Leveraging an understanding of solid state properties gained from API solid form screening and characterization, our scientists provide support and direction to design robust formulations for preclinical and clinical use. Our teams work closely together or with external providers to transfer knowledge and support drug product manufacture and scale-up activities of unit operations, including granulation, blending, milling, compression or preparation of solutions and semi-solids.
An unexpected interaction that affects the chemical or physical properties of the API or another critical component in the formulation can be deleterious to the development of a drug. These stability problems often lead to formulation changes that can require bridging studies, ultimately resulting in increased time to market. Our excipient compatibility studies save both time and cost by assessing the risk of excipient interactions prior to formulation development. We characterize the resulting materials to determine changes in both chemical and physical properties.
Enabling Poorly Water-Soluble Compounds
Our approaches to enable preclinical and early clinical evaluation of APIs with poor water solubility characteristics include supersaturated solutions and amorphous solid dispersions. Our scientists apply increasing solution concentration (or useful supersaturation) in aqueous formulations to identify suitable excipient combinations at varied concentrations and temperatures. We monitor physical stability to assess how effective excipients can inhibit crystallization. Based on these results, we conduct further experiments using a concentration gradient of the API and the most promising formulations from the initial study. Our experts then conduct scale-up of lead candidate formulations and determine thermodynamic solubility with respect to the API (or hydrate, if known).
A poorly water-soluble API processed with materials, such as polymers, can result in molecular dispersions where the API is embedded in a polymer matrix in a highly disordered or amorphous phase. We conduct screening for amorphous solid dispersions using manual experiments, where the particular combination of methods used — including spray drying, rotary evaporation and lyophilization — is determined based on the properties of the API and other excipients used in the composition. Given the importance of maintaining physical stability in the solid state and upon exposure to aqueous media, we conduct rigorous stress studies under various conditions to look for deliquescence and crystallization and in aqueous solutions to look for evidence of crystallization.
Given that the intended purpose of amorphous solid dispersions is to overcome the poor water solubility of the API, we conduct dissolution testing in both aqueous formulation buffers and biorelevant media over the relevant physiological pH range as criteria for amorphous solid dispersion candidate selection. We have developed test methods with the knowledge that the solid may not fully dissolve and that sink conditions will not be achieved in the GI tract, due in part to the distribution in the fluid volumes in vivo.
Upon identification of a composition with desired performance attributes, our scientists continue to support you through development. These activities can include development of reconstitution instructions for preparing an aqueous suspension for preclinical use all the way to dosage form development containing the amorphous solid dispersion.