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Sitagliptin phosphate crystal and preparation method and application thereof

A technology of sitagliptin phosphate and phosphoric acid aqueous solution, which is applied in the field of pharmaceutical chemical crystallization, can solve the problems of different drug dissolution rate and bioavailability, influence on drug absorption and utilization, and difference in drug solubility, so as to reduce drug load and improve Drug efficacy, the effect of reducing production energy consumption

Active Publication Date: 2015-12-23
SHENZHEN HAIBIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no specific crystallization process, and the temperature drop is low, and more energy is consumed during industrialized mass production
[0011] As we all know, different crystal forms of the same drug often lead to differences in drug solubility, which can cause differences in drug dissolution and bioavailability, thereby affecting the absorption and utilization of drugs in the body, and then resulting in differences in drug efficacy

Method used

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  • Sitagliptin phosphate crystal and preparation method and application thereof
  • Sitagliptin phosphate crystal and preparation method and application thereof
  • Sitagliptin phosphate crystal and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: Preparation of Sitagliptin Phosphate Monohydrate Crystals

[0070] At room temperature, 10.175 g of sitagliptin, 43.5 mL of isopropanol, and 11.25 mL of water were added to the reactor, and then 5 mL of 45% phosphoric acid aqueous solution was added dropwise; the temperature was raised to 75 °C, and dissolved into a transparent liquid; cooled to 70 °C, The reaction was stirred for 3 hours. Then, the solution was stirred and cooled to 60°C at a cooling rate of 8°C per hour; then it was left to stand, and during the standing process, the solution was cooled to 44°C at a cooling rate of 8°C per hour; then cooled to 21°C with stirring in 30 minutes; White solid. Within 30 minutes, 32 mL of isopropanol was added dropwise, and then stirred for 15 minutes; suction filtration, washed twice with 40.7 mL of isopropanol-water (V / V=6:1) system; after vacuum degree -0.08MPa, 25 It was dried at °C for 3 hours, and dried at 40 °C for 3 hours to obtain 12.59 g of a white...

Embodiment 2

[0076] Example 2: Preparation of Sitagliptin Phosphate Monohydrate Crystals

[0077] At room temperature, 12.21 g of sitagliptin, 52 mL of isopropanol, and 13.5 mL of water were added to the reactor, and then 6 mL of a 45% volumetric phosphoric acid aqueous solution was added dropwise; the temperature was raised to 75 °C, and dissolved into a transparent liquid; then cooled to 65 °C, and the reaction was stirred for 3 hours. Then cool down to 25°C with stirring at a cooling rate of 8°C per hour; within 30 minutes, add 38 mL of isopropanol dropwise, then stir for 30 minutes, filter with suction, and use isopropanol-water (V / V=6:1) 56 mL of the system was washed twice. Dry at -0.08MPa and 35°C for 5 hours to obtain 15.17g of white crystalline solids. After detection, HPLC (%): 99.85%; moisture: 3.64%; molar yield: 96.7%.

[0078] The X-ray diffraction pattern, infrared spectrum and differential scanning calorimetry (DSC) curve of the sitagliptin phosphate monohydrate crystal...

Embodiment 3

[0079] Example 3: Preparation of Sitagliptin Phosphate Monohydrate Crystals

[0080] At room temperature, 8.14 g of sitagliptin, 16.3 mL of isopropanol, and 7.3 mL of water were added to the reactor, and then 1.73 mL of 85% phosphoric acid aqueous solution was added dropwise; the temperature was raised to 80 °C, and dissolved into a transparent liquid; cooled to The reaction was stirred for 2 hours at 70°C. After that, it was stirred and cooled to 54°C at a cooling rate of 8°C per hour, and then cooled to 22°C with a cooling rate of 16°C per hour, and a large amount of white solids were precipitated. Within 40 minutes, 57 mL of isopropanol was added dropwise, and then stirred for 15 minutes; filtered with suction, washed twice with 40.7 mL of isopropanol-water (V / V=11:1) system; After drying at °C for 5.5 hours, 10.22 g of a white crystalline solid was obtained. After detection, HPLC (%): 99.91%; moisture: 3.54%; molar yield: 97.7%.

[0081] The X-ray diffraction pattern, ...

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Abstract

The invention provides a crystal-type sitagliptin phosphate monohydrate and a preparation method, pharmaceutical composition and application thereof. The solubility of the sitagliptin phosphate crystal is high and obviously higher than that of a sitagliptin phosphate monohydrate in the prior art, and the sitagliptin phosphate crystal is good in both stability and hygroscopicity under the conditions of high temperature, high humidity and illumination. Compared with the prior art, the crystal-type sitagliptin phosphate monohydrate has the advantages that the solubility is higher, and the great significance for improving the pharmaceutical effect and reducing the pharmaceutical loading capacity is achieved; the preparation method is easy to operate, good in repeatability and beneficial for cost control in industrialized production and has the extremely high economic value; the time period of industrialized mass production is greatly shortened, the production efficiency is improved, the production energy consumption is reduced, and the cost of industrialized mass production is lowered.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry crystallization. Specifically, it relates to a monohydrate crystal of sitagliptin phosphate, and also relates to a preparation method of the crystal form, its pharmaceutical composition and use. Background technique [0002] Sitagliptin phosphate was developed and developed by Merck and was launched in Mexico and the United States in 2006. It was approved by the European Union for the treatment of type 2 diabetes in 2007. Peptidase-4 (DPP-4) inhibitor to prevent and treat type 2 diabetes, hyperglycemia, insulin resistance, obesity and hypertension, and certain complications. At present, sitagliptin phosphate has become the second largest oral diabetes drug in the United States. [0003] The function of sitagliptin phosphate is that it can reduce hunger while stimulating insulin secretion, and will not cause weight gain, hypoglycemia and edema. It is suitable for diabetes mellitus wit...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4985A61P3/10
CPCC07B2200/13C07D487/04
Inventor 唐天声汪小华卢兆强张验军任鹏刘路尚万里
Owner SHENZHEN HAIBIN PHARMA
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