title: The influence of polymer content on early gel-layer formation in HPMC matrices: The use of CLSM visualisation to identify the percolation threshold.
abstract: Percolation theory has been used for several years in the design of HPMC hydrophilic matrices. This theory predicts that a minimum threshold content of polymer is required to provide extended release of drug, and that matrices with a lower polymer content will exhibit more rapid drug release as a result of percolation pathways facilitating the faster penetration of the aqueous medium. At present, percolation thresholds in HPMC matrices have been estimated solely through the mathematical modelling of dissolution data. This paper examines whether they can be also identified in a novel way: through the use of confocal laser scanning fluorescence microscopy (CLSM) to observe the morphology of the emerging gel layer during the initial period of polymer hydration and early gel formation at the matrix surface. In this study, matrices have been prepared with a polymer content of 5-30% w/w HPMC 2208 (Methocel K4M), with a mix of other excipients (a soluble drug (caffeine), lactose, microcrystalline cellulose and magnesium stearate) to provide a typical industrially realistic formulation. Dissolution studies, undertaken in water using USP apparatus 2 (paddle) at 50rpm, provided data for the calculation of the percolation threshold through relating dissolution kinetic parameters to the excipient volumetric fraction of the dry matrix. The HPMC percolation threshold estimated this way was found to be 12.8% v/v, which was equivalent to a matrix polymer content of 11.5% w/w. The pattern of polymer hydration and gel layer growth during early gel layer formation was examined by confocal laser scanning fluorescence microscopy (CLSM). Clear differences in gel layer formation were observed. At polymer contents above the estimated threshold a continuous gel layer was formed within 15min, whereas matrices with polymer contents below the threshold were characterised by irregular gel layer formation with little evidence of HPMC particle coalescence. According to percolation theory, this implies that a continuous cluster of HPMC particles was not formed. The images provide the first direct evidence of how the percolation threshold may be related to the success or failure of early gel layer development in HPMC matrices. It also shows how extended release characteristics are founded on the successful coalescence of hydrated polymer particles to form a continuous coherent diffusion barrier, which can then inhibit further percolation of the hydration medium. The correlation between percolation thresholds estimated from dissolution and imaging techniques suggests that confocal imaging may provide a more rapid method for estimating the percolation thresholds, facilitating the rational design of HPMC extended release matrices at lower polymer contents with minimal risk of dose dumping.
authors.affiliation: Formulation Insights, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Laura Michelle
authors.initials: LM
authors.lastname: Mason
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Seville, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Campiñez
authors.affiliation: Merck Sharp & Dohme Ltd, Hoddesdon EN11 9BU, UK.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Pygall
authors.affiliation: Formulation Insights, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Burley
authors.affiliation: Formulation Sciences, PSCS, MRL, Kenilworth, NJ 07033, USA.
authors.forename: Pranav
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Merck Sharp & Dohme Ltd, Hoddesdon EN11 9BU, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Storey
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, University of Seville, Spain.
authors.forename: Isidoro
authors.initials: I
authors.lastname: Caraballo
authors.affiliation: Formulation Insights, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK. Electronic address: colin.melia@nottingham.ac.uk.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Melia
mesh_terms: D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry*; D005782:Gels / Q000737:chemistry*; D065347:Hypromellose Derivatives / Q000737:chemistry*; D007700:Kinetics; D018613:Microscopy, Confocal / Q000379:methods*; D012995:Solubility; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D005079:Excipients; D005782:Gels; D013607:Tablets; D065347:Hypromellose Derivatives
keywords: Confocal microscopy; Controlled release; Drug release; HPMC; Hydroxypropyl methylcellulose; Matrix; Percolation theory; Percolation threshold