Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA) with Various Carboxylic Acids: Crystallography, Hirshfeld Surfaces, and Dissolution Study

Abstract

Three new pharmaceutical co-crystals: 1 PZA-MA (malonic acid), 2 PZA-SA (succinic acid, a new polymorph of a reported one), and 3 PZA-GA (glutaric acid) have been prepared and characterized by differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), and single-crystal X-ray diffraction. Wherein, PZA formed 1:1 co-crystals with MA and GA by acid–amide and acid–py heterosynthon, while it formed 2:1 co-crystal with SA by amide–amide homosynthon in addition to acid–amide and acid–py heterosynthon. Their melting points follow the order, PZA-GA < PZA-MA < PZA-SA, which are lower than the melting points of the individual components. Hirshfeld surface analysis revealed that N–H···O hydrogen bonding and π···π interactions for PZA in them follow the order: PZA-MA > PZA-SA > PZA-GA, while H–H and O–O interactions follow the order: PZA-MA < PZA-SA < PZA-GA. We also compared the Hirshfeld surfaces of the present co-crystals with the nine reported PZA co-crystals, which obtained important results. The studies of the solubility and dissolution showed a semiempirical inverse relationship with the melting point: the solubility follows the order, PZA-SA < PZA-GA < PZA-MA and dissolution rate follows the order, PZA-SA < PZA-MA < PZA-GA.

Pharmaceutical cocrystals of the anti-tuberculosis drug pyrazinamide with dicarboxylic and tricarboxylic acids

“…This trend may be explained by the coformers solubility rule: cocrystal solubility is directly proportional to the solubility of the coformer, which means that more soluble coformers lead to more soluble cocrystals. 23,24 It's worth pointing out that the reported semiempirical inverse relationship between melting point and solubility 17 was however not observed in this study. …”

“…Thus, dicarboxylic and tricarboxylic acids would be suitable for the design of cocrystals with PZA through I and II hydrogen bonding synthons. Particularly, all of the reported cocrystals of PZA with dicarboxylic acids (including succinic acid, fumaric acid, malonic acid, and glutaric acid) 15,17 share the same synthon (mainly synthon I), while the cocrystal with glutaric acid (refcode: SIHQOR) contains synthon II exclusively. In this work, a series of dicarboxylic and tricarboxylic acids based coformers were designed and systematically screened (Table S1, ESI †).…”

Investigation of the Crystal Structure, Characterization, Hirshfeld Surface, and Theoretical Study of (C6H14N)5[HP2Mo5O23]·4H2O

“…This analysis is one of most effective method to get information about intermolecular contacts. It helps to understand environment and strength of intermolecular interactions by their visualization using appropriate color codes on the Hirshfeld surface, which is defined by points, where the amount to the electron density from the molecule of interest is equal to the contribution from all the other molecules. Two distances are calculated for each point on that isosurface: de and di , representing the distance from the point to the nearest nucleus external/internal to the surface.…”

Pharmaceutical Cocrystals: An Overview

“…This synthon approach is used to estimate the possibility of hydrogen bond formation between API and coformer [24] . Over the past few years, various methods have been evolved to determine the intermolecular interactions in crystal structures qualitatively and quantitatively, such as the conformational similarity index for proteins, graphset analysis for hydrogen bonds, Voronoi-Dirichlet polyhedral for crystal packing, continuous symmetry measures, and the Hirshfeld surface by using computer programs such as ESCET, COMPACK, TOPOS, Xpac, Crystal Explorer, and dSNAP, respectively [80] .…”