A Supramolecular Gel Phase Crystallisation Strategy

药物中使用的原料药的晶体形式（称为“多晶”形式）对制药业来说是一个非常重要的问题。晶体的性质直接决定了晶体的溶解度、溶出率、药物生物利用度、稳定性、吸湿性和保湿性以及给药性和易滤性等力学参数。对原料药进行筛选以确定其所有可能的多态形式是一项监管要求和实际需要。这一过程通常是经验性的，可能无法识别关键的晶体形式，特别是当它们成核缓慢时。20世纪90年代末，由于未能确定最稳定的抗艾滋病药物利托那韦，雅培公司不得不召回产品并重新配制，为此花费了数百美元。该项目的总体目标是利用超分子凝胶技术最大限度地提高制药行业固体形式筛选的效率和可靠性。我们将通过开发一个合理的超分子凝胶结晶介质工具包和固体形式筛选方案来实现这一目标。由此产生的凝胶相结晶方法将与药物开发期间进行的传统盐和多晶筛选同时使用（并作为其一部分）。凝胶的设计将基于其结构的计算计算和原料药可能的多晶型的计算计算。然后，凝胶将用于目标晶化的多晶，这些多晶是通过计算预测的，但不是通过普通的结晶技术实验观察到的。这个想法是，一种新的活性药物成分（API）将受到合理设计的凝胶相固体形式筛选，更确定地发现难以成核或瞬态固体形式。对于制药行业来说，确定全范围的固体形式以防止后期出现的不溶性或麻烦的形式，确保全面的知识产权保护并优化诸如生物利用度，可加工性和溶出率等特性至关重要。此外，利用先进的结晶方法，以计算预测的固体形式为目标，而不是通过实验观察到的能力，对我们理解结晶过程具有关键的基础重要性。该项目由两个学术实验室、一家大型制药公司和一家专业晶体形式筛选合同研究机构合作完成。学术实验室专注于(1)先进的结晶方法和超分子凝胶，(2)理论计算晶体结构计算。工业合作伙伴的参与确保了该方法适用于固体形式筛选的实际应用，并且可以充分利用其影响。

The crystal form of drug substances (termed 'polymorphic' form) used in medicines is an issue of extraordinary importance to the pharmaceutical industry. The properties of the crystal directly determine solubility, dissolution rate, drug bioavailability, stability, moisture absorption and retention and mechanical parameters such as tabletability and ease of filtration. It is a regulatory requirement and practical necessity for drug substances to be screened to identify all of their possible polymorphic forms. This process is generally empirical and can fail to identify key crystal forms, particularly if they are slow to nucleate. The failure to identify the most stable form of the HIV drug ritonavir in the late 1990's resulted in a product recall and reformulation at a cost of hundreds of missions of dollars for Abbott labs. The overall aim of this project is to maximise the efficiency and reliability of solid form screening in the pharmaceutical industry using supramolecular gel technology. We will achieve this aim by developing a rational toolkit of supramolecular gel crystallization media and a solid form screening protocol for their use. The resulting gel phase crystallization approach will be used in parallel with (and as part of) traditional salt and polymorph screening undertaken during drug development. Gels will be designed based on computational calculation of their structure and computational calculation of the likely polymorphs of the drug substances. The gels will then be used to target the crystallization of polymorphs that are computationally predicted but not observed experimentally by ordinary crystallization techniques. The idea is that a new active pharmaceutical ingredient (API) will be subjected to rationally designed gel-phase solid form screening with far greater certainty of discovering hard-to-nucleate or transient solid forms. It is vital for the pharmaceutical industry to identify the full range of solid forms to prevent late-emerging insoluble or troublesome forms, ensure full IP protection and optimise properties such as bioavailability, processability and dissolution rate. Moreover the ability to use advanced crystallization methods to target computationally predicted solid forms that are not otherwise experimentally observed is of key fundamental importance in our understanding of the crystallization process. This project is a collaboration between two academic labs, a large pharma company and a specialist crystal form screening contract research organization. The academic labs specialize in (1) advanced crystallization methods and supramolecular gels, and (2) theoretical computational crystal structure calculations. The involvement of the industrial partners ensures that the methodology is suitable for real world application in solid form screening and that its impact can be fully exploited.