Onyx is now licensed to manufacture commercial API from our UK facility
Batch crystallization is a critical part of the development pathway for an API. The level of understanding and time associated with the development of this operation should be considered as a phase appropriate undertaking that is iterative, where the level of investment and subsequently the control achievable increases as candidate development progresses.
The ideal target is a cooling crystallization process, be that for API or API as a salt version. These are typically easier to control as there are fewer variables, yet with the appropriate choice of solvent still deliver in terms of yield. The anti-solvent driven alternative is of course viable, but without sufficient care and understanding can be more prone to the generation of high super-saturation. This in turn can lead to unwanted effects such as oiling out (phase separation), vessel fouling and impurity entrainment.
Another critical element of crystallization development is communication between chemical development and the crystallization team such that both understand the specification targets that can be realistically achieved, in particular during early development where batch history and number are limited. The nature of the material, the associated impurities (organic and inorganic) and wt-wt assay are all important data points to consider.
More importantly, the behaviour of a ‘process typical’ batch of non-purified API versus that of the purified phase is also a critical piece of data to articulate. It is often a lack of understanding of the nature of batch composition, associated impurities, the instability of the API and impurities and the impact these can have upon a crystallisation that lead to failure. Of course, all of this detail takes time and effort to evolve throughout development, but commitment to feedback from the various groups as batch number increases facilitates the avoidance of risk through greater understanding.
The foundation for any crystallization development process is solubility. A pragmatic study of the available solvents using the desired form, conducted in a tightly controlled manner at ambient temperature e.g. 20°C +/- 1°C should provide a platform for the design of a viable process. If this is coupled with a study of the purge of impurities and material observation during a cycled heating and cooling operation, a platform for process design can be readily obtained.
Once solvent selection has taken place, critical process operations such as seeding point and loading, cooling rate, anti-solvent addition rate and maturation times/cycle times can be identified.
Even for early phase candidates a brief review of the above, coupled with an in-process review of crystallization kinetics and control of super-saturation can provide the detail required to deliver a suitable purification, fit for transfer to clinical production and also fit for scale-up from gram to multi-kilo batch production.
For those candidates whose behaviour is relatively simple, control over morphology may also be delivered if sufficient information is already in hand to guide a target particle size specification. As development progresses, such critical attributes naturally become more readily controlled as understanding and investment in the process increases and feedback from both chemistry and formulators continues to help guide optimisation of both drug substance and drug product.
Onyx has navigated multiple complex crystallization development programs through Phase 1, a number of which have progressed to Commercialisation, including isolation of meta-stable forms, navigation of complex solvate-hydrate form inter-conversions and manipulation of enantiotropic systems to deliver the target form.
Our experienced leadership teams and the facilities within solid form development and chemical development, located at the same site provide the basis for an efficient progression of your candidate molecule.