Hovione (Portugal)

Predicting drug solubility remains a major challenge in the pharmaceutical industry, given its central role in formulation development and bioavailability. In this context, the conductor-like screening model for real solvents (COSMO-RS) is widely employed to estimate solvation and solubility properties, yet the accuracy of these predictions can strongly depend on the molecular conformations provided as input. Although this issue has been addressed in previous studies for specific molecules, no systematic evaluation of the influence of conformer-generation methods on the quality of COSMO-RS solubility predictions has been reported using large and chemically diverse datasets. Here, we assess four representative conformer-generation workflows, ranging from simple RDKit-based approaches to more elaborate semiempirical and density functional theory (DFT)-based pipelines, using a curated dataset comprising 942 experimental solubility values and 416 free energies of solvation. Despite substantial methodological differences and computational cost, all workflows yield comparable accuracy across the full dataset, with mean absolute errors close to one logarithmic unit, and all tend to underperform in the low-solubility regime, which remains a persistent challenge in computational chemistry. We further examine the use of conformer ensembles for representative molecules and compare their performance with solvent-aware single-conformer pipelines. For the cases analyzed, ensemble averaging provides moderate improvements but does not systematically outperform solvent-aware lowest-energy conformer selection. Notably, incorporating solvent information into the lowest-energy conformer identification stage can improve accuracy for molecules capable of establishing intramolecular interactions, such as hydrogen bonds. Overall, our results provide practical guidance for selecting conformer-generation strategies in high-throughput COSMO-RS applications and highlight solvent-aware workflows as a promising direction to improve predictive robustness without compromising computational efficiency.

Palladium-catalyzed coupling reactions represent an important tool for modern organic synthesis and have been extensively used in the pharmaceutical industry for the past 30 years to produce active...

This review summarizes the synthetic methodologies used in the last 25 years for the synthesis of chalcones, which are a class of flavonoids having a 1,3-diphenyl-2-propene-1-one backbone. These compounds are considered a hot topic in the field of medicinal chemistry, due to their pharmacological activity and because they are important precursors for the synthesis of heterocyclic compounds with therapeutic applications such as: flavones, flavanones, isoxazolines, benzothiazepines, pyrimidines and pyrazolines derivatives.

Aminals are an interesting moiety limited by the harsh conditions preceding their preparation. Herein is described a novel procedure for the preparation of aminals under mild conditions and explore their stability and applications.

Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. The new thermodynamic model presented combines DSC analysis and application of Hess's law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.