Development of Paracetamol-Caffeine co-crystals to improve compressional, formulation and in-vivo performance

Abstract

Paracetamol, a frequently used antipyretic and analgesic drug, has poor compression moldability owing to its low plasticity. In this study, new co-crystals of paracetamol (PCM) with caffeine (as a co-former) were prepared and delineated. Co-crystals exhibited improved compaction and mechanical behavior. A screening study was performed by utilizing a number of methods namely dry grinding, liquid assisted grinding (LAG), solvent evaporation (SE) and anti-solvent addition using various weight ratios of starting materials. LAG and SE were found successful in the screening study. Powders at 1:1 and 2:1 weight ratio of PCM/CAF by LAG and SE respectively resulted in the formation of co-crystals. Samples were characterized by PXRD, DSC and ATR-FTIR techniques. Compressional properties of PCM and developed co-crystals were analyzed by in-die heckle model. Mean yield pressure (Py), an inverse measure of plasticity, obtained from the heckle plots decreased significantly (p<0.05) for co-crystals than pure drug. Intrinsic dissolution profile of co-crystals showed up to 2.84 fold faster dissolution than PCM and physical mixtures in phosphate buffer pH 6.8 at 37 oC. In addition co-crystals formulated into tablets by direct compression method showed better mechanical properties like hardness and tensile strength. In vitro dissolution studies on tablets also showed enhanced dissolution profiles (~90- 97%) in comparison to the tablets of PCM prepared by direct compression (~55%) and wet granulation (~85%) methods. In a single dose sheep model study co-crystals showed up to two fold increase in AUC and Cmax. A significant (p < 0.05) decrease in clearance as compared to pure drug was also recorded. In conclusion new co-crystals of PCM were successfully prepared with improved tabletability in-vitro and in-vivo profile. Enhancement in AUC and Cmax of PCM by co-crystallisation might suggest the dose reduction and avoidance of side effects.