Polymer Percolation Threshold in HPMC Extended Release Formulation of Carbamazepine and Verapamil HCl

Abstract

Abstract. The principles of the percolation theory were applied to further understand and design hydroxypropyl methylcellulose (HPMC) extended release matrix tablets containing carbamazepine and verapamil HCl. This statistical theory studies disordered or chaotic systems where the components are randomly distributed in a lattice. The application of this theory to study the hydration and drug release of hydrophilic matrices allows describing the changes in hydration and drug release kinetics of swellable matrices. The aim of this work was to study and develop extended release matrix formulations for carbamazepine and verapamil HCl, containing hypromellose (HPMC, METHOCEL™ Premium K100M CR) as rate controlling polymer using the concepts of percolation theory. The knowledge of the percolation threshold of the components of the matrix formulations contributes to improve their design. First, reducing the time to market and second, avoiding to formulate in the nearby of the percolation threshold, which will result in a lower variability. Therefore these formulations will be more robust when they are prepared at industrial scale. The HPMC percolation threshold for drugs with very different water solubilities was determined and it was shown that there was no significant influence of drug solubility on the HPMC critical concentration threshold (excipient percolation threshold). This may be related to the versatility and broad functionality of the swelling hydrophilic matrices.

Effect of particle size and diluent type on critical parameters for disintegration of tablets containing croscarmellose sodium as a disintegrant

“…As stated by percolation theory, a transitional change occurred at a critical concentration of components in a system when one component forms a cluster spreading throughout the whole system. This critical concentration, known as percolation threshold (Cp), is assigned to the volumetric ratio (% v/v) of the percolating component [13,14].…”

“…It is considered as infinite or percolating cluster after this cluster spreads from one side to the other sides of the network. The concentration of a component that causes a maximum probability of appearance of a cluster of this component is named percolation threshold [13][14]. In terms of solid dosage form design, the critical concentration of disintegrant or percolation threshold of disintegrant is required to achieve the minimum disintegration time.…”

The influence of polymer content on early gel-layer formation in HPMC matrices: The use of CLSM visualisation to identify the percolation threshold

“…The Caraballo group suggested that rapid drug release below the percolation threshold may be related to the failure of matrices to develop an effective surface 'gel' barrier, one of the critical features controlling the drug release from HPMC matrices [14,30,31,38,40].…”

“…For a percolating cluster to be formed, the material must be present at a concentration above the percolation threshold for that system. In the case of HPMC matrix tablets, it has been postulated that the HPMC when hydrated must be present in sufficient volume to form a cluster which percolates the whole matrix and results in the formation of a sufficiently controlling gel layer [31]. Below the polymer percolation threshold, the HPMC cannot form a percolating cluster and the matrix is less likely to have extended release properties [30].…”

Quality by Design approach to understand the physicochemical phenomena involved in controlled release of captopril SR matrix tablets

“…3 shows the captopril release profiles from the HPMC matrices where there is a significant change in the release profiles between 5% and 10% w/w of HPMC K15M. Above 10% w/w of HPMC K15M (the polymer percolation threshold), an infinite cluster of this component is formed which is able to control the hydration and release rate (Gonçalves-Araújo et al, 2010). Above 25% w/w of HPMC K15M, the release rate does not decrease, which is usual in formulations of drugs that are highly soluble in water (Maderuelo et al, 2011).…”