Formulation and optimization of chronomodulated press-coated tablet of carvedilol by Box–Behnken statistical design

Abstract

Objective: The primary objective of the present investigation was to formulate and optimize chronomodulated press-coated tablets to deliver the antihypertensive carvedilol at an effective quantity predawn, when a blood pressure spike is typically observed in most hypertensive patients. Experimental work: Preformulation studies and drug excipient compatibility studies were carried out for carvedilol and excipients. Core tablets (6 mm) containing carvedilol and 10-mm press-coated tablets were prepared by direct compression. The Box–Behnken experimental design was applied to these press-coated tablets (F1–F15 formula) with differing concentrations of rate-controlling polymers. Hydroxypropyl methyl cellulose K4M, ethyl cellulose, and K-carrageenan were used as rate-controlling polymers in the outer layer. These tablets were subjected to various precompression and postcompression tests. The optimized batch was derived both by statistically (using desirability function) and graphically (using Design Expert ® 8; Stat-Ease Inc). Tablets formulated using the optimized formulas were then evaluated for lag time and in vitro dissolution. Results and discussion: Results of preformulation studies were satisfactory. No interaction was observed between carvedilol and excipients by ultraviolet, Fourier transform infrared spectroscopy, and dynamic light scattering analysis. The results of precompression studies and postcompression studies were within limits. The varying lag time and percent cumulative carvedilol release after 8 h was optimized to obtain a formulation that offered a release profile with 6 h lag time, followed by complete carvedilol release after 8 h. The results showed no significant bias between predicted response and actual response for the optimized formula. Conclusion: Bedtime dosing of chronomodulated press-coated tablets may offer a promising alternative to control early morning hypertensive increase. swelling and erosion of the outer coat until the desired lag time has been achieved. 15–18 The ratio of hydrophilic polymers that affects the lag time, ie, the amount of HPMC K4M, EC, and K-carrageenan in the outer layer, were selected based on screening experiments. This ratio was confirmed using computer-aided optimization using a three factors, three-level, Box–Behnken experiment design (BBD) with constraints on lag time and percent cumulative carvedilol release after 8 h.