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 (mPa·s), 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.
|
