Leveraging the fundamental understanding of solid-state properties gained during API solid form screening and characterization, SSCI scientists can provide support and direction to design robust formulations for pre-clinical and clinical use. SSCI then works closely with other AMRI sites or other external providers identified by our clients 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.
The consequences of finding 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 which can require bridging studies ultimately resulting in increased time to market. Excipient compatibility studies run at SSCI can save both time and cost by assessing the risk of excipient interactions prior to formulation development. The studies rely on intimate contact between the API and excipients and try to maximize the affective exposed surface area. Excipient compatibility samples are stressed at an appropriate condition and the resulting materials are characterized by a number of analytical techniques to look for changes in both chemical and physical properties.
Enabling Poorly Water Soluble Compounds
Strategies to enable pre-clinical and early clinical evaluation of poorly water soluble APIs include supersaturated solutions and amorphous solid dispersions. Increasing solution concentration (or useful supersaturation) in aqueous formulations using manual and semi-automated approaches are used by SSCI scientists to identify suitable excipient combinations at varied concentrations and temperatures. By this approach, physical stability is monitored to assess the effectiveness of excipients to inhibiting crystallization. Based on these results, further experiments are conducted using a concentration gradient of the API and the most promising formulations from the initial study to determine the upper bound of API supersaturation. Scale-up of lead candidate formulations is then conducted and thermodynamic solubility with respect to the API (or hydrate, if known) is determined.
Where a solid material with new and potentially useful properties is desired, poorly-water soluble API processed with materials, such as polymers, can result in molecular dispersions, where the API may be embedded in a polymer matrix in a highly disordered or amorphous phase. Molecular dispersions are typically used to attain greater dissolution rates. However, the amorphous materials are metastable relative to the crystalline state, with a thermodynamic tendency to recrystallize, thus offsetting the potential beneficial effects of the greater aqueous solubility. The pharmaceutical implications of developing materials containing one or more amorphous components has been discussed in the context of understanding the microstructure, where different methods of processing may produce materials with similar x-ray powder diffraction (XRPD) patterns and different physical properties. Materials described as ‘x-ray amorphous’ are typically characterized further by thermal analysis techniques where the appearance of a glass transition temperature (Tg), provides support for the non-crystalline nature of the material.
It has been demonstrated that it is not always possible to determine the physical state of these materials, that is miscible or phase separated, based only on the determination the glass transition temperature (Tg) using differential scanning calorimetry (DSC), where one Tg apparently indicates a single amorphous phase and two Tg values indicate phase separation of the two phases. To this end, high-quality, low background XRPD measurements of the individual components can be used in an attempt to describe the formulated samples containing API and polymer and used to show that a system exhibiting only one Tg still can be completely phase separated as an amorphous mixture. Such a system may have long term stability issues leading to drug product failure.
Screening for amorphous solid dispersions at SSCI is conducted 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. A broad range of pharmaceutically-acceptable stabilization agents at various loadings is used initially. Given the importance of maintaining physical stability in the solid state and upon exposure to aqueous media, SSCI conducts rigorous stress studies under various conditions such as at elevated humidity to look for deliquescence and crystallization and in aqueous solutions to look for evidence of crystallization.
Given the intended purpose of amorphous solid dispersions is to overcome the poor water solubility of the API, SSCI conducts dissolution testing in both aqueous formulation buffers and biorelevant media over the relevant physiological pH range as an essential criteria for amorphous solid dispersion candidate selection. Test methods used by SSCI have been developed with the knowledge that solid may not fully dissolve and sink conditions will not be achieved in the GI tract, due in part to the distribution in the fluid volumes in-vivo.
Materials determined to be x-ray amorphous with an apparent increase in Tg as prepared (where relevant), that are non-deliquescent with no evidence of crystallization on stressing, and that achieve solution concentrations that exceed the thermodynamic solubility of the API over the timeframe necessary for improved in-vivo exposure are preferentially advanced and recommended for further development.
Upon identification of a composition with desirable performance attributes, SSCI scientists continue to support our clients through development based on our experience and understanding of the properties of the solid form. These activities can include development of reconstitution instructions for preparing an aqueous suspension for pre-clinical use all the way to dosage form development containing the amorphous solid dispersion.