It is well known that the implementation of the conventional model-fitting (CMF) method leads to several indistinguishable ‘best’ candidate models (BCMs) for a single-step isothermal solid-state reaction (ISSR), meaning that subjective selection becomes unavoidable. Here, we developed a more robust comprehensive model-fitting method (COMF) which, while maintaining the mathematical simplicity of CMF, utilizes a ranking criterion that enables automatic and unambiguous determination of the BCM. For each model evaluated, COMF, like CMF, fits the integral reaction rate, but, unlike CMF, it also fits the experimental conversion fraction and reaction speed. From this, three different determination coefficients are calculated and combined to rank the considered models. To validate COMF, we used two sets of experimental kinetic data from the literature regarding the isothermal desolvation of pharmaceutical solvates: (i) tetrahydrofuran solvates of sulfameter, and (ii) methanol solvates of ciclesonide. Our results suggest that from an algorithmic perspective, COMF could become the model-fitting method of choice for ISSRs making the selection of BCM easier and more reliable.

The Navier–Stokes/Cahn–Hilliard (NSCH) system of equations has been extensively used for investigating the dynamics of two-phase flows of Newtonian fluids. However, the accurate calculation of interfacial tension via NSCH has been perceptibly doubted, and thus, a successive solution of NSCH equations is rarely not accompanied by mesh adaptation techniques and complex numerical schemes. In this work, it is demonstrated that the cause of such a miscalculation of the interfacial tension is inherent when following the conventional way of coupling the Navier–Stokes with the Cahn–Hilliard equation in their dimensionless form, where the capillary number is defined by assuming that the fluid/fluid interface is flat and at equilibrium. Hence, an alternative NSCH model was developed for the more accurate computation of interfacial tension that does not rely on any such a priori assumptions, and it uses a more abstract coupling by accounting for the distribution of the binary system’s energy on the interfacial region. This model was implemented on two different cases: (i) an investigation of the effects of inertia and capillarity on the deformation of liquid drops in simple shear flow and (ii) a study of an interfacial instability due to viscosity stratification. To solve the set of governing equations, implicit time integration schemes based on finite differences were further developed and implemented. The results regarding the topological evolution of the fluid/fluid interface from both cases were additionally cross-validated with other methods from the literature as well as with the conventional NSCH model. The comparison suggests that our NSCH model indeed remedies the standard NSCH model, without the need of mesh adaptation or any complex numerical scheme, by more accurately computing the interfacial tension for binary systems consisting of incompressible, immiscible, and Newtonian fluids.

In drug manufacturing, solvent-based methods are used for the crystallization of active pharmaceutical ingredients (APIs). Often, the solvent interacts with the API resulting in the formation of a new solid compound, the solvate. When desolvation occurs upon heating, it might result in the formation of new solid forms with significantly different physicochemical properties. Therefore, in this work, we study the desolvation kinetics by combining in situ powder X-ray diffraction (PXRD), all-atom molecular dynamics (MD) simulations, and macroscopic solid-state reaction kinetics modeling. The fluorobenzene (FB) solvate of Bruton’s tyrosine kinase inhibitor Ibrutinib (IBR) was used as a model system. While the macroscopic solid-state modeling provides information about the desolvation kinetics, the MD simulations were used to trace individual FB molecules inside the crystal lattice. The activation energy of confined solvent diffusion, obtained by MD simulations, agrees well with results of the macroscopic solid-state reaction kinetics modeling. In addition, MD simulations provided detailed information about the IBR–FB interactions at the nanoscale. The mechanism revealed is that the solvent molecules diffusion, controlled by distinct open-close gating conformational changes of the drug, triggers the desolvation throughout the crystal lattice.