Application of model-independent and model analysis for the investigation of effect of drug solubility on its release rate from hydroxypropyl methylcellulose sustained release tablets

Abstract

The effect of drug solubility on the dissolution from the sustained release (SR) matrix tablet prepared with hydroxypropyl methylcellulose (HPMC) 2910 4000 cps was investigated using model-independent moment analysis and Higuchi-type model analysis. In this study, seven model drugs which have various solubilities in the dissolution medium were used for preparation of tablets and dissolution studies were then performed. To determine the mechanisms behind the sustained release, the infiltration rate of the medium into the matrix tablet and the erosion rate of the matrix tablet were also investigated. The model-independent moment parameters i.e. mean dissolution time (MDT), mean medium infiltration time (MIT), mean tablet erosion time (MET), mean swelling time (MSWT) and mean diffusion time (MDFT) as well as Higuchi-type model analysis which, based on release mechanisms, were demonstrated for optimization of HPMC matrix tablets. Both in the model-independent and model analyses, the relationships obtained between drug solubility and release characteristics were similar. Regarding the poorly soluble drug, U-78875, the observed dissolution rate is slower than the erosion rate of the matrix tablet, which indicates that the main rate limiting factor for the dissolution is erosion of the matrix tablet. In the case of drugs whose solubilities are between 0.5 mg/ml and 5 mg/ml (methyl-paraben, ethyl-paraben and propyl-paraben), dissolution rates are observed between the erosion rate of the matrix tablet and the infiltration rate of medium into the matrix tablet, and. the dissolution rate increases with increasing drug solubility. Regarding highly soluble drugs, whose solubilities are more than 5 mg/ml (procaine hydrochloride, acetaminophen, and theophylline), the dissolution rates are not influenced so much by drug solubility but show a similar rate of medium infiltration into matrix. In the latter two cases, the primary rate limiting factor of dissolution is infiltration of medium into the matrix tablet. The reported MDT and MDFT values were within the range 3.16-8.75 h and 1.11-6.70 h, respectively, except for U-78875. Also, MIT, MET and MSWT values as device matrix characteristics were 2.05, 12.05 and 10.00 h, respectively. The model-independent moment parameters, MDT, MIT, MET, MSWT and MDFT are directly comparable to each other. Further, these parameters would be applicable in comparing the device and dissolution characteristics of different types of formulation. These model-independent analytical approaches allow us to optimize the SR matrix formulation at the development stage.