Solubilization of entecavir by povidone to overcome content uniformity challenges for low-dose tablet formulations

Abstract

Development of 0.1, 0.5, and 1.0 mg entecavir tablet formulations for the treatment of hepatitis B virus was challenging for content uniformity. Entecavir with pK_a of 2.8 and 9.8 does not have sufficient solubility in acidic or alkaline medium or in common pharmaceutical solvents such as ethanol to dissolve the drug in granulating fluid to prepare the homogeneous granulation. Povidone (PVP), a commonly used binder, was found to increase entecavir solubility depending on the PVP concentration and temperature of the solution. At 15% w/w PVP concentration, entecavir solubility increased from 2 mg/mL to about 8 mg/mL at room temperature. When the PVP solution was heated to 50°C or 70°C, the solubility was increased to about 23 or 33 mg/mL, respectively. Based on Raman spectra of entecavir in PVP solution, the increase in entecavir solubility in the presence of PVP may not be due to any molecular interactions between them. Solubilization of entecavir in PVP and eventual granulation did not change the polymorphic form of the drug based on the powder X-ray and differential scanning calorimetric (DSC), and thermo-gravimetric analysis (TGA) of neat entecavir re-crystallized from the PVP solution. The enhancement in the solubility of entecavir by PVP was sufficient to keep the amount of solution, which was used for granulation, to be about 20% w/w of the batch size like the traditional aqueous granulation. The granulation manufactured using this approach provided better tablet content uniformity than one using micronized entecavir.

Keywords::

• Content uniformity
• solubilization
• povidone
• low-dose
• wet granulation
• tablet
• interactions