(M1530-08-50) Comparison of Colloids from HPMCAS Grades Across Physiologically Relevant Media

Purpose: Low solubility compounds have emerged as the predominant candidates in drug discovery, highlighting the need for solubility enhancement to enable viable drug products. Amorphous solid dispersions (ASDs) are a key technology for enhancing bioavailability of poorly soluble compounds. HPMCAS is often formulated with an API as an ASD because of its material properties that promote supersaturation, prevent recrystallization, and rapidly resupply free drug to the epithelial membrane. The crystalline solubility of discovery drugs can be significantly lower than their amorphous solubility, resulting in high pill burdens and inadequate exposure levels for the crystalline form. Since many new API candidates are DCS II (low solubility, high permeability) or IV (low solubility, low permeability), solubility enhancement and sustainment are essential for reaching sufficient exposure. Beyond solubility enhancement, compounds that are prone to crystallization must be well dispersed in polymer matrices to prevent nucleation and precipitation. ASDs that form polymer colloids in biorelevant media protect amorphous APIs from crystal nucleation by physically separating the API from itself. Therefore, it is essential to study polymer colloids under physiologically relevant conditions to evaluate how their chemical properties influence the physical attributes that affect the performance of the polymer. The material properties of an API determine which grade of HPMCAS could be most beneficial for sustainment and supersaturation. The grade of HPMCAS is determined by the ratio of succinyl (ionizable) and acetyl (non-ionizable) content; acetyl side chains contribute to a polymer’s relative hydrophobicity due to lack of ionizable groups, which restricts interactions with polar media. From a formulating perspective, neither HPMCAS-L, HPMCAS-M, nor HPMCAS-H are superior; rather, an effective ASD is created by balancing the material properties of the polymer with that of the API. To clarify the physical properties of HPMCAS in physiologically relevant conditions, HPMCAS was dissolved in various biorelevant media, and the resulting colloids were examined via DLS for size and distribution.

Methods: 28 mM Sodium Phosphate media was prepared at pH 5.8, 6.5, and 7.2, reflecting FaSSIF V1 composition and ionic strength. Polymers were dissolved in media at concentrations of 0.5 and 5 mg/mL. Samples were micro-centrifuged in an Eppendorf 5430 Centrifuge at 13,200 and 1,000 RPM for 3 minutes, respectively. Colloidal species were evaluated through dynamic light scattering using a Zetasizer Nano Instrument.

Results: Initial measurements show that polymer colloid size is dependent on the degree of hydrophobicity in HPMCAS. Amongst media centrifuged at 13200 RPM, polymer colloid size increased from HPMCAS-L (highest succinyl content) to HPMCAS-H (lowest succinyl content). The respective pH of the biorelevant media offers no clear trend on polymer size; HPMCAS-H has the largest colloids, while HPMCAS-L has the smallest colloids across media. Similarly, polymer concentration generally did not affect HPMCAS size ordering with respect to acetyl/succinyl content. Notably, when HPMCAS was prepared at 5 mg/mL in pH 5.8 media, large colloid size trended with higher succinyl content, indicating that other factors than acetyl-succinyl ratios may contribute to colloidal size. HPMCAS grades have clear ordering with respect to size and hydrophobicity when centrifuged to remove all undissolved species, however, this trend is ambiguous with light centrifugation. This discrepancy highlights the need for careful experimental planning when examining API-polymer interactions. Non-sink dissolution samples are often micro-centrifuged at speeds that eliminate small, undissolved particles without removing significant portions of dense colloids. In contrast, experiments that have pre-dissolved polymer, which aim to stabilize titrated API, typically have no centrifugation. API-polymer interactions examined at 0.5 mg/mL polymer at physiologically relevant pH 6.5 media may yield contradictory data if colloid size and density influence drug-polymer interactions. Although colloid size is an important consideration for API sustainment and supersaturation, it is also relevant to diffusivity in the gastrointestinal tract (GIT), as diffusivity is inversely correlated to hydrodynamic radius. Colloid sizes observed at 13200 RPM may be most relevant for passive diffusion as the largest colloids observed at 1000 RPM may be too big to significantly contribute to diffusion across the unstirred water layer. As an ASD travels through the human GIT, environmental pH will rise from ~5.8 in the duodenum to ~7.2 in the distal ileum. Across these biorelevant pHs, it is likely that HPMCAS-L would diffuse the fastest due to it relatively small hydrodynamic radius, while HPMCAS-H would diffuse the slowest.

Conclusion: This study establishes a novel and strong baseline understanding of how industry-relevant polymers exist in biorelevant media. In aqueous media, decreased succinyl content in HPMCAS is correlated with larger colloids. As a result, HPMCAS-L exhibited the smallest colloids, with HPMCAS-H showing the largest across a range of biorelevant pH’s. In future work, DLS measurements will be complemented by assay values measured by HPLC to determine what fraction of polymer is removed by moderate microcentrifugation. This will offer a deeper understanding of colloidal size with respect to the total dissolved polymer population.

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