Understanding the Formation of Indomethacin–Saccharin Cocrystals by Anti-Solvent Crystallization

Abstract

Pharmaceutical cocrystals are a novel drug form with the potential to enhance pharmaceutical properties, including the solubility and dissolution behavior for BCS class II drug substances such as indomethacin (IMC). Recently, we reported that pure indomethacin–saccharin (IMC–SAC) cocrystals were prepared via anti-solvent crystallization. In this study, we investigated the solubility behavior of IMC–SAC cocrystals and individual components in methanol–water cosolvent. Also, the phase solubility diagram (PSD) of the cocrystal was determined to increase our understanding of cocrystallization. The criterion for pure IMC–SAC cocrystal formation was proposed and verified through supporting experiments performed with different concentrations. We also found that S cocrystal and S cocrystal/S drug are critical factors for the design of the cocrystallization process via anti-solvent addition. Real-time monitoring of the cocrystallization process was performed using an in-line near-infrared (NIR) system. Principal component analysis (PCA) was applied to NIR spectral analysis. Based on the PCA results, distinct differences were observed in the pathways of IMC–SAC cocrystal formation depending on the initial concentrations.

DSC, FTIR and Raman Spectroscopy Coupled with Multivariate Analysis in a Study of Co-Crystals of Pharmaceutical Interest

“…To realize the objective of the study, widely investigated co-crystals of indomethacin with saccharin [ 8 , 10 , 16 , 18 , 19 , 20 , 21 ] and furosemide with p -aminobenzoic acid [ 12 , 14 , 22 ] were chosen as the model samples. Their crystal structure is already known to consist of ingredient dimers connected via hydrogen bonds.…”

“…Thermogravimetry (TG) enables differentiation between solvation and co-crystallization of API [ 4 , 5 ]. Infrared with Fourier transformation (FTIR) [ 6 , 7 ], near infrared (NIR) [ 8 ] and Raman [ 9 , 10 ] spectroscopies, in turn, are commonly used as tools allowing recognition of structural modification in co-crystal lattice by non-covalent bonding formation. Furthermore, NIR can be used on-line as a method for monitoring co-crystal formation [ 11 , 12 ].…”

Recent advances in improving oral drug bioavailability by cocrystals

“…Generally, cocrystals can be prepared by solution-based or solid state reactions. The solution-based techniques include slow solvent evaporation, 33 spray drying, 34 slurry crystallization, 26 and anti-solvent addition 35 while solid-state methods include neat grinding, 36 liquid assisted grinding, 37 and melt crystallization. 38 To form a cocrystal by solvent evaporation, solutions of the drug and coformer are prepared at different solvents then the solvents are removed to crystallize the intended cocrystal.…”

“…A nanococrystal (NCC) can theoretically combine the dissolution rate enhancement potential of a nanocrystal with solubility improvement advantage of cocrystal which leads to improved GI absorption and efficacy of poorly water-soluble drugs. Development of NCCs is more challenging than developing nanocrystals because of differences in solubility of cocrystals components in solvents 35 and phase instability of cocrystals in the aqueous medium. 110 …”

Predicting the Solubility of Pharmaceutical Cocrystals in Solvent/Anti-Solvent Mixtures

“…In the literature, there exist only a few studies investigating the CC phase behavior in solvent (or solvent/anti-solvent) mixtures [21,36,37,38,39,40,41]. Solely, Sheikh et al [36], Wang et al [39] and Lee et al [37] estimated CC solubility in solvent/anti-solvent mixtures using a solubility product. However, all of them calculated Ks ideal via Equation (2), neglecting the activity coefficients of the components forming the CC.…”