Extending the Range of Nitrofurantoin Solid Forms: Effect of Molecular and Crystal Structure on Formation Thermodynamics and Physicochemical Properties

Abstract

In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with isonicotinamide, picolinamide, 2-hydroxybenzamide, and 2-aminobenzamide have been obtained and thoroughly characterized by various analytical techniques. The crystal structures of the solid forms have been elucidated by single-crystal X-ray diffraction, and the energy distribution of intermolecular interactions has been further quantified on the basis of QTAIMC analysis. Eight distinct supramolecular heterosynthons of hydrogen bonding have been identified in the studied crystals, and their relative stability has been ranked in terms of total interaction energies. The thermodynamics of the cocrystallization reactions has been systematically investigated using two independent experimental techniques, namely solution calorimetry and phase solubility diagram, which allowed us to assess both the enthalpic and the entropic contributions to the cocrystal formation driving force. The pH-solubility behavior of the cocrystals has been investigated at different pH values using eutectic concentrations of the components. Although all of the cocrystals reported here were found to be more soluble than the parent drug, their advantage in thermodynamic solubility did not translate into enhanced dissolution performance due to a rapid solution-mediated phase transformation in aqueous media. In addition, the effect of cocrystallization on other pharmaceutically relevant properties of nitrofurantoin, including photostability and membrane permeability, has been considered and analyzed.

Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals

“…It is known that the relative stability of a cocrystal with respect to a physical mixture of the parent constituents at a given temperature can be quantitatively expressed in terms of the free-energy change, Δ form G, of the cocrystallization reaction [ 37 , 39 , 40 , 45 ]. Analyzing the temperature dependence of the Gibbs formation energy can provide further information on the enthalpy and entropy contributions to the driving force of the process as well as help to estimate the thermodynamic transition temperature, which determines the stability domains of a cocrystal and its individual constituents [ 40 , 43 ].…”

“…Unfortunately, the thermodynamic parameters of the cocrystallization process are rarely discussed in the literature. Currently, only a few experimental investigations that deal with the thermodynamics of a multicomponent crystal formation have been comprehensively addressed utilizing Gibbs energy and both its enthalpic and entropic contributions [ 40 , 41 , 42 , 43 , 44 , 45 , 46 ], as opposed to the numerous structural studies of cocrystals. Although theoretical works assert that the enthalpic term controls the stability of multicomponent crystals [ 47 , 48 ], experimental evidence suggests that the relative contributions of the enthalpic and entropic components to the driving force can vary significantly, resulting, in some cases, in the formation of entropically favorable cocrystals [ 43 ].…”

Discovery and exploration of new solid forms of dipeptide: l-alanyl-l-glutamine

“…Lattice energy calculation. The crystal lattice energies 38 of different polymorphs were calculated using the DMol3 program of Materials Studio. Gradient-corrected functionals Perdew-Burke-Ernzerhof (PBE) in generalized gradient approximation (GGA) and the double numeric with polarization (DNP) basis set were used, and the Grimme method was used to correct DFT-D. 39,40 Molecular packing similarity calculation.…”

How Molecular Packing Affects the Thermodynamic Parameters of Cocrystal Formation: The Case of Carbamazepine Cocrystals

“…However, this approach may not always lead to a reliable result, as it does not consider the compromise between all the intra- and/or intermolecular interactions. , The compromise principles of cocrystal design can be quantified by the thermodynamic parameters of the cocrystal formation process. Unfortunately, the experimental studies devoted to the determination of the formation Gibbs energy, enthalpy, and entropy for new pharmaceutical cocrystals are not numerous as compared to the structural investigations. − Most probably, a frequently used method for determination of the cocrystal formation thermodynamic functions (the phase solubility diagram method) is rather time-consuming and costly . In this turn, the cocrystal solubility method (CSM) is a convenient and precise tool for determination of the cocrystal/salt formation thermodynamic parameters. ,− …”