Computational Screening of Multicomponent Solid Forms of 2-Aryl-Propionate Class of NSAID, Zaltoprofen, and Their Experimental Validation

Abstract

A rational coformer screening methodology was adopted to identify new multicomponent solid preformulations of the 2-aryl propionate class of nonsteroidal anti-inflammatory drugs. The coformer screening was performed using a modified molecular electrostatic potential based site−pair interaction energy computations used in conjunction with the free energy of cocrystal formation calculations to attain better predictability. The computational results were validated against the available experimental data and used for optimizing the cocrystal screening methodology for the drug zaltoprofen. A new polymorph and three new cocrystal forms of zaltoprofen were reported in the study, which exhibits up to four times enhancement in the drug solubility than that of the marketed form. We also report one new salt and two new cocrystals of (+)-ibuprofen, a drug from the same 2-aryl propionate family. In hindsight, we propose incorporating secondary heteromeric interactions formed by homo/heterodimer in the calculations of site−pair interaction energy differences for improving the predictability of the molecular electrostatic potential (MESP) based screening.

Extensive Analyses on Expanding the Scope of Acid–Aminopyrimidine Synthons for the Design of Molecular Solids

“…The method given by Hunter and co-workers was used to transform MESP minima and maxima into hydrogen bond donor and acceptor site parameters (α and β), followed by calculating the site–pair interaction energy difference (Δ E site‑pair ) . Hunter and co-workers used the value of Δ E site‑pair for estimating cocrystal formation; however, for obtaining better predictability, a modified approach was used considering the top α and β for cocrystal formation …”

“…57 Hunter and co-workers used the value of ΔE site-pair for estimating cocrystal formation; however, for obtaining better predictability, a modified approach was used considering the top α and β for cocrystal formation. 58 The initial geometry retrieved from the asymmetric unit (ASU) of the studied cocrystals (viz., BA-2-AP, 4-FBA-2-AP, 4-CBA-2-AP, 4-BBA-2-AP, and 4-IBA-2-AP) was subjected to geometry optimization of chemical compounds followed by frequency calculation to check whether the structure corresponds to a stationary point at the same level of theory in the gas phase. The optimized structure at the potential energy surface had no imaginary frequency values, indicating that the structures were optimized well.…”

Cocrystal Formation in l-Menthol/Phenol Eutectic System: Experimental Study and Thermodynamic Modeling

“…Correlative models, such as regular solution theory or the nonrandom two-liquid (NRTL) model, have been successfully used in the literature to model SLE in nonideal eutectic systems. − However, predictive models are preferable to prevent the need for experimental data to model SLE. The conductor-like screening model for realistic solvation (COSMO-RS) was proposed to calculate the activity coefficients and thus predict the eutectic point and the phase diagram of ionic and nonionic DESs. ,, SLE calculations using COSMO-RS have been exclusively performed assuming that the constituents crystallize in pure form, i.e., the simple eutectic behavior. ,, However, cocrystal formation has been identified in some DESs. , Cocrystal, hydrate, and solvate formations in binary eutectic mixtures have been successfully modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). − To the best of our knowledge, no study has evaluated the performance of COSMO-RS in predicting the phase diagram of binary eutectic systems with cocrystal formation, as COSMO-RS has been only used in several studies to screen and select suitable coformers apriori. − Loschen and Klamt used COSMO-RS to predict the SLE phase diagram of several ternary systems containing an active ingredient, coformer, and solvent. However, due to the strong association in the liquid phase, an additional binary interaction parameter was introduced and fitted to experimental data, which withdrew COSMO-RS predictive ability.…”

Thermal method usage features for multicomponent crystal screening

“…6,7 The most popular methods are liquid-assisted grinding (LAG) [8][9][10] and slow crystallization from a solution or from a mixture of solvents. [11][12][13] Moreover, each method has its own limitations. 14 Mechanochemical methods can lead to an undesirable transition of a mixture to an amorphous state.…”