A Supramolecular Gel Phase Crystallisation Strategy

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.

The crystal form of drugs determines their solubility, dissolution rate, bioavailability and mechanical properties. A complete understanding of the possible crystal forms of a drug is a regulatory requirement for pharmaceutical registration for use in humans, as encompassed by the International Conference on Harmonisation Q6A guidelines. Currently, pharmaceutical companies rely on high throughput screening of different crystallisation conditions in the hope of identifying suitable stable polymorphs, but with no guarantee of success. A particular commercial risk is a late-appearing stable and hence insoluble solid form, while a change of form to a more soluble material can have toxic effects. This project does not seek to replace current screening methods. Rather it adds to them, expanding the methods available to discover new solid forms by providing carefully engineered gels that can stabilize hitherto unknown forms, particularly those with a high nucleation barrier. The economic case is clear in an industry with a US$ 105.7 billion annual turnover. Even one new solid form or one avoided disaster will pay for this project many times over. Furthermore, using an easily applied gel toolkit is likely to result in swifter identification of relevant solid forms at a reduced cost and typically within a shorter time frame than conventional methods alone. The beneficiaries of this research are therefore industrial drug preformulators and formulators, pharmacists and ultimately patients. This project also sheds fundamental light on the enduring question of why it is possible to computationally calculate more crystal structures than can be experimentally observed. This project will help to establish whether these predicted structures can be produced in practice by aiding their nucleation, or whether they are an artifact of the computational methodology. This will benefit all scientists involved with crystallization phenomena and have practical application in guiding solid form choice in drug and also agrochemical formulation. The project's results will be developed in an industrial setting at AstraZeneca and crystal forms discovery company Circe.