奥氮平从无定形固体分散体中结晶的同时差示扫描量热法-X 射线衍射研究,Molecular Pharmaceutics

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奥氮平从无定形固体分散体中结晶的同时差示扫描量热法-X 射线衍射研究
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-10-19 , DOI: 10.1021/acs.molpharmaceut.0c00846
Sean Askin ₁ , Andrea D Gonçalves ₂ , Min Zhao _{3,

4} , Gareth R Williams ₁ , Simon Gaisford ₁ , Duncan Q M Craig ₁

Affiliation

水溶性聚合物中 II 类和 IV 类生物制药分类系统药物的无定形固体分散体 (ASD) 是公认的提高溶出度的方法，而疏水聚合物中的此类分散体构成了微米和纳米颗粒技术的基础。然而，药物重结晶给产品开发带来了重大问题，并且所涉及的机制和途径知之甚少。在这里，我们概述了使用组合差示扫描量热法 (DSC)-同步加速器 X 射线衍射来监测分散在一系列聚合物中时奥氮平 (OLZ) 多晶型物的连续外观。在最近的一项研究 ( Cryst. Growth Des. 2019, 19,2751-2757），我们报道了一种新的 OLZ 多晶型物（IV 型），它是从 OLZ 在聚乙烯吡咯烷酮中的喷雾干燥分散体中结晶出来的。在这里，我们扩展我们先前的研究，探讨聚OLZ分散体（丙交酯共-乙交酯) (PLGA)、聚丙交酯 (PLA) 和醋酸琥珀酸羟丙基甲基纤维素 (HPMCAS)，目的是确定加热每个分散体时的形态生成顺序。虽然喷雾干燥的 OLZ 导致形成晶型 I，但具有 HPMCAS 的喷雾干燥材料包含 ASD，并且在加热时生成 I 型和 IV 型。PLGA 和 PLA 产生的产物同时含有无定形 OLZ 和二氯甲烷溶剂化物；加热时，无定形材料转化为 I、II 和 IV 型，溶剂化物转化为 I 和 II 型。我们的数据表明，不仅可以定量评估多晶型生成序列，还可以定量评估作为温度函数的相对比例。特别值得注意的是，形式生成的顺序比单独的 DSC 数据可能表明的要复杂得多，随着材料加热同时产生不同的多晶型物和复杂的相互转化。我们认为，这可能不仅对多晶型生成的机制理解有影响，而且还有助于确定单一药物分子可能产生的多晶型范围。

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A Simultaneous Differential Scanning Calorimetry–X-ray Diffraction Study of Olanzapine Crystallization from Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) of class II and IV biopharmaceutics classification system drugs in water-miscible polymers are a well-recognized means of enhancing dissolution, while such dispersions in hydrophobic polymers form the basis of micro- and nanoparticulate technologies. However, drug recrystallization presents significant problems for product development, and the mechanisms and pathways involved are poorly understood. Here, we outline the use of combined differential scanning calorimetry (DSC)-synchrotron X-ray diffraction to monitor the sequential appearance of polymorphs of olanzapine (OLZ) when dispersed in a range of polymers. In a recent study (Cryst. Growth Des.2019,19, 2751–2757), we reported a new polymorph (form IV) of OLZ which crystallized from a spray-dried dispersion of OLZ in polyvinylpyrrolidone. Here, we extend our earlier study to explore OLZ dispersions in poly(lactide-co-glycolide) (PLGA), polylactide (PLA), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), with a view to identifying the sequence of form generation on heating each dispersion. While spray-dried OLZ results in the formation of crystalline form I, the spray-dried material with HPMCAS comprises an ASD, and forms I and IV are generated upon heating. PLGA and PLA result in a product which contains both amorphous OLZ and the dichloromethane solvate; upon heating, the amorphous material converts to forms I, II, and IV and the solvate to forms I and II. Our data show that it is possible to quantitatively assess not only the polymorph generation sequence but also the relative proportions as a function of temperature. Of particular note is that the sequence of form generation is significantly more complex than may be indicated by DSC data alone, with coincident generation of different polymorphs and complex interconversions as the material is heated. We argue that this may have implications not only for the mechanistic understanding of polymorph generation but also as an aid to identifying the range of polymorphic forms that may be produced by a single-drug molecule.

更新日期：2020-11-02

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