Dissolution and Release Behavior of Swellable Matrix Tablets: Influence of the solubility and dissolution rate enhancement of model substance

Doctoral thesis, 2010

Tablets exhibiting extended drug release have in many therapeutical applications shown both compliance and clinical advantages. One way of achieving extended drug release from a tablet is by employing the concept of swellable matrices. These formulations have been a primary candidate for oral dosage forms, due to their advantages in regulatory, manufacturing and drug delivery. Numerous studies in regards to the influence of drug dissolution on the release mechanism of these formulations are a testament of their complexity and also the industrial need for exploring this subject. The aim of this thesis was to shed light on the effect of i) the solubility of additives (components other than the polymeric back bone of the tablets) and ii) the dissolution rate improvement of poorly soluble model drugs on the release from these tablets. A mechanistic view of the influence of solubility on the dissolution and release robustness of swellable matrices was presented. High rate of water transport into the matrix rendered the dissolution characteristics of the tablets significantly more sensitive to shear forces in the dissolution medium. This behavior was seen below the so called polymer percolation threshold of the polymer in the composition. Employment of solid dispersion technology enhanced the dissolution rate and inhibited crystallization of amorphisized model substances. This effect was observed in different degrees, depending on the type of polymeric carrier used in the dispersions. The carriers used in this thesis were PEG 4000, HPMC 100 cps and HPMCAS-MF. In terms of the release of the amorphisized model substance from the matrix, two findings were observed; 1) a balance, which can alter the release mechanism from the matrix can exist between the rate of aqueous dissolution and the crystallization of molecularly dispersed drug, 2) by choosing a proper crystallization inhibitor, drug substances can be delivered in a more readily dissolvable state than that of the crystalline form to the gastrointestinal bulk. The findings in this thesis can help formulators to design more robust tablets and new concepts for prevailing over the issue of low dissolution rate as bioavailability limiting factor.