Onyx is now licensed to manufacture commercial API from our UK facility
A preformulation risk assessment for a drug includes evaluation of salt forms of the API and is best addressed during the early phases of a candidate’s life cycle. This will include a thorough physicochemical evaluation of both the parent and any new salts under consideration.
The preformulation studies should be phase appropriate and iterative, building upon the learnings and understanding from earlier investigations and be inclusive of feedback from all research activities. Ultimately, a well-defined and risk mitigated roadmap for development should become clear.
In order to answer these questions early in development does not necessarily require a significant material cost, this being especially important where more than one viable candidate is moving out of lead optimisation.
This question and the workflow to be applied is guided to a degree by the performance indications already in place for the API. If these do not exist or are entirely predictive, they should ideally be verified (such as pKa and LogD/LogP). This is of particular importance for those compounds that display poor physicochemical characteristics such as very low aqueous solubility and/or poor bioavailability.
The review should focus on distinguishing between the viability of salt versions vs the API – particularly where pKa values (either predicted or measured) suggest a thermodynamically stable salt may be challenging to develop. A typical source of challenge at this point is disproportionation, either in solution or in the solid state at the surface of the solid, and is a critical characteristic to understand as early as possible.
This can be accomplished by a rapid, yet robust ‘health check’ of the selected API or competing lead candidates.
An understanding of the general solubility characteristics should be benchmarked in an aqueous and aqueous organic environment across a range of pH and buffer types. This should be underpinned by a review of the chemical stability of the candidate with degradation pathways mapped under a variety of conditions. This stability review is a foundation for all activities conducted at Onyx and is instrumental in the design of screens that aim for success from the outset.
With stability established, the pH solubility profile of the candidate should be reported. This is best accomplished alongside a crystallisation screen of the API to identify a crystalline form for assessment in parallel with the amorphous phase, if both are accessible.
A micro-screen with the aim of accessing salt versions via a number of methodologies, be that classical solution based screening or suspension based maturation within a range of acid chemotypes are typical studies to include.
The resulting profile should deliver information relative to the viability of salt formation, the uplift in solubility salts might deliver and any kinetic improvement in the dissolution of the candidate when presented as a salt.
This should also be supported by a kinetic and thermodynamic review of biorelevant performance that will improve the understanding provided by the pH solubility profile and give an early indication of how each version might differ when presented in vivo.
In conjunction with a solid state stability review of the versions available, a decision of which candidate to progress may be taken on the basis of a reliable data set. The option to support this with a PK study of each version can also be justified to demonstrate improved exposure or parability and continue to embellish material understanding.
This review is also significant where a salt will not form based upon structure and will aid in the decision of whether to elect an alternative development pathway such as a spray dried amorphous dispersion or cocrystal formation.