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Preparation method of perindopril arginine salt with gamma crystal form

A technology of indopril arginine salt and arginine, which is applied to the synthesis of arginine perindopril and the preparation of γ crystal form perindopril arginine salt, so as to save costs and reduce active ingredients. Churning, easy-to-manipulate effects

Pending Publication Date: 2022-03-08
JIANGSU SINOBIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to solve the above-mentioned problem that existing perindopril arginine salt preparation method exists, provide a kind of new preparation method of gamma crystal form perindopril arginine salt, the applicable range of crystallization temperature of this method is relatively low. Wide range, the obtained product is easy to filter, easy to separate, and has a high quality level

Method used

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  • Preparation method of perindopril arginine salt with gamma crystal form
  • Preparation method of perindopril arginine salt with gamma crystal form
  • Preparation method of perindopril arginine salt with gamma crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 5.0g of perindopril, 2.4g of L-arginine and 20ml of water into the reaction bottle, stir at room temperature until completely dissolved, filter, add 60ml of dimethyl sulfoxide dropwise to the filtrate, without temperature control during the dropwise addition, The temperature will not exceed 50°C. After the dropwise addition, cool down to 20~30°C, continue to stir for 1 hour, filter with suction, rinse the filter cake with 50ml acetone and 50ml n-heptane in sequence, drain it, and dry the filter cake to obtain Perindopro Arginine salt gamma crystal form. The XRD pattern of the gamma crystal form that this water / dimethyl sulfoxide system makes is as follows figure 1 shown.

Embodiment 2

[0024] Add 5.0g of perindopril, 2.4g of L-arginine and 20ml of water into the reaction bottle, stir at room temperature until completely dissolved, filter, add 100ml of acetone dropwise to the filtrate, do not need to control the temperature during the dropwise addition, the temperature will not When the temperature exceeds 50°C, drop the temperature down to 20-30°C after the dropwise addition, continue to stir for 1 hour, filter with suction, rinse the filter cake with 50ml of n-heptane, drain it, and dry the filter cake to obtain perindopril arginine salt γ crystal type. The XRD pattern of the gamma crystal form thing that this water / acetone system makes is as follows figure 2 shown.

Embodiment 3

[0026] Add 11.8kg of perindopril, 5.5kg of L-arginine and 42.5kg of purified water into the reaction kettle, stir to dissolve, and filter. Add 240kg of dimethyl sulfoxide aqueous solution that has been cooled to below 10°C, start stirring, filter for 1 hour, wash with 118kg of acetone, filter for 20 minutes, then wash with 70kg of n-heptane, filter for 20 minutes, put the filter cake into a baking tray , vacuum drying at 45°C for 10 hours, and then vacuum drying at 80°C for 30 hours to obtain the industrially produced product of perindopril salt arginine gamma crystal form. (Purity: 99.62%, Impurity B: 0.081%, Impurity F: 0.205%)

[0027] The preparation process of the pharmaceutical composition of perindopril arginine salt gamma crystal form (10 mg / tablet) is as follows:

[0028] Prescription composition:

[0029] Perindopril Arginine 10mg

[0030] Lactose monohydrate 145mg

[0031] Magnesium Stearate 0.9mg

[0032] Maltodextrin 18mg

[0033] Colloidal silicon dioxide 0...

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Abstract

The invention provides a preparation method of gamma crystal form perindopril arginine salt, which comprises the following steps: adding perindopril and L-arginine into water, stirring and dissolving until the solution is clear, filtering, mixing the filtrate and an organic solvent in a dropwise adding manner, cooling to room temperature after dropwise adding, stirring and crystallizing for 1-2 hours, performing suction filtration to obtain a filter cake, leaching and draining the filter cake, and drying to obtain the gamma crystal form perindopril arginine salt. And drying the filter cake to obtain the gamma crystal form perindopril arginine salt. The method does not need low-temperature, freeze-drying and other operations, has no special requirements on equipment, also does not need reflux or heating operation, and is wide in crystallization temperature application range, and the obtained product is easy to filter, easy to separate and high in quality level.

Description

technical field [0001] The invention relates to a synthesis method of perindopril arginine, in particular to a preparation method of gamma crystal form perindopril arginine salt, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Perindopril is a third-generation angiotensin-converting enzyme inhibitor, commonly used clinically for the treatment of hypertension and heart failure, and its pharmacological properties mainly inhibit angiotensin I-converting enzyme (or kininase II). Can prevent the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor), and on the other hand prevent the degradation of bradykinin (a vasodilator) into an inactive peptide. It makes perindopril have beneficial effects on cardiovascular diseases, especially arterial hypertension and heart failure. Perindopril was first marketed in the form of tert-butylamine salt, which has the advantages of small dose, wide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42C07C279/14C07C277/08
CPCC07D209/42C07C279/14C07C277/08C07B2200/13
Inventor 黄乐群王磊汪静郭露粉
Owner JIANGSU SINOBIOPHARMA
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