Utilization of Quality by Design Principles to Define Formulation Best Practices for a Direct Compression Excipient
Introduction: Quality by Design (QbD) initiatives enable pharmaceutical manufacturers to proactively design quality and performance into drug products, with the ultimate goal to maximize safety and efficacy for the patient. Hydrophilic matrix tablets represent one of the most prevalently utilized modified-release oral drug delivery systems, which are relatively straightforward to develop and cost-efficient to manufacture. Hydroxypropyl methylcellulose (HPMC) is a common rate-modifying polymer incorporated into hydrophilic matrices. The water-soluble HPMC particles are uniformly distributed throughout the matrix tablet. Upon contact with aqueous gastrointestinal media, the particles hydrate and swell. The particles coalesce to form a swollen polymer network layer. The release of active pharmaceutical ingredient (API) from the tablet is modulated by both diffusion through the swollen network and erosion of the outermost surface. <p’>Matrix tablet performance can be impacted by a number of variables, such as API physicochemical properties (solubility, crystalline morphology), physicochemical properties of the rate-modifying polymer (particle shape and size, viscosity grade), formulation composition (filler, glidant, lubricant selection) and manufacturing methodology (blending, direct compression vs. granulation, tableting conditions). The Dow Chemical Company has recently begun commercial-scale production of a new direct compression grade HPMC, METHOCEL™ DC2, to complement the finer particle size, but less flowable controlled release grade, METHOCEL™ CR. We used QbD principles to characterize properties and performance of matrix tablets containing METHOCEL™ DC2 in order to determine and balance optimal performance regimes for tablet physical properties and modified-release (MR). The results of these investigations will be presented along with formulation guidances and best practices. Particular emphasis will be placed on filler selection, HPMC molecular weight and morphology grade, and polymer concentrations utilized to ensure robust MR performance.
