Engineering a New Access Route to Metastable Polymorphs with Electrical Confinement
Engineering a New Access Route to Metastable Polymorphs with Electrical Confinement
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DOI：
10.1021/acs.cgd.9b01100
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发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Castro-Dominguez, Bernardo
中科院分区：
文献类型：
--
作者：
Al-Ani, Aneesa J.;Herdes, Carmelo;Castro-Dominguez, Bernardo
多态性是包括活性药物成分（原料药）在内的固体物质以结构独特的排列方式存在的能力。多态的存在和分子排列的差异使晶体具有多种不同的物理性质。因此，实验控制和预测多晶形成的能力对于获得api的期望性质的一致访问至关重要。在这项研究中，对乙酰氨基酚（paracetamol； PCM）的亚稳态形式II进行了多态控制，结合使用电喷涂（一种利用电雾化前体并在小液滴表面产生电荷的方法）和模板成分metacetamol （MCM）。以前，api的多态控制受到限制，因为缺乏通过改变单个变量（如电喷雾实验中的电压）在多态形式之间切换的能力。此外，在广泛的api之间转移以获得多态控制的单一结晶方法通常是不可用的。电喷雾技术作为一种结晶方法提供了一种潜在的强大的、机械上独特的、高溶剂效率的替代方法，有望克服这些限制。这项工作表明，多晶的形成直接受到诱导结晶的热力学条件的影响，并且可以通过电喷涂来影响，通过电场取向和约束来指导晶体的分子排列。电喷雾在制药结晶方面具有广泛应用的潜力，它可以提供一个替代的起点，将多晶系统转移到工业规模的连续制造平台。
Polymorphism is the ability of solid materials, including active pharmaceutical ingredients (APIs), to exist in structurally distinctive arrangements. The existence of polymorphism and the difference in molecular packing can cause crystals to have a variety of different physical properties. Therefore, the ability to experimentally control and predict polymorph formation is vital to gain consistent access to desired properties of APIs. In this study, polymorphic control of the metastable form II of acetaminophen (paracetamol; PCM) was achieved, coupling the use of electrospraying (a method that uses electricity to atomize the precursor and create a charge on the surface of small droplets) and a template component, metacetamol (MCM). Previously, polymorphic control of APIs has been limited by the lack of ability to switch between polymorphic forms with the change of a single variable (such as voltage in electrospray experiments). Also, a single crystallization method that is transferable between a wide range of APIs to gain polymorphic control is not generally available. The electrospray technique as a crystallization method offers a potentially powerful, mechanistically distinct, and highly solvent-efficient alternative approach that promise to overcome these limitations. This work shows that polymorph formation is directly influenced by the thermodynamic conditions that induce crystallization and that they can be affected by electrospraying, guiding the crystal's molecular arrangement via electric field orientation and confinement. Electrospray has the potential for broad applications in pharmaceutical crystallization and it can provide an alternative starting point to transfer polymorphic systems into continuous manufacturing platforms at an industrial scale.