Quality by Design Applied Development of Immediate-Release Rabeprazole Sodium Dry-Coated Tablet

Abstract

The aim of this study was to develop immediate-release oral rabeprazole sodium tablets with rapid efficacy and gastric stability for the treatment of gastroesophageal reflux disease. Rabeprazole sodium is a commonly prescribed proton pump inhibitor; however, it is extremely unstable and degrades in acidic environments. Hence, it has been manufactured and supplied only in enteric-coated tablet form, while immediate-release (IR) formulations for this drug are very limited. In this study, we applied the quality by design (QbD) approach to formulate and optimize an IR dry-coated tablet containing rabeprazole sodium as an inner core with an outer sodium bicarbonate layer to stabilize the active pharmaceutical ingredient at gastric pH. We also investigated the stability of the pharmaceutical dosage form and its pharmacokinetic profile. The results show that the developed tablets are stable for approximately 12 months and have a high dissolution rate, greater than or equal to 90% at 30 min. Further, in vivo beagle pharmacokinetics confirmed that the newly developed IR tablet had an AUC_t which is bioequivalent to the existing delayed-release rabeprazole tablet; however, its T_max was 0.5 h, which is up to seven times faster than that of the existing tablet. Moreover, the IR tablet was found to immediately absorb in the stomach. Hence, the development of IR tablets can be used as a platform to overcome the technical and commercial limitations currently associated with various proton pump inhibitors used to treat patients with gastroesophageal reflux disease that require immediate therapeutic relief.

Keywords: immediate release; pharmacokinetics; proton pump inhibitor; quality by design; rabeprazole sodium; sodium bicarbonate.

Figure 1

Changes in the appearance of (a) rabeprazole sodium and (b) sodium bicarbonate in the range of pH 1.2–12.0 (apparent solubility test method).

Figure 1

Changes in the appearance of (a) rabeprazole sodium and (b) sodium bicarbonate in the range of pH 1.2–12.0 (apparent solubility test method).

Figure 2

(a) Rabeprazole sodium/ each excipient compatibility test via differential scanning calorimetry (DSC). (b) Rabeprazole sodium/ each excipient compatibility test via impurities of HPLC.

Figure 2

(a) Rabeprazole sodium/ each excipient compatibility test via differential scanning calorimetry (DSC). (b) Rabeprazole sodium/ each excipient compatibility test via impurities of HPLC.

Figure 3

Effects of critical material attributes (CMAs) depicted by pareto chart and residual, factorial, contour, interaction, and response surface plots.

Figure 3

Effects of critical material attributes (CMAs) depicted by pareto chart and residual, factorial, contour, interaction, and response surface plots.

Figure 3

Effects of critical material attributes (CMAs) depicted by pareto chart and residual, factorial, contour, interaction, and response surface plots.

Figure 3

Effects of critical material attributes (CMAs) depicted by pareto chart and residual, factorial, contour, interaction, and response surface plots.

Figure 4

The in vitro dissolution profiles of RS dry-coated tablet at pH 8.0.

Figure 5

Mean (±SD) plasma concentrations-time profiles of rabeprazole following single oral administration of RS dry-coated tablet (20/800 mg) and Pariet tablet (20 mg) to beagles.