Investigation of the functionality related characteristics of hydroxypropyl methylcellulose for the release from matrix tablets

Doctoral thesis, 2011

Hydrophilic matrix tablets are a compressed well mixed composite of drug substance and excipients including a hydrophilic polymer. When the tablet comes in contact with biological fluids, the hydrophilic polymer starts to dissolve, a process that decreases the water penetration through the tablet and involves dimensional changes of the tablet due to swelling of the solvated polymers. At a certain dilution the polymer will erode from the surface and the tablet will eventually dissolve. The processes involving tablet hydration, swelling and erosion will affect the drug release from the matrix and are all related to the polymer properties. Thus, to formulate robust matrices with predictable drug release rates and mechanisms, functionality related parameters, FRCs, of the polymers must be known and controlled. Hydroxypropyl methylcellulose, HPMC, is one of the most commonly used polymers in hydrophilic matrix tablets. However, HPMC is a heterogeneous material in both size and chemical substitution and hence the known FRCs have not always shown to be sufficient for the prediction of drug release from hydrophilic matrix tablets. The aim of the present thesis has therefore been to characterise additional FRCs for the drug release from matrix tablets. With the use of endoglucanases, which selectively catalyse the hydrolysis of the cellulose backbone, differences were found in substituent heterogeneity between HPMC batches of the same commercial grades. These structural differences were related to their properties in solution and their behaviour in hydrophilic matrix tablets. It was found that the more heterogeneously substituted HPMC batches obtained more amphiphilic behaviour, where transient hydrophobic interactions between the more highly substituted regions were formed in solution. These interactions increased with temperature and HPMC concentration and they gave rise to slower polymer erosion and increased swelling of the tablets. Consequently, the drug release was highly affected by the substituent heterogeneity of the polymers in the matrices. In addition, it was found that, dependent on the polymer structure, the polymer-drug interactions affected the robustness, i.e. tablet erosion rate, to different extents. The conclusion drawn in the present thesis is therefore that the substituent heterogeneity of HPMC should be regarded as an FRC for drug release from matrix tablets.