What if Cocrystallization Fails for Neutral Molecules? Screening Offered Eutectics as Alternate Pharmaceutical Materials: Leflunomide-a Case Study

Abstract

Background: The manuscript is aimed to optimize the biopharmaceutical parameters of a poorly soluble, neutral anti-rheumatic drug ‘leflunomide’ by preparing its non-covalent derivatives (NCDs). For this various monocarboxylic acids- (adipic acid, picolinic acid) and dicarboxylic acids (maleic acid, malonic acid, sorbic acid), as well as pyridine carboxamide derivatives (nicotinamide, isonicotinamide), are used as coformers. Methods: The novel solid forms were rationally prepared and systematically characterized. Further, these solid forms were subjected to equilibrium solubility and intrinsic dissolution rate (IDR) analysis in three aqueous media (pH 1.2, pH 4.5 and pH 6.8). In vivo plasma studies in male Wistar rats were done to assess the effect on area under the curve (AUC) and the maximum concentration (Cmax) of leflunomide in prepared solid forms. Results: These NCD were primarily characterized to be eutectics rather than cocrystals as expected. The stoichiometry was established by phase diagrams. The negative value of heat of mixing indicated them to be of cluster type. In addition, leflunomide in eutectics showed approximately 9 folds increase in solubility up to 4 hours. Besides this, approximately 4 folds enhancement in the in IDR was also observed. Maximum increase in bioavailability indicated by enhanced values of AUC and Cmax (490.29 μg h-1 mL-1 and 31.42 μg mL-1, respectively) for leflunomide-maleic acid eutectic in comparison to pure LEF (AUC: 193.20 μg h-1 mL-1 and Cmax: 12.09 μg mL-1). Conclusion: The unsuccessful cocrystallization experiments were found be the latent eutectics. The evaluation of these novel eutectics of poorly soluble drug exhibited possibility to further amplify the scope of accessible material phase options other than pure active pharmaceutical ingredient (API) without disturbing the structural integrity.