What is Solid Form Discovery & Selection?
In the pharmaceutical (and agrochemical) industry, the field of Solid Form Discovery & Selection covers activities that help in the discovery of novel solid forms (polymorphs, salts and cocrystals) of New Chemical Entities (NCEs) followed by the selection of the most viable solid form for development. The term “Solid Form Screening & Selection” is also often used to describe these activities which typically include polymorph screening, salt screening and cocrystal screening as appropriate.
Why is Solid Form Screening & Selection Important?
Novel solid form screening and selection is an essential part of drug development with significant legal, financial and medical implications. By the time of an NDA submission, the FDA requires an applicant to have established whether (or not) the drug substance exists in multiple solid forms (e.g. polymorphs, solvates, hydrates) and whether these affect the dissolution and bioavailability of the drug product. Solid forms such as polymorphs, salts, cocrystals and their hydrates and relevant solvates are also patentable, thereby creating significant intellectual property for pharmaceutical companies. From a technical perspective, the selected solid form needs to be made using a robust scalable process, have good physical and chemical stability and have the required bioavailability. Failure on any of these counts can lead to a drug not making it to the market; this makes the activities of polymorph screening, salt screening and cocrystal screening a critical part of drug development.
It is important to note that salts and cocrystals can have their own polymorphs, solvates and hydrates which are independent of the polymorphs, solvates and hydrates of the free molecule.
What are polymorphs and why are they important?
Polymorphs are different crystalline structures of the same chemical compound. Different polymorphs often have different physicochemical properties and the most reliable way to discover them is by carrying out polymorph screening experiments. The FDA's 2007 Guidance on Polymorphism talks about the influence of polymorphism on solubility, dissolution, bioavailability, manufacturing and stability of active pharmaceutical ingredients (APIs).
What are salts and why are they important?
Salts are formed when an ionizable molecule forms a strong ionic interaction with an oppositely charged counterion. For ionizable molecules, salt screening can improve the physicochemical or biopharmaceutical (e.g. improved bioavailability) properties of the free form API. The most reliable way to discover salts is by carrying out salt screening experiments. Salts can have their own polymorphs, solvates and hydrates which are independent of the polymorphs, solvates and hydrates of the free molecule. Typically, salt screening experiments are followed by polymorph screening experiments on the selected salt.
What are cocrystals and why are they important?
Cocrystals are crystalline materials composed of two or more different molecules, typically API and cocrystal formers (coformers), in the same crystal lattice. Cocrystals are distinguished from salts because unlike salts, the components that coexist in the cocrystal lattice with a defined stoichiometry interact nonionically. For non-ionizable or weak base/acid APIs, cocrystals can help find suitable development candidates with the desired physicochemical and biopharmaceutical properties. The FDA's recently finalized (2018) guidance on cocrystals has led to significant interest in this field. Cocrystals can have their own polymorphs, solvates and hydrates which are independent of the polymorphs, solvates and hydrates of the free molecule. Typically, cocrystal screening experiments are followed by polymorph screening experiments on the selected cocrystal.
When Should We Begin Solid Form Screening Activities?
Solid Form Screening activities should typically start post discovery, once gram scale quantities (~ 0.5 g – 1 g) of the drug are available. Typical activities include running polymorph screens, salt screens and/or cocrystal screens as appropriate, selection of the most viable solid form and crystallization process development activities (including particle engineering and scale up). Solid Form and/or Crystallization support is needed throughout drug development and even during commercial manufacturing.
What is an Ideal Solid Form Screening Strategy?
An ideal Solid Form Screening strategy should identify polymorphs, salts and cocrystals as appropriate using a risk-based approach (risk identification and mitigation). Polymorph screening, salt screening and cocrystal screening can be completed in parallel or in series as appropriate. With constantly shrinking drug development timelines, the objective should be finding an optimal solution to the solid form problem based on time and resources available. The workflows being used should be easily customizable based on the structure of the drug molecule and the drug development timeline (Phase-Appropriate).
