title: Understanding and managing the impact of HPMC variability on drug release from controlled release formulations.
abstract: The purpose of this study is to identify critical physicochemical properties of hydroxypxropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance.
authors.affiliation: AbbVie Inc, North Chicago, Illinois, 60064.
authors.forename: Deliang
authors.initials: D
authors.lastname: Zhou
authors.forename: Devalina
authors.initials: D
authors.lastname: Law
authors.forename: Judie
authors.initials: J
authors.lastname: Reynolds
authors.forename: Lynn
authors.initials: L
authors.lastname: Davis
authors.forename: Clifford
authors.initials: C
authors.lastname: Smith
authors.forename: Jose L
authors.initials: JL
authors.lastname: Torres
authors.forename: Viraj
authors.initials: V
authors.lastname: Dave
authors.forename: Nishanth
authors.initials: N
authors.lastname: Gopinathan
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Hernandez
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Springman
authors.forename: Casey Chun
authors.initials: CC
authors.lastname: Zhou
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D057927:Hydrophobic and Hydrophilic Interactions; D065347:Hypromellose Derivatives / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D012995:Solubility; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D013607:Tablets; D065347:Hypromellose Derivatives
keywords: HPMC variability; NMR; controlled release; diffusion; dissolution; erosion; hydrophilic matrices