Onyx is now licensed to manufacture commercial API from our UK facility
A pre-formulation 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 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 riskmitigated road map 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.
Where sufficient information exists from prior review or stability dictates that a salt is a requirement, a robust salt screen should be conducted. This work is also a natural next step following an early preformulation studies to better map out the available salt landscape, also generating valuable intellectual property.
While selection of the salt development pathway is relatively common, the foundations that support salt screening are applicable also to cocrystal screening as discussed below, although the design of the screen and prior selection criteria for salt or coformers is not equivalent.
As with all screening activity, understanding the impurity profile, composition and chemical stability of the API provides the foundation of a successful screen. This information used in conjunction with organic and aqueous-organic temperature solubility profiles of the candidate provide the platform from which parallel salt crystallisation screens may be conducted. Achieving the critical nucleation step for new versions and forms entails a certain degree of material understanding and attention to detail. So, whilst parallel screening is a pragmatic method to access a wide variety of conditions, the need to manipulate each screen in a variable manner should be expected. Subtle changes in solubility, supersaturation states, temperature and solvent composition are often the key to success and are not achieved by remote, predominantly automated screening.
The potential advantages of a salt or co-crystal such as improved dissolution characteristics and solubility, improved oral bioavailability and solid form stability will all aid in de-risking future development strategies.
Dissolution and solubility form a critical part of the salt review and selection process and include biorelevant assessment and assessment across a range of buffers. This information is used in conjunction with solid form stability under accelerated conditions, cycled DVS studies and process implications to arrive at a lead candidate for selection.
This data is interrogated in conjunction with information from our chemical development teams to consider process strategy and impurity rejection. It is also wise to project the downstream implication of a salt version as this and other factors (bulk density, flowability), may all impinge on the next phases of development. It is also not unusual to elect more than one candidate salt at this early juncture for differentiation and candidate selection following a review of the polymorphism landscape of each version.