Solid-state characterization of rifampicin samples and its biopharmaceutic relevance

Abstract

Polymorphism of rifampicin has been postulated to be responsible for its variable bioavailability from solid oral dosage forms. In this regard, it was believed that form II is the preferred form and the content of amorphous needs to be critically monitored. However, there was no study in literature that determines solubility advantage associated with rifampicin polymorphs and further the desired raw material characteristics for the consistent bioavailability. Hence, this investigation was undertaken with an objective to determine biopharmaceutic relevance of rifampicin physical forms and to propose critical raw material specifications for rifampicin bulk material. For this purpose, solid-state properties of standard form I, form II, amorphous and commercial samples acquired from rifampicin manufacturers were characterized by differential scanning calorimetry (DSC), Fourier transformed infrared spectroscopy (FTIR), hot stage microscopy (HSM), thermogravimetric analysis (TGA), powder X-ray diffraction (p-XRD), solid-state nuclear magnetic resonance (NMR) and molecular modelling. In addition, intrinsic dissolution of standard samples, powder dissolution as well as particle size distribution of all the samples and powder dissolution of various sieve fraction of commercial samples were done in order to study the influence of polymorphism and other factors on rate and extent of dissolution. It was found that rifampicin in commercial bulk samples exist as various combinations of form I, form II and amorphous. As physical forms show comparable intrinsic dissolution rate (IDR) at all the pH values, solubility advantage associated with rifampicin polymorphs is negligible. Nevertheless, powder dissolution of commercial samples was influenced by particle size. In powder dissolution of different sieve fractions of commercial samples, fine particles below 100 μm have shown high rate and extent of dissolution irrespective of polymorphic content, whereas particles above 100 μm exhibited reduced dissolution. In intrinsic dissolution, thermodynamically unstable form II exhibited lower IDR than stable form I. Further, this difference is evident only at pH 2.0 and at all other pH values there was no difference in IDR of these two forms. For this unexpected finding, two hypotheses based on differences in H-bonding of the polymorph have been proposed.