals through suspension crystallization
  • Method for preparing pharmaceutical cocrystals through suspension crystallization
  • Method for preparing pharmaceutical cocrystals through suspension crystallization

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Preparation of theophylline-acetaminophen (THEO-APAP) co-crystal in six different solvents: methanol, ethanol, acetonitrile, acetone, butanone, and nitromethane:

[0036] Among these six solvents, theophylline (THEO) is used as API, and acetaminophen (APAP) is used as CCF. There is no solvate in THEO and APAP in the six solvents. 1:1 co-crystal theophylline-acetaminophen. First prepare 1000 mL of a saturated solution of APAP paracetamol. In the six solvents of methanol, ethanol, acetonitrile, acetone, butanone, and nitromethane, the solubility of APAP acetaminophen is 216.3, 139.9, 22.2, 73.6, 48.0, 3.9 mg / mL, and the solubility of THEO theophylline is respectively 6.1, 3.4, 1.6, 2.3, 1.6, 1.5 mg / mL. Add 18.0g of theophylline THEO (0.1mol) and 15.1g of acetaminophen APAP (0.1mol) into the saturated solution of APAP, so that each of THEO and APAP put into the CCF saturated solution is 0.1mol, and the solid loading rate is 33.1g / L. After the suspension was thoroughly...

Embodiment 2

[0038] Caffeine and oxalic acid, maleic acid, and malonic acid form eutectics with a molar ratio of 2:1 in acetonitrile

[0039] In acetonitrile, caffeine (CAF) was used as API, oxalic acid (OXA), maleic acid (MEI), and malonic acid (MON) were used as CCF respectively, and neither API nor the three different CCFs were present in acetonitrile solvate.

[0040] Prepare 1000 mL of a saturated solution of oxalic acid OXA. Add 77.7g caffeine (0.4mol) and 18.0g oxalic acid (0.2mol) into the saturated solution, so that the molar ratio of CAF and OXA put into the CCF saturated solution is 2:1, and the solid loading rate is 95.7g / L. After fully mixing and stirring at 25° C. for 6 hours, the solid was taken for XRD test, which proved that the solid was a pure eutectic phase. The resulting solid is vacuum filtered, washed with CCF saturated solution, and the solid obtained after the drying process is 2CAF-OXA ( image 3 ). The XRD characteristic peaks of all substances are consistent...

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Abstract

The invention relates to a method for preparing pharmaceutical cocrystals through suspension crystallization. The method concretely comprises the following steps: firstly screening solid forms of active pharmaceutical ingredients API and cocrystal formation CCF in different solvents, preparing a CCF saturation solution together with a solvent which cannot generate solvate together with the API and CCF; feeding the prepared CCF saturation solution into a vessel type stirrer, feeding the solid API and CCF according to a certain solid load rate, and deciding the ratio of molar weight of the API and CCF according to the cocrysal chemical metrological ratio; and sampling to do XRD or DSC testing after fully stirring and mixing, so as to prove that the cocrystal solid phase is pure, performing vacuum filtration to the obtained solid, and washing and drying the CCF saturation solution to obtain a solid, namely a final cocrystal product. Compared with other methods, the method is low in energy consumption, less in used solvent, low in cost, simple in technology, easy to amplify, fast and easy to obtain, high in the purity of products, and suitable for industrial large-batch synthesized pharmaceutical cocrystals.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a method for preparing drug co-crystals from suspended crystals. The invention provides a preparation method of drug eutectic with simple process, easy enlargement, low cost, high production efficiency and 100% purity. Background technique [0002] In 1988, French scientist Lehn (Jean-Marie Lehn. Supramolecular Chemistry—Scope and Perspectives Molecules, Supermolecules, and Molecular Devices (Nobel Lecture), Angewandte Chemie International Edition in English, 1988, 27:89-112) first proposed supramolecular chemistry concept. Supramolecular chemistry is the chemistry of molecular aggregates formed based on intermolecular non-covalent interactions. The properties and functions of matter depend not only on the properties of the molecules that make up the system, but also on the aggregation form of the molecules and the higher-level structures above the molecules. Sup...

Claims

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Application Information

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IPC IPC(8): C07D473/08C07C233/25C07C231/24C07D473/12C07C55/06C07C55/08C07C57/145C07C51/43
CPCC07C231/24C07D473/08C07D473/12C07C233/25
Inventor 刘晓敏刘海芬厉爱凤
Owner NANJING UNIV OF TECH
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