Pre-formulation

Pre-formulation is defined broadly as the physicochemical characterization of an active pharmaceutical ingredient (API). The data on compound properties collected during the pre-formulation stage inform future directions of a drug development program, particularly the formulation development and design of storage stability studies. The issues addressed include solubility of an API relative to expectations of the drug development team, compatibility with excipients, short term solution and solid state stability, and other concerns. In general, a systematic and comprehensive pre-formulation study is a prerequisite for developing a successful and robust formulation. Proper attention to the pre-formulation stage of a drug development program can save a great deal of time and effort as the API is progressed toward clinical trials.

WLI routinely designs and performs pre-formulation studies for its clients. WLI appreciates that the scope of pre-formulation work, indeed any project, must be adapted to a client’s current needs, financial constraints, and business and scientific plan. The design of pre-formulation studies is customized further based on projected mode of administration and estimated dosing requirements. For pre-nomination stage compounds or for lead selection, rigorous pre-formulation studies may be inappropriate. In these cases, a customized discovery formulation screen is a useful alternative. 

WLI performs pre-formulation work with a variety of drug substances, including small molecules, peptides, proteins, oligonucleotides, and cytotoxic materials.

To read an article on pre-formulation, click here.

X-Ray Powder Diffractometry

X-ray powder diffractometry (XRPD, also called XRD) is an analytical technique used to distinguish different solid forms. An XRPD pattern is a unique identifier of a particular crystalline solid state and changes in percent crystallinity of a sample relative to another sample of the same material also may be estimated by visual inspection of the pattern. Similarly, contamination by another crystalline form, a polymorph or a solvate, may be detected by XRPD analysis. This technique is indispensable in salt screening, solid state stability studies, polymorph screening, development of solid dosage forms. Moreover, pre-formulation and formulation development work may require understanding of solid state structure for proper interpretation of solubility and dissolution rate data.

In the figure above, a series of crystalline products was obtained by successive purifications. Comparison of the XRPD patterns was useful, in conjunction with other experimental data, in determining how many purifications need to be performed to obtain the desired product.

Salt Screening

The benefits that can accrue from undertaking a salt screen, provided that a lead compound can form a salt, include improved stability and handling properties, a better solubility profile, lower dosage mass, and improved bioavailability. These improvements, when used as a foundation for further development, may lead to a more efficacious drug, which is formulated in a simpler and cheaper delivery vehicle.

The proper salt selection can have a substantial impact on the stability of an active pharmaceutical ingredient and its physicochemical properties. Determination of a pH-solubility profile should proceed a salt screen. The entire process is recommended prior to candidate nomination.

A series of complimentary techniques are brought to bear for selection of a salt form for further development. The relevant parameters to consider include, but are not limited to, melting point; solid state properties like crystallinity, polymorphism, and polymorph interconversion; chemical and physical solid state stability; hygroscopicity; particle size and morphology, reproducibility of synthesis and purification, etc. On the basis of an entire data set obtained for each salt form under review, selection is made for a lead and a back up drug substance to take into development. In this fashion, salt forms with detected liabilities that could delay or derail a development program are eliminated.

In the case study table above, Salt A was selected for development.