Understanding and Managing the Impact of HPMC Variability on Drug Release from Controlled Release Formulations

The purpose of this study is to identify critical physicochemical properties of hydroxypropyl 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 performe...

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Published inJournal of pharmaceutical sciences Vol. 103; no. 6; pp. 1664 - 1672
Main Authors Zhou, Deliang, Law, Devalina, Reynolds, Judie, Davis, Lynn, Smith, Clifford, Torres, Jose L., Dave, Viraj, Gopinathan, Nishanth, Hernandez, Daniel T., Springman, Mary Kay, Zhou, Casey Chun
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.06.2014
Elsevier Limited
Subjects
Chromatography, High Pressure Liquid
controlled release
Delayed-Action Preparations
diffusion
dissolution
erosion
HPMC variability
hydrophilic matrices
Hydrophobic and Hydrophilic Interactions
Hypromellose Derivatives - chemistry
Magnetic Resonance Spectroscopy
NMR
Solubility
Tablets
controlled release
hydrophilic matrices
diffusion
NMR
HPMC variability
dissolution
erosion
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Summary:The purpose of this study is to identify critical physicochemical properties of hydroxypropyl 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1664–1672, 2014
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ISSN:0022-3549
1520-6017
DOI:10.1002/jps.23953