Design and Development of HPMCAS-Based Spray-Dried Dispersions

Abstract

Low-solubility compounds comprise nearly one third of all active pharmaceutical ingredients (APIs) in early development, and up to 70 % of oncology and anti-infective compounds. Spray-dried dispersions (SDDs) of low-solubility compounds using hydroxypropyl methylcellulose acetate succinate (HPMCAS) have proven particularly effective at enhancing oral bioavailability. They do so by (1) enhancing solubilized drug levels compared with crystalline drug, (2) enhancing the dissolution rate compared with crystalline drug, and (3) sustaining enhanced solubilized drug levels in intestinal milieu for a physiologically relevant time.

HPMCAS also has properties that promote solid-state kinetic stabilization of SDDs. These properties include: (1) a heterogeneous distribution of functional groups that interact with a broad range of chemical moieties; (2) a high glass transition temperature (T _g), which limits mobility and stabilizes amorphous drug; and (3) relative hydrophobicity, which limits plasticization of the SDD when stored at high relative humidity (RH) or in the presence of residual solvent from the spray-drying process.

Spray drying has proven to be a robust and scalable method (from milligrams to metric tons) to manufacture drug/polymer dispersions from early formulation screening through commercial manufacture. Spray drying from an organic solution enables rapid drying kinetics, which can be critical for preparing homogeneous amorphous dispersions of drug and HPMCAS. The resulting SDDs have routinely exhibited excellent physical stability.

This chapter describes SDDs as a platform technology to enhance oral bioavailability of poorly soluble compounds and covers formulation and process-selection specification, and in vitro performance utilizing HPMCAS-based polymers.