Early solid form characterization and selection: a key point for the development of topical pharmaceuticals.

Often neglected before reaching an advanced stage of development, understanding and controlling the solid form of a new chemical entity (NCE) is a critical factor in the selection of a drug candidate and its successful development especially via topical route.

In the solid state, a compound can be organized following various arrangements depending on the type and number of bonds that molecules are able to form together. For a given compound, each of these different structures (called polymorphs) may have radically different physico-chemical properties (e.g. solubility, bioavailability, dissolution rate...). This behavior, specific to each molecule, is not predictable and the appearance of new polymorph is possible throughout the entire development process. Therefore, controlling the solid form of an NCE is crucial, especially for topical development since the drug candidate is preferentially solubilized during formulation. Late appearance of a more stable (and therefore less soluble) polymorph could indeed ruin all early formulation work. It is also a prerequisite from regulatory agencies during the filing process.

 For topical applications, solubility in specific excipients is a key parameter to optimize during the drug discovery process. Therefore, it is important to perform solid phase study and selection very early in the candidate selection process, ideally before the final candidate selection. When only a small number of lead molecules remain it is interesting to perform a preliminary solid form investigation, to have a flavor of the solid form behavior of the molecule and to make sure that solubility data are robust.

That’s what we have implemented in our process development team (especially with solid form expert Jean-Marie Arlabosse). The starting point of our solid phase studies is to subject the potential drug candidates to an extensive set of conditions (temperatures, solvents, additives...) in order to generate crystalline phases and thus determine their propensity to form polymorphs. Each phase is then fully characterized and the relative stability of each polymorph is evaluated. Typical characterization techniques include differential scanning calorimetry (DSC), X-Ray Powder Diffraction (XRPD), microscopic analysis, thermogravimetric analysis, NMR, water content…

A selection is made in order to choose the polymorphic form most suited for development (stability, robustness, solubility ...) and early formulation work can start. If targeted solubility cannot be reached, additional investigations (salt formation, new solvates…) can be performed to fulfill requirements of preclinical and clinical programs.

Early solid form characterization and selection is an extremely important step in the development of a new drug candidate, especially for a topical rout of administration. It is also a way to build great scientific relationships with our drug designer, synthetic medicinal chemists and formulation colleagues.