A molecularly enhanced proof of concept for targeting cocrystals at molecular scale in continuous pharmaceuticals cocrystallization.

It is impossible to optimize a process for a target drug product with the desired profile without a proper understanding of the interplay among the material attributes, the process parameters, and the attributes of the drug product. There is a particular need to bridge the micro- and mesoscale events that occur during this process. Here, we propose а molecular engineering methodology for the continuous cocrystallization process, based on Raman spectra measured experimentally with a probe and from quantum mechanical calculations. Using molecular dynamics simulations, the theoretical Raman spectra were calculated from first principles for local mixture structures under an external shear force at various temperatures. A proof of concept is developed to build the process design space from the computed data. We show that the determined process design space provides valuable insight for optimizing the cocrystallization process at the nanoscale, where experimental measurements are difficult and/or inapplicable. The results suggest that our method may be used to target cocrystallization processes at the molecular scale for improved pharmaceutical synthesis.

Molecular engineering of cocrystallization process in holt melt extrusion based on kinetics of elementary molecular processes.

Continuous co-crystallization in a twin-screw granulator is a promising technology. In order to fundamentally optimize the process flow, it is necessary to investigate the kinetics of molecular interactions within the mixture and the effect of these interactions on co-crystal formation. In this study, the processes governing the co-crystallization of ibuprofen and nicotinamide were considered. Density functional theory calculations employing the Hirshfeld partitioning scheme were used to identify donor-acceptor sites on each molecule. A total of twenty-one different molecular interactions was identified (nine of ibuprofen and nicotinamide (resembling co-crystals), three of ibuprofen and itself (resembling the ibuprofen dimer), and nine of nicotinamide and itself (resembling the nicotinamide dimer)). Each interaction was defined as an artificial reversible reaction and the kinetics were calculated using the transition state theory of chemical reactions, where linear and quadratic synchronous transition methods were utilized to identify transition-state structures; the minimum energy path was determined using the nudged elastic band method. A kinetic Monte Carlo framework was used to study the collective/coupled effect of reactions on the progress of the co-crystallization process. it was found that operating at low temperatures (especially lower or very close to the melting temperature of ibuprofen) for longer residency times creates a safe route for maximizing the presence of ibuprofen and nicotinamide co-crystals. If the proposed route is applied, the purity and properties of the produced co-crystal would be significant, especially its desirable availability within the body.

Incomplete cocrystalization of ibuprofen and nicotinamide and its interplay with formation of ibuprofen dimer and/or nicotinamide dimer: A thermodynamic analysis based on DFT data.

Cocrystallization of ibuprofen and nicotinamide in hot melt extrusion process has been subject of many studies addressing low ibuprofen bioavailability. However, it is observed that the process of cocrystal formation of ibuprofen and nicotinamide might be incomplete. We hypothesized that formation of dimers of ibuprofen-ibuprofen or dimers nicotinamide- nicotinamide might be the cause of such poor cocrystalization process by altering the phase behaviour of the mixture. This paper addresses the molecular thermodynamics of mixtures of ibuprofen and nicotinamide, with special focus on the possibility of formation of these dimers and their corresponding interplay with mixture phase behaviour. For this purpose, density functional theory calculations are used to calculate electron donor-acceptor sizes on each molecule and accordingly possible dimers of each molecule are analysed. The free energies and phase diagram are determined for (1) when a dimer is formed or (2) no dimer is formed, over a wide operating temperature range of 273.15 K-390 K. The binding and solvation energies are calculated to identify/rank dimers. Calculations showed that formation of dimers requires an energy input which can be accessible noting to the external heating in hot melt extrusion process. The calculated solvation energies of the dimers suggest that addition of liquid binder (water) can mitigate the risk of dimer formations. Addition of proper binder/excipient is an easy route to compensate such dimer formation and to engineer ibuprofen and nicotinamide cocrystallization behaviour.

A molecular scale analysis of TEMPO-oxidation of native cellulose molecules.

The native cellulose, through TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical)-mediated oxidation, can be converted into individual fibers. It has been observed that oxidized fibers disperse completely and individually in water. It is believed that electrostatic repulsive forces might be responsible for such observations. In order to study the TEMPO-oxidation of cellulose molecules, we used Density Functional Theory (DFT) calculations and Flory-Huggins theory combined with molecular dynamics (MD). The surface electrostatic potential in native cellulose and TEMPO-oxidized cellulose were calculated using DFT calculations. We found that TEMPO-oxidized cellulose accommodates a threefold screw conformation where the negatively charged (-COO-) functional groups are pointed away from the surface in all spatial directions. This spatial orientation causes that TEMPO-oxidized cellulose molecules repulse each other due to strong negatively charged surface. At the same time, the spatial orientation increases the hydrophilicity in TEMPO-oxidized cellulose molecules. These observations explain the improved dispersion in water and separability of TEMPO-oxidized cellulose molecules. We obtained large and positive Flory-Huggins interaction parameters for TEMPO-oxidized cellulose molecules indicating their higher dispersion once in water.

Using quantum chemical modeling and calculations for evaluation of cellulose potential for estrogen micropollutants removal from water effluents.

This paper is devoted to investigate the suitability of cellulose for estrogens micropollutants removal from water effluent. For this purpose, the sorption of eight estrogens including Estradiol, Estrone, Testosterone, Progesterone, Estriol, Mestranol, Ethinylestradiol and Diethylstilbestrol were investigated. The charge density profiles and sorption curves were obtained and discussed using quantum chemical calculations where the Accelrys Materials Studio software and COSMO-SAC model were employed. The geometry optimization of compound molecule and energy minimizations was performed using the Dmol3 Module and density functional theory of generalized gradient approximate and Volsko-Wilk-Nusair functional. We found that cellulose cannot be a reliable choice of sorbent for removal of Estrone and Estradiol, but it is a poor choice of sorbent for removal of Estriol, Ethinylestradiol. Cellulose can be used for Diethylstilbestrol, Mestranol, Testosterone and Progesterone removal from estrogens containing effluents.

Polymer-water partition coefficients in polymeric passive samplers.

Passive samplers are of the most applied methods and tools for measuring concentration of hydrophobic organic compounds in water (c 1W ) in which the polymer-water partition coefficients (D) are of fundamental importance for reliability of measurements. Due to the cost and time associated with the experimental researches, development of a predictive method for estimation and evaluation of performance of polymeric passive samplers for various hydrophobic organic compounds is highly needed and valuable. For this purpose, in this work, following the fundamental chemical thermodynamic equations governing the concerned local equilibrium, successful attempts were made to establish a theoretical model of polymer-water partition coefficients. Flory-Huggins model based on the Hansen solubility parameters was used for calculation of activity coefficients. The method was examined for reliability of calculations using collected data of three polymeric passive samplers and ten compounds. A regression model of form ln(D) = 0.707ln(c 1p ) - 2.7391 with an R 2  = 0.9744 was obtained to relate the polymer-water partition coefficients (D) and concentration of hydrophobic organic compounds in passive sampler (c 1p ). It was also found that polymer-water partition coefficients are related to the concentration of hydrophobic organic compounds in water (c 1W ) as ln(D) = 2.412ln(c 1p ) - 9.348. Based on the results, the tie lines of concentration for hydrophobic organic compounds in passive sampler (c 1p ) and concentration of hydrophobic organic compounds in water (c 1W ) are in the form of ln(c 1W ) = 0.293ln(c 1p ) + 2.734. The composition of water sample and the interaction parameters of dissolved compound-water and dissolved compound-polymer, temperature, etc. actively influence the values of partition coefficient. The discrepancy observed over experimental data can be simply justified based on the local condition of sampling sites which alter these effective factors.