Antisolvent Crystallization Process for Polymorph and CSD Control

多态是指化合物具有两种或两种以上的晶体结构。晶体结构的不同导致晶体和物理化学性质的变化。在制药行业，由于其生物利用度的差异，控制多态性是必要的。反溶剂结晶法广泛应用于制药行业，以提高产量。然而，在反溶剂结晶中控制多晶的添加方法还没有得到足够的讨论。在这项研究中，使用了吲哚美辛，它有三个多态性。本研究的目的是建立抗溶剂结晶中所需晶型的生产方法。通过加入抗溶剂产生过饱和。然而，为了只获得稳定形式，溶液组成不能超过亚稳形式的溶解度。通过模拟实验确定了满足上述条件的反溶剂加成速率。从输运现象和质量平衡的角度出发，建立了三元相图和表达结晶现象的模型。实验采用了四种不同的添加方法。方法A适应从开始到结束以恒定速率连续添加。在方法B的情况下，添加速率逐步改变。方法C表示间歇添加。这三种方法均在恒温条件下进行。而恒温法在模拟确定的条件下，选择性地获得了稳定形态的晶体。在方法A和方法B中，抗溶剂添加率在实验初期不能很高。因此，在实验初期，抗溶剂加成速率增加，并选择性地获得稳定的形态。通过三维（温度、IMC浓度和反溶剂浓度）溶解度图和模拟，在反溶剂结晶过程中成功获得了所需的晶型。少

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