Elucidating the Molecular Mechanism of Drug-Polymer Interplay in a Polymeric Supersaturated System of Rifaximin.

Supersaturated drug delivery system (SDDS) enables the solubility and sustained membrane transport of poorly water-soluble drugs. SDDS provides higher drug concentration in the dispersed phase and equilibrium in the continuous phase, which corresponds to amorphous solubility of the drug. Rifaximin (RFX) is a nonabsorbable BCS class IV drug approved for the treatment of irritable bowel syndrome and effective against Helicobacter pylori. RFX shows slow crystallization and precipitation in an acidic pH of 1.2-2, leading to obliteration of its activity in the gastrointestinal tract. The objective of the present study is to inhibit the precipitation of RFX, involving screening of polymers at different concentrations, using an in-house developed microarray plate method and solubility studies which set forth hydroxypropyl methylcellulose (HPMC) E15, Soluplus, and polyvinyl alcohol to be effective precipitation inhibitors (PIs). Drug-polymer precipitates (PPTS) are examined for surface morphology by scanning electron microscopy, solid-phase transformation by hot stage microscopy, the nature of PPTS by polarized light microscopy, and drug-polymer interactions by Fourier transform infrared and nuclear magnetic resonance spectroscopy. Besides, the unfathomed molecular mechanism of drug-polymer interplay is discerned at the air-water interface using sum-frequency generation spectroscopy to correlate the interfacial hydrogen bonding properties in bulk water. Surprisingly, all studies disseminate HPMC E15 and Soluplus as effective PIs of RFX.

Insights on role of polymers in precipitation of celecoxib from supersaturated solutions as assessed by focused beam reflectance measurement (FBRM).

Supersaturating drug delivery systems (SDDS) have dominated the commercial and academic spheres owing to their potential in overcoming the solubility issue of poorly soluble drugs. Precipitation inhibitors are used as excipients in such formulations which has necessitated the development of supersaturation assays that evaluate their precipitation-inhibition efficacy. Such assays are able to give relative estimates of polymer efficacy ceteris paribus within a given set-up. However, the estimates of different laboratories cannot be compared with each other owing to high variability in procedure. Microarray plate method allows comprehensive replicates and decent statistics that make the method an edge over the other exploratory assays. In the current study, the precipitation-inhibition performance of three polymers on the precipitation of a model BCS class II drug was evaluated using the microarray plate method. Quantitative estimations were made through application of Poisson equation for nucleation rates and area under curve. Insights of the precipitation process at particle level were obtained through focused beam reflectance measurement (FBRM) technique coupled with end-process PVM imaging. Through real-time particle size analysis, FBRM technique demonstrated the potential for discerning the role of polymer as nucleation-inhibitor or crystal growth inhibitor. The events observed in the scaled-up FBRM analysis could be correlated with the events observed visually and spectrophotometrically. Powder X-ray diffraction and scanning electron microscopy were performed to capture the influence of polymers on the precipitates formed. This study was able to demonstrate the applicability of microarray plate method for quantitative estimations of precipitation kinetics that can be utilized for excipient screening for poorly soluble drugs having intra-luminal precipitation as a problem. FBRM analysis is highly valuable to gain mechanistic insights and put to rest the prevalent conjecture-based role attribution for polymers.