A Supramolecular Gel Phase Crystallisation Strategy

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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.