An investigation into effects of in vitro test condition on the release properties of theophylline from HPMC matrices using factorial design.

The purpose of this study was to investigate the effect of various in vitro test conditions, on the release properties of theophylline (TP) from aminophylline (AP) matrices based on different hydroxypropylmethylcellulose (HPMC) ratio and viscosity grades. The general full factorial experimental design 3 x 3 x 3 was used, based on three independent variables: applied in vitro test (X1), HPMC/drug ratio (X2) and polymer viscosity grade (X3). The drug release percent at 2h (Y(2h)), 4h (Y(4h)) and 8 h (Y(8h)) and time for 50% of TP release from matrices (Y(T50%)) were response variables. Three in vitro tests were used: test 1 and test 4 (theophylline extended-release capsules, USP 30) and half-change method. According to factorial design analyses, in vitro test was the most significant factor influencing mechanism and amount of drug release. For half change method erosion was the predominant mechanism indicating case - II transport, while for test 1 the release mechanism were followed by both diffusion and erosion. The lowest release exponent n values, obtained from Ritger-Pepass equation, for test 4 indicate diffusion process inclining from Fickian diffusion to anomalous transport. Therefore, it is in the stage of development, useful to consider the influence of various in vitro test conditions on the formulation, in order to choose an optimal test for the purpose of future drug release examination.

Application of mixture experimental design in the formulation and optimization of matrix tablets containing carbomer and hydroxy-propylmethylcellulose.

Using mixture experimental design, the effect of carbomer (Carbopol((R)) 971P NF) and hydroxypropylmethylcellulose (Methocel((R)) K100M or Methocel((R)) K4M) combination on the release profile and on the mechanism of drug liberation from matrix tablet was investigated. The numerical optimization procedure was also applied to establish and obtain formulation with desired drug release. The amount of TP released, release rate and mechanism varied with carbomer ratio in total matrix and HPMC viscosity. Increasing carbomer fractions led to a decrease in drug release. Anomalous diffusion was found in all matrices containing carbomer, while Case - II transport was predominant for tablet based on HPMC only. The predicted and obtained profiles for optimized formulations showed similarity. Those results indicate that Simplex Lattice Mixture experimental design and numerical optimization procedure can be applied during development to obtain sustained release matrix formulation with desired release profile.

Biopharmaceutical characterization of carbamazepine immediate release tablets. In vitro-in vivo comparison.

A growing concern for the biopharmaceutical characterization of pharmaceutical products increased the interest in the evaluation and identification of physicochemical properties of drugs and dosage forms that govern its biological performance. In vitro and in vivo characteristics of two carbamazepine (CAS 298-46-4) immediate release tablets were investigated and compared in order to establish level A in vitro-in vivo correlation. An in vivo study was conducted as a controlled, two-way, complete cross-over, single dose, pharmacokinetic trial in 18 subjects. The in vitro study was performed using various dissolution media in order to evaluate their potential influence on drug release and distinguish the set of experimental conditions relevant to the in vivo behavior of the investigated drug products. Beside significant differences among in vitro release profiles, the in vivo data indicated bioequivalence of the two formulations. Although a high level of correlation between in vivo and in vitro data was observed in some media, there was no single in vitro-in vivo correlation model applicable to both investigated products. The obtained results add to the existing debate on the rationale for the use of surfactants in drug release media and their in vivo relevance, emphasizing the importance of in vitro dissolution testing in addition to in vivo bioequivalence testing.