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Hydrophilic gel-forming matrix tablets are extensively used for oral extended release dosage forms due to their simplicity, cost effectiveness, and reduction of the risk of systemic toxicity due to dose dumping.1,2) Furthermore, pHindependent drug release is preferable for oral extended release formulations, so drug release in the GI tracts is not affected by intra-and inter-subject variations in both gastric pH and GI transit time. Hydroxypropylmethylcellulose (HPMC) is a pH-independent material and the drug release rates from HPMC matrix formulations are generally independent of processing variables such as compaction pressure, drug particle size, and the incorporation of a lubricant. 3)Therefore, HPMC is widely used to prepare the extended release dosage forms of water-insoluble drugs such as promethazine and water-soluble drugs such as acetaminophen. [3][4][5] Propranolol, a non-selective beta-adrenergic blocking agent, has been widely used in the treatment of hypertension, angina pectoris, and many other cardiovascular disorders. It is highly lipophilic and is almost completely absorbed after oral administration. However, much of the drug is metabolized by the liver during its first passage through the portal circulation; on average, only about 30% reaches the systemic circulation. Its elimination half-life is also relatively short (about 2-6 h).6-8) Therefore, it was chosen as a model drug for preparation of the once-daily extended-release dosage form.In the development of an extended release dosage form, an important issue was to design an optimized pharmaceutical formulation with an appropriate dissolution rate in a short time period and minimum trials. For this purpose, a computer optimization technique, based on a response surface methodology (RSM) utilizing a polynomial equation and artificial neural networks (ANN) has been widely used. [9][10][11][12] The optimization procedure involved systematic formulation designs to minimize the number of trials and analyze the response surfaces in order to realize the effect of causal factors and to obtain the appropriate formulations with target goals and the acceptable component region as process control conditions in practical preparation. Therefore, the primary purpose of this study was to develop and optimize the propranolol extended release formulations with target release profiles using RSM and multiple response optimization utilizing a quadratic polynomial equation. The second aim of the study was to evaluate and demonstrate the usefulness of RSM with multiple response optimization technology in the development of extended-release dosage forms containing water-soluble drug. MATERIALS AND METHODS MaterialsPropranolol hydrochloride and p-hydroxybenzoate-butyl ester were purchased from TCI Co. (Japan). Hydroxypropylmethylcellulose (HPMC, viscosity 4000 grade) was obtained from Shin Etsu (Japan). Microcrystalline cellulose (Avicel) was purchased from Asahi Co. (Japan). All other chemicals and solvents were of analytical reagent grade.Preparation of Propranol...

ABSTRACT:The influences of some formulation variables and manufacturing processes of the release rates of propranolol from gelation of hydroxypropylmethylcellulose (HPMC) matrices tablets were investigated. The amount of propranolol was determined by UV-Vis spectroscopy at 290 nm. The effects of extended release of matrices tablets were evaluated by the in vitro dissolution test and were compared to the United States Pharmacopoeia (USP) monograph specifications. The results showed that the lowest viscosity grade of HPMC (Metolose 4000) used gave the least burst effect in the earlier stage. The drug/Metolose ratio was an important influence on the drug release; increasing the polymer content decreased the dissolution rate of the drug. The release rate was increased with increase in the tablet content of avicel. The release curve of experimental formulation with 17% avicel was optimal compared with the USP monograph specification; there was no burst effect in the earlier stage (the release percent at 1.5 h was 26.6%) and almost total drug was released from matrices tablet after 24 h (97.4%). The other factors such as lubricant level (0.5 to 2.0%), compaction pressure (100 to 200 kPa), brand of HPMC (HPMC 4000 from Shin Etsu or Methocel K4MP from Dow Chemical Co.), and manufacturing process (tabletted from wet-massed granules or by direct compression) appeared not to modify release rates.