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Antisolvent Crystallization Process for Polymorph and CSD Control

用于多晶型物和 CSD 控制的反溶剂结晶工艺

基本信息

批准号：
17560658
负责人：
TAKIYAMA Hiroshi
金额：
$ 1.98万
依托单位：
Tokyo University of Agriculture and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17560658/
关键词：
Crystallization Anti-solvent Polymorph 晶折

项目摘要

Polymorphism means that a compound has two or more crystal structures. Difference in crystal structures causes changes in crystalline and physicochemical properties. In the pharmaceutical industry, it is necessary to control polymorphs because of their differences in bioavailabilities. Anti-solvent crystallization is widely used in the pharmaceutical industry for high yield production. However, addition methods to control polymorphs in anti-solvent crystallization have not been discussed enough.In this study, indomethacin, which has three polymorphs, was used. The purpose of this study is to establish a production method of the required polymorph in the anti-solvent crystallization.Supersaturation was generated by adding anti-solvent. However, in order to obtain only stable form, solution compositions must not exceed the solubility of metastable form. A simulation was performed to determine the anti-solvent addition rate, which satisfied these solution conditions. The simulation was ba … More sed on the ternary phase diagram and the models that expressed the crystallization phenomena from a viewpoint of transport phenomena and mass balances. Experiments were carried out using four different kinds of addition methods. Method A adapted continuous addition at constant rates from the beginning to the end. In the case of Method B, addition rates were changed stepwise. Method C indicates intermittent addition. These three methods were operated at constant temperature.While the constant temperature methods, stable form crystals were selectively obtained under the conditions determined by the simulations. In Method A and Method B, anti-solvent addition rate could not be high at early stages of experiments. Consequently, at early stages of experiments, anti-solvent addition rate was increased, and stable form was selectively obtained. By using a 3-dimensional (temperature, IMC concentration, and anti-solvent concentration) solubility diagram and the simulation, the required polymorph was successfully obtained in the anti-solvent crystallization. Less

多晶性是指一种化合物有两种或两种以上的晶体结构。晶体结构的不同会导致晶体和物理化学性质的变化。在制药工业中，由于生物利用度的差异，控制多晶型是必要的。反溶剂结晶法在医药工业中被广泛应用于高产率生产。然而，在反溶剂结晶中如何控制多晶型还没有得到足够的讨论。本研究使用了三种多晶型的吲哚美辛。本研究的目的是建立一种反溶剂结晶所需晶型的生产方法，通过加入反溶剂产生过饱和。然而，为了只获得稳定的形态，溶液组成不得超过亚稳态的溶解度。通过模拟确定了满足这些溶液条件的抗溶剂加入量。模拟是基于…的更详细地介绍了三元相图和从传输现象和质量平衡的观点描述结晶现象的模型。使用四种不同的添加方法进行了实验。方法A采用自始至终恒速连续加法。在方法B的情况下，添加速率被逐步改变。方法C表示间歇添加。这三种方法在恒温下工作，而恒温法在模拟确定的条件下选择性地获得了稳定的晶体。在方法A和方法B中，抗溶剂加入量在实验的早期阶段不能很高。因此，在实验的早期阶段，增加了反溶剂的加入量，并选择性地获得了稳定的形式。通过使用三维(温度、IMC浓度和反溶剂浓度)溶解度图和模拟，成功地获得了反溶剂结晶所需的晶型。较少