Cocrystals have gained attention in the pharmaceutical industry due to their ability to improve solubility, stability, in vitro dissolution rate, and bioavailability of poorly soluble drugs. Conceptually, cocrystals are multicomponent solids that contain two or more neutral molecules in stoichiometric amounts within the same crystal lattice. There are several techniques for obtaining cocrystals described in the literature; however, the focus of this article is the Reaction Crystallization Method (RCM). This method is based on the generation of a supersaturated solution with respect to the cocrystal, while this same solution is saturated or unsaturated with respect to the components of the cocrystal individually. The advantages of the RCM compared with other cocrystallization techniques include the ability to form cocrystals without crystallization of individual components, applicability to the development of in situ techniques for the screening of high quality cocrystals, possibility of large-scale production, and lower cost in both time and materials. An increasing number of scientific studies have demonstrated the use of RCM to synthesize cocrystals, mainly for drugs belonging to class II of the Biopharmaceutics Classification System. The promising results obtained by RCM have demonstrated the applicability of the method for obtaining pharmaceutical cocrystals that improve the biopharmaceutical characteristics of drugs.

Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase-4, used for the treatment of type 2 diabetes mellitus. The crystal structure of active pharmaceutical solids determines their physical and chemical properties. The polymorphism, solvates and hydrates can influence the free energy, thermodynamic parameters, solubility, solid-state stability, processability and dissolution rate, besides directly affecting the bioavailability. Thus, the physicochemical characterization of an active pharmaceutical ingredient is required to guarantee the rational development of new dosage forms. In this context, we describe herein the solid-state characterization of three crystalline forms of sitagliptin: sitagliptin phosphate monohydrate, sitagliptin phosphate anhydrous and sitagliptin base form. The investigation was carried out using differential scanning calorimetry (DSC), thermogravimetry (TG)/derivative thermogravimetry (DTG), spectroscopic techniques, X-ray powder diffraction (XRPD) and morphological analysis by scanning electron microscopy. The thermal analysis revealed that during the dehydration of sitagliptin phosphate monohydrate (Tpeak = 134.43 °C, ΔH = −1.15 J g⁻¹) there is a characteristic crystalline transition event, which alters the physicochemical parameters of the drug, such as the melting point and solubility. The crystalline behavior of sitagliptin base form differs from that of sitagliptin phosphate monohydrate and sitagliptin phosphate anhydrous, mainly with regard to the lower temperature of the fusion event. The melting point (Tpeak) values obtained were 120.29 °C for sitagliptin base form, 206.37 °C for sitagliptin phosphate monohydrate and 214.92 °C for sitagliptin phosphate anhydrous. In relation to the thermal stability, sitagliptin phosphate monohydrate and sitagliptin phosphate anhydrous showed a slight difference; however, both are more thermostable than the base molecule. Therefore, through this study it was possible to establish the most suitable crystalline form of sitagliptin for the development of a safe, effective and appropriate pharmaceutical dosage form.