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.
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.
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 pre-formulation health check 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.
“We were delighted with the service provided by Onyx Scientific in conjunction with Reach Separations in carrying out full characterisation and identification. The joint effort allowed us to undertake impurity synthesis to get a positive identification of impurity followed by the purification of a sample by prep LC. We found the whole process to be quick, efficient and cost-effective.”Sam Hubbard, Analytical Laboratory Manager at Oxford Analytical Ltd
“We have found Onyx Scientific to be a cost-effective CMO for API scale-up as well as related analytical and solid state development related to ESN364, Euroscreen’s clinical candidate currently in clinical trials. In fact, we found Onyx Scientific to be cost competitive even when compared against certain Indian CMOs. In addition to this, Onyx Scientific offers the added advantage of proximity in terms of location (and time zone), ease of communication as well as their experience and know-how.”Hamid Hoveyda, Director of Chemistry at Euroscreen SA
“Onyx Scientific has proven to be technically very capable when it comes to carrying out analytical projects. The team took their time to understand our specific requirements and came up with solutions to overcome any challenges. Communication with the team has been particularly excellent. Importantly for us, the speed of delivery was also exceptional.”David Childs, Director CMC at Shield Therapeutics