Applying Quality by Design for Extended Release Hydrophilic Matrix Tablets - Pharmaceutical Technology

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Applying Quality by Design for Extended Release Hydrophilic Matrix Tablets
This study examines the effect and interaction of variations in hypromellose physicochemical properties.

Pharmaceutical Technology
Volume 36, Issue 10, pp. 106-116

Hydrophilic matrix products

Hydrophilic matrices are a well-established ER delivery platform due to their flexibility in delivering a wide range of drugs, relatively simple manufacturing, and generally good product stability and shelf-life. The majority of marketed hydrophilic matrix products use high-viscosity hypromellose (HPMC) as the rate-controlling polymer. HPMC polymers are semisynthetic materials derived from cellulose with chemical modification to add both the methoxyl (CH3–O–) and hydroxypropoxyl (CH3CHOHCH2–O–) functional groups. In addition to the type and distribution of these functional groups, the polymer molecular weight (measured indirectly by apparent viscosity) and particle size are key material attributes that could affect drug-product manufacturability and performance.

Methocel for hydrophilic matrix applications uses two types of chemical substituent groups signified by either "E" or "K" designations (7). Methocel E chemistry is the USP substitution type 2910; K chemistry is the substitution type 2208. The number that follows the chemistry designation identifies viscosity in millipascal-seconds (mPas), measured at 2% weight/volume aqueous solution at 20 C. The letter "M" is used to represent a multiplier of 1000.

Along with the polymer, ER matrix formulations typically consist of the API, filler, binder, glidant, and lubricant. Other functional ingredients also may be added, such as additional polymers to modify the release rate, buffering agents to mitigate the effects of pH-dependent drug solubility, stabilizers, and surfactants. Commonly, a matrix-tablet formulation also will be film-coated with a conventional immediate-release coating or may be coated with a functional modified-release coating system.

Accordingly, the matrix formulation can be designed to influence the mechanism and rate of drug release. The design can include polymer type and concentration, drug solubility and dose, polymer-to-drug ratio, filler type and concentration, polymer-to-filler ratio, the particle size of the drug and polymer, and the shape of the matrix (8–12). Drug solubility is an important factor in determining the mechanism of drug release from hypromellose hydrophilic matrices (i.e., diffusion, diffusion and erosion, or erosion) and guides the selection of other excipients as well as the viscosity and chemistry grade of the hypromellose.

Nevertheless, as the principal rate-controlling excipient, it is important to assess the criticality of both polymer concentration and the effect of material-attribute variation (within the manufacturer's sales-specification limits) on the final drug-product quality. This knowledge is important to justify development of a robust formulation and to set an appropriate control strategy for consistent manufacture of a high-quality finished product.


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