Method for determining the stability of sirolimus and process for preparing stable forms thereof

A sirolimus, form technology, applied in the field of preparing stable forms of sirolimus or sirolimus analogues, can solve problems such as inability to apply crystallinity measurement

Inactive Publication Date: 2011-12-14
BIOCON LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method cannot be applied to on-line or in-line crystallinity measurements

Method used

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  • Method for determining the stability of sirolimus and process for preparing stable forms thereof
  • Method for determining the stability of sirolimus and process for preparing stable forms thereof
  • Method for determining the stability of sirolimus and process for preparing stable forms thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] NIR Spectroscopy for Determination of Sirolimus Crystallinity

[0039] Amorphous sirolimus and crystalline sirolimus were mixed in different proportions. The NIR spectrum of the obtained sample was measured using a NIR spectrophotometer. The spectrum is processed by taking the second derivative of the spectrum (see figure 1 ). Sirolimus samples with different crystallinity at 4973.6cm -1 The second derivative value at wavenumber (T") is plotted against crystallinity. Linear regression of this data yields the following equation:

[0040] T"=0.1975×crystallinity+0.0111R 2 =0.9981

[0041] In order to determine the crystallinity of a test sample, the NIR spectrum of the sample is measured and its second derivative is obtained. Will be at 4973.6cm -1 The second derivative at the wave number was substituted into the above equation to obtain the crystallinity of the test sample, which was found to be 99%.

Embodiment 2

[0043] Sirolimus crystallization

[0044] A 130 ml ethyl acetate layer containing 15 g sirolimus was charged into a 650 ml stirred vessel. The temperature of the solution was maintained at about 25°C. To this solution was added 260 ml of n-heptane at a rate of 0.54 ml / min with stirring. After the addition was complete, the mixture was kept under stirring for 12 hours. The crystals formed were filtered and dried under vacuum for 48 hours. These crystals were analyzed by NIR spectroscopy according to the method described in Example 1. The degree of crystallinity of the crystals was measured to be 100%.

Embodiment 3

[0046] Sirolimus crystallization

[0047] 10 g of sirolimus was dissolved in 68 ml of acetonitrile at 25°C. To this solution was added 204 ml of water at a rate of 0.425 ml / min with stirring. After the addition was complete, the mixture was kept under stirring for 12 hours. The crystals formed were filtered and dried under vacuum for 24 hours. Crystals were analyzed by NIR spectroscopy according to the method described in Example 1. The degree of crystallinity of the crystals was measured to be 97%.

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Abstract

The present disclosure provides solution to the problems involved in determining the crystallinity of sirolimus. More particularly, the instant disclosure is successful in providing a method to determine crystallinity of sirolimus or its analogues using Near-Infrared [NIR] spectroscopy. Also, the instant disclosure provides a method for crystallization of sirolimus or its analogues.

Description

technical field [0001] The present invention relates to an assay for determining the crystallinity of sirolimus or analogs of sirolimus. The invention also relates to the use of this assay to predict the stability of sirolimus or analogs of sirolimus. The invention also relates to processes for preparing stable forms of sirolimus or analogs of sirolimus. Background technique [0002] Sirolimus, also known as rapamycin, is an immunosuppressant. sirolimus Sale. Sirolimus is also used in the coating of stents to reduce restenosis rates. Several derivatives of sirolimus have demonstrated immunosuppressive activity, inhibition of tumor growth and / or reduction of restenosis rates. For example, sirolimus ester (temsirolimus, temsirolimus), which is the 42-ester of sirolimus and 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (sirolimus 42- ester), has been proven to have a significant inhibitory effect on tumor growth, and to Sale. Another derivative, everolimus (40-O-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N21/35C07D498/18B01D9/02G01J3/28
CPCB01D9/0054G01N21/3577B01D9/0077G01N21/359
Inventor 雷克什·拜亚拉姆·门德昂卡尔·普拉卡什·桑坦阿米特·阿南特拉·帕坦勒尼丁·索帕拉·帕蒂尔
Owner BIOCON LTD
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