Conceptuation, formulation and evaluation of sustained release floating tablets of captopril compression coated with gastric dispersible hydrochlorothiazide using 2(3) factorial design

Abstract

Ambulatory blood pressure monitoring is regarded as the gold standard for hypertensive therapy in non-dipping hypertension patients. A novel compression coated formulation of captopril and hydrochlorothiazide (HCTZ) was developed in order to improve the efficacy of antihypertensive therapy considering the half-life of both drugs. The synergistic action using combination therapy can be effectively achieved by sustained release captopril (t1/2= 2.5 h) and fast releasing HCTZ (average t1/2= 9.5 h). The sustained release floating tablets of captopril were prepared by using 2(3) factorial design by employing three polymers i.e., ethyl cellulose (EC), carbopol and xanthan gum at two levels. The formulations (CF1-CF8) were optimized using analysis of variance for two response variables, buoyancy and T50%. Among the three polymers employed, the coefficients and P values for the response variable buoyancy and T50% using EC were found to be 3.824, 0.028 and 0.0196, 0.046 respectively. From the coefficients and P values for the two response variables, formulation CF2 was optimized, which contains EC polymer alone at a high level. The CF2 formulation was further compression coated with optimized gastric dispersible HCTZ layer (HF9). The compression coated tablet was further evaluated using drug release kinetics. The Q value of HCTZ layer is achieved within 20 min following first order release whereas the Q value of captopril was obtained at 6.5 h following Higuchi model, from which it is proved that rapid release HCTZ and slow release of captopril is achieved. The mechanism of drug release was analyzed using Peppas equation, which showed an n >0.90 confirming case II transportation mechanism for drug release.

Keywords: Ambulatory blood pressure monitoring; analysis of variance; compression coating; ethyl cellulose; floating drug delivery; non-dipping.

Figure 1

Pictorial representation of mechanism of floating of compression coated tablet

Figure 2

Comparison of floating times of various formulations

Figure 3

Zero order plot of captopril formulations

Figure 4

Line fit plots for response of buoyancy

Figure 5

Line fit plots for the response of T50%

Figure 6

Comparison of disintegration time of various hydrochlorothiazide formulations

Figure 7

Zero order plot of all hydrochlorothiazide formulations

Figure 8

The images of compression coated formulation

Figure 9

Zero order plot of pure drug, marketed and optimized compression coated formulation of captopril

Figure 10

Zero order plot of pure drug, marketed and optimized compression coated formulation of hydrochlorothiazide

Figure 11

Fourier transform infrared spectroscopy spectra of captopril

Figure 12

Fourier transform infrared spectroscopy spectra of hydrochlorothiazide

Figure 13

Fourier transform infrared spectroscopy spectra of optimized compression coated formulation

Figure 14

Differential scanning calorimetry of pure captopril

Figure 15

Differential scanning calorimetry of optimized compression coated formulation

Figure 16

Thermo gravimetric analysis of pure captopril, graph generated by V. Dushyanth reddy, Maharaja Sayajirao University of Baroda

Figure 17

Thermo gravimetric analysis of optimized compression coated formulation, graph generated by V. Dushyanth reddy, Maharaja Sayajirao University of Baroda