High hydrophobicity and intrinsically low water solubility are increasingly common characteristics of development candidates, and ultimately marketed drugs. To meet this pharmaceutical challenge, various solubilization technologies have been developed including amorphous solid dispersion, salt formation, drug particle size reduction and solubilization in lipid vehicles. Among these technologies, amorphous solid dispersions which kinetically stabilize an active pharmaceutical ingredient (API) in an amorphous state stand out and become important formulation approaches to enhance drug solubility and dissolution rate, particularly for non-ionizable compounds.<br/><br/>The design and development of successful amorphous solid dispersion formulations requires the integration of scientific, technological and biopharmaceutical aspects to arrive at a robust drug product. Despite decades of research on amorphous solid dispersions, there still remain many unanswered questions regarding their performance due to complexities in these systems. This has also resulted in a low number of amorphous systems being commercialized. The main reason for the poor understanding of amorphous systems is due to limited knowledge on i) the mechanism of API-excipient interactions in the solid state, and ii) the API release mechanism both in-vitro and in-vivo.<br/><br/>In this study, we performed anti-nucleation experiments to understand API-polymeric excipient interactions at the molecular level in amorphous solid dispersions. Hydroxypropyl methylcelluloses (HPMCs) with different ratios of methoxyl and hydroxypropyl (HP) substitutions, and viscosity were chosen to investigate how the interactions (i.e. H-bonding or hydrophobic) affect API nucleation and supersaturation. We first evaluated the polymers with a high throughput screening (HTS) experimental approach. Then, a scale-up study using a fiber optic system was performed on the selected polymers that showed best performance from the HTS.The results from both HTS and fiber optic system have shown that higher hydroxypropyl (HP) substitution in HPMC results in less supersaturation of the API in solution and shorter crystallization induction times, indicating that hydrophobic and/or H-bonding interactions between the API and polymer may contribute to maintain API supersaturation and inhibit nucleation growth. Further investigations will be focused on NMR studies to monitor API-polymer interactions both in solid dispersions and during dissolution.

Mechanistic understanding of polymeric excipients for inhibiting active pharmaceutical ingredient (API) nucleation in amorphous solid dispersions

256th National Meeting (2018)

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