Application of the quality control methodologies to a novel solid dosage co-crystal model system

Co-crystals are multi-component, single phase materials in which the co-crystal formers exist in an uncharged state. This interaction between components occurs without affecting the intra-molecular covalent bonding of the involved components or altering their chemical integrity. This class of materials has recently gained the interest in the pharmaceutical industry for modifying the physico-chemical properties of some active pharmaceutical ingredients (APIs) such as solubility, hygroscopicity, and mechanical properties. However like all multi-component systems, there are some analytical challenges associated with using traditional quality control (QC) tools that involve sample preparation steps prior to the analysis. This can sometimes have an impact on the physical state of such systems and therefore affect the outcomes of analysis correlated with the actual materials. Flurbiprofen (FBP) and nicotinamide (NCT) in this work were selected to form a model co-crystal system. FBP falls in the carboxylated group of non steroidal anti-inflammatory drugs (NSAIDs), used herein as an API. It belongs to class II of the Biopharmaceutics Classification System (BCS), therefore its low aqueous solubility and dissolution rate affect its bioavailability. NCT is a vitamin B3 derivative and generally regarded as safe (GRAS) substance. It is used as co-crystallising agent due to its solubility enhancing property. FBP-NCT co-crystal system was previously studied by Berry et al., where a FBP-NCT co-crystal was prepared using Kofler method and screened by means of the hot-stage microscopy (HSM). FBP-NCT co-crystal was recently prepared via rapid evaporation from ethanol solution, and screened for its physicochemical and mechanical properties by Shing et al. who found an improvement in such properties compared to the pure API (FBP). There is a wide range of methods for preparing co-crystals, of which methodologies with minimal environment impact were mainly adopted in this work i.e., Ko er fusion and co-grinding methods. Within the Kofler fusion method, it was feasible to identify and screen simultaneously parent components as well as the emerging material at room temperature (RT) by means of confocal Raman microscopy. Detailed information from Raman mapping on the investigated phases were achieved using statistical analysis. The analysis resulted in a refinement regarding the traditional assumption about the binary phase diagram. It also revealed the presence of two forms of FBP-NCT co-crystals which were consequently explored by coupling thermal analysis with Raman spectroscopy and X-ray diffraction. Using co-grinding preparation, FBP-NCT co-crystals were prepared on a large scale; enough for solid dosage formulation. Subsequent crystallisation of the resulting compound using a solution method generated single crystals suitable for x-ray crystal structure determination. Moreover in this work, a solid-state dosage form of FBP-NCT co-crystal was prepared for the first time, then investigated using transmission Raman spectroscopy. The investigation included the presence of drug and excipient, and their composition in tablets. This procedure can be considered as a platform for studying the QC of drug preparation, using a reliable, non-destructive, non-invasive, and very rapid analytical tool. Such type of study complied well with the food and drug administrative (FDA) outlines on employing process analytical technology (PAT) protocol for analysing and controlling pharmaceutical manufacturing processes