Authors: Jernej Štukelj
Source: Työväentutkimus Vuosikirja (article, 2021-05-21)
Field: Materials Science — Materials Chemistry

Machine Vision for Enhanced Understanding of Solid-State Impact on Solubility of Drug Compounds The two parameters used to characterize the effect of a drug in the body are potency and selectivity. Despite their importance, the biopharmaceutical classification system (BCS) and the developability classification system (DCS) are constructed based on permeability and solubility. Furthermore, solubility is not only a molecular property as it is highly affected by the solid-state of a compound. Thus, obtaining a complete understanding of the solid-state impact on the solubility of a drug candidate early in the drug development process is crucial for well-informed decision-making. The overall aim of this thesis was to detect, investigate and quantify the impact of different solid-state forms on the solubility of pharmaceutical compounds using the image-based single-particle analysis (SPA) method.\n\nFirst, the apparent solubility of polymorphs in different solvents was measured. It was demonstrated that the solubility ratio between the two polymorphs is determined by the difference in Gibbs free energy between the polymorphs and it is not affected by changes in pH, ionic-strength and surfactant concentration in dissolution media. \n\nNext, the amorphous solubility of a particulate quench-cooled amorphous sample was measured directly. The results correlated well with the two orthogonal methods – standardized supersaturation and precipitation method, and theoretical estimation based on thermal analysis. Moreover, the direct approach of measuring amorphous solubility has proven superior when dealing with highly hygroscopic and fast crystallizing samples. Furthermore, the newly established direct approach of measuring amorphous solubility was then, concurrently with X-ray powder diffraction, used to track two amorphous samples stored at different conditions over an extended period of time. Differences in the crystallization process and its\nimpact on solubility were observed.\n\nMachine-vision-detected solid-state changes were demonstrated to provide additional information for the interpretation of the measured pH-solubility profiles of pharmaceutical salts. Based on pH-solubility profiles, values such as pKa, pHmax and Ksp were easily obtained. Moreover, the potential effect of the microenvironmental pH shift was evaluated in the context of solubility measurements.\n\nFinally, the solubility of extremely poorly soluble drug – itraconazole – and its co-crystals was measured across a wide pH range and also in biorelevant buffers. A considerable improvement in solubility was detected upon co-crystal formation. Moreover, the solubility of itraconazole in biorelevant buffers was in good agreement with the results in literature obtained previously by the conventional shake-flask method.\n\nIn summary, all of the above was achieved with less than 100 μg of a sample per\nmeasurement. Moreover, non-specificity and the demonstrated broad applicability make the SPA method highly suitable for use in the early stages of the drug discovery and development. The possibility of acquiring a broad level of physicochemical characterization using a single analytical method could significantly accelerate and improve data acquisition leading to enhanced understating of solid-state impact on solubility. Furthermore, with the data quality\ncomparable to the current ‘gold standard’ technique the SPA method could thread the path towards more accurate in silico solubility predictions. Thus, eventually leading to more informed decision-making processes and, finally, optimized and more affordable drug products. Solubility ; Drug ; Chemistry ; Solid-state ; Computer science ; Medicine ; Pharmacology ; Organic chemistry ; Physical chemistry Crystallization and Solubility Studies ; Computational Drug Discovery Methods ; Analytical Chemistry and Chromatography