Hydrogen bonding network present in monomer and dimer + 2OXA models of cocrystal.

The objectives of the study were to screen and prepare cocrystals of anti-cholesterol drug ezetimibe (EZT) with the aim of increasing its solubility and dissolution rate. Thermodynamic phase diagram based high throughput screening was performed using wet milling/grinding or solution crystallization methods. A large number of coformers were tested and the resulting solids were preliminarily characterized using X-ray powder diffraction (PXRD) and Raman spectroscopy. Potential cocrystals of EZT with L-proline and imidazole and a solvate formamide were identified in the screening experiments. The cocrystal hits were further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solution Proton nuclear magnetic resonance spectroscopy (¹H-NMR) and single crystal XRD. The dissolution properties and stability of cocrystals were determined. Single-crystal X-ray diffraction data were obtained for EZT, EZT-IMI cocrystal and formamide solvate of ezetimibe. All three systems were crystallized in non-centrosymmetric orthorhombic space group P2₁2₁2₁ with Z = 4. Robust O–H⋯O, O–H⋯N, N–H⋯O and C–H⋯O hydrogen bonds played an important role in all these crystal structures. EZT-PRO cocrystal showed improved apparent solubility and solid state stability.

Nitrofurantoin (NTF) has been used as an antibacterial drug to treat bacterial infections of the urinary tract. The purpose of this work is to predict the hydrogen bonds (potential synthons) present in the cocrystal of nitrofurantoin-L-proline (NTF-LP) through a computational approach (DFT calculations) and validate using vibrational spectroscopic studies. The present study illustrates the formation and characterization of the cocrystal of NTF-LP. The molecular structure of the NTF-LP cocrystal has been predicted by forming several models on the basis of the hydrogen bonding patterns observed in other NTF cocrystals. A conformational study and potential energy surface scan have been plotted around three flexible bonds of the cocrystal molecule and two stable conformers have been obtained. NBO analysis of the second order perturbation theory of the Fock matrix suggests that interaction n₁O(39) → σ*(N13–H21) is responsible for the stabilization of the molecule. Quantum theory of atoms in molecules (QTAIM) explains that all interactions are medium and partially covalent in nature as ∇²ρ_BCP > 0, H_BCP < 0. The molecular electrostatic potential surface (MEPS) of the cocrystal has been visualized for its most electropositive potential in the region of the NH₂ ⁺ group and most electronegative potential in the vicinity of the COO⁻ group. The HOMO and LUMO energies and electronic charge transfer (ECT) confirms that charge flows from the co-former (LP) to NTF (API). Local reactivity descriptor parameters have been used to predict the reactive sites of the cocrystal and global reactivity descriptor parameters suggest that the cocrystal is softer thus more reactive in comparison to NTF. The experimental and theoretical results support the formation of the cocrystal through the strong hydrogen bond present between the NH group of NTF and carboxylate COO⁻ group of LP and shows that LP is present in the zwitterionic form.

Objectives were to study mechanical properties of various solid forms of paracetamol and relate to their crystal structures. Paracetamol form I (PRA), its cocrystals with oxalic acid (PRA-OXA) and 4,4-bipyridine (PRA-BPY) and hydrochloride salt (PRA-HCL) were selected. Cocrystals and salt were scaled-up using rational crystallization methods. The resulting materials were subjected to different solid-state characterizations. The powders were sieved and 90–360 µm sieve fraction was considered. These powders were examined by scanning electron microscopy (SEM) and densities were determined. Tablets were made at applied pressures of 35–180 MPa under controlled conditions and the tablet height, diameter and hardness were measured. Tensile strength and porosity of the tablets were estimated using well known models. Crystal structures of these systems were visualized and slip planes were identified. Cocrystal and salt of PRA were physically pure. Sieved powders had comparable morphologies and particle size. The apparent and theoretical densities of powders were similar, but no clear trends were observed. The tensile strengths of these compacts were increased with increasing pressure whereas tabletability decreased in the order oxalic acid > PRA-HCL ≈ PRA-OXA > BPY > PRA-BPY. Tablet tensile strength decreases exponentially with increasing porosity with the exception of PRY-BPY and BPY. Slip plane prediction based on attachment energies may not be independently considered. However, it was possible to explain the improved mechanical properties of powders based on the crystal structure. Cocrystallization and salt formation have introduced structural features that are responsible for improved tableting properties of PRA.