It is well established that a large number of modern APIs demonstrate at least two polymorphic forms. The impact of not considering propensity to form change has also been well established over recent years with products suddenly failing against specification and performance criteria due to a significant change in solubility or dissolution rate. The cost of the subsequent development step required to understand and control the new form that has driven the change is significant and increases the further along the development pipeline the change is first noted.
For this reason, a robust screen of the polymorphic behaviour of an API or salt version is a necessity, irrespective of the intended route of formulation. A phase appropriate approach should be adopted.
In early development very little is known and many candidates are isolated as amorphous solids and with limited supply of material. However, conducting polymorphic screening, or ‘crystallisation review’, with a limited number of solvents is not expensive in terms of compound or resource (0.5-2.5 g, 1-2 weeks). This type of screen is especially useful where more than one development lead is presented and can aid in candidate selection.
Starting to gain an understanding of the physicochemical traits of the selected API aids in de-risking the development pathway and is considered a critical part of the pre-formulation evaluation for a compound, in particular when considering the relative merits of the API vs salt forms.
As more material becomes available and the route of synthesis fixed, a more rigorous investigation is warranted. The importance of impurity profile during this early work should not be underestimated. Working closely with the chemical development team to secure material of high purity is essential. That said, a degree of screening is often required to aid in this delivery rather than simply resorting to preparative HPLC purification.
Regardless, an understanding that impurities can have a marked impact upon the polymorphic behaviour of a compound should be a message that is retained throughout development. Our in-house screens typically start with highly purified material and subsequently include a screen that overlaps in terms of solvents and methodology using ‘process typical’ input, if this is deemed appropriate.
Polymorphic screening should always be taken as a compound specific operation and never based on a standard template. Whilst screening is conducted in parallel, observation of material behaviour is considered a critical activity.
This helps design a more informative screen that expands from an initial, broad solvent/temperature/solubility review. Stability should also be considered in advance of significant effort as whilst material may be taken as clean at input, degradation within solvent systems at temperature may lead to a perturbation of behaviour that will require further investigation.
As always, the more you study the more you learn and as the compound progresses toward later phase development, a subsequent and broader screen will become necessary in order to confirm that changes in chemistry/impurities have not triggered a change in form This is best placed once the synthetic route is established and development has progressed to a point where the impurity profile, composition and stability are well understood.
That said, no matter how robust and expansive the screen, it is optimistic to consider that all eventualities can be predicted. However, if polymorphism is taken as an iterative activity and communication between development groups is well established, the right steps can be taken in the right order to provide a successful development pathway that is based upon a fundamental understanding of the behaviour of the API.
To date Onyx has established the polymorphic landscape of hundreds of candidates, most of which have demonstrated complexity in terms of multiple forms, solvation, hydration and enantiotropic systems.
In combination with the varying degree of complexity regarding stability, complex synthesis and purge of impurity challenges, our teams have the right tools and credentials to successfully guide your compound from early development to the clinic and beyond.
“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