Machine-Vision-Enabled Salt Dissolution Analysis.

Salt formation is a well-established method to increase the solubility of ionizable drug candidates. However, possible conversion of salt to its original form of free acid or base-disproportionation-can have a drastic effect on the solubility and consequently the bioavailability of a drug. Therefore, during the salt selection process, the salt dissolution behavior should be well understood. Improved understanding could be achieved by a method that enables simultaneous screening of small sample amounts and detailed dissolution process analysis. Here, we use a machine-vision-based single-particle analysis (SPA) method to successfully determine the pH-solubility profile, intrinsic solubility, common-ion effect, pKa, pHmax, and Ksp values of three model compounds in a fast and low sample consumption (<1 mg) manner. Moreover, the SPA method enables, with a particle-scale resolution, in situ observation of the disproportionation process and its immediate effect on the morphology and solubility of dissolving species. In this study, a potentially higher energy thermodynamic solid-state form of diclofenac free acid and an intriguing conversion to liquid verapamil free base were observed upon disproportionation of the respective salts. As such, the SPA method offers a low sample consumption platform for fast yet elaborate characterization of the salt dissolution behavior.

Image-based dissolution analysis for tracking the surface stability of amorphous powders.

Poor solubility of crystalline drugs can be overcome by amorphization - the production of high-energy disordered solid with improved solubility. However, the improved solubility comes at a cost of reduced stability; amorphous drugs are prone to recrystallization. Because of recrystallization, the initial solubility enhancement is eventually lost. Therefore, it is important to understand the recrystallization process during storage of amorphous materials and its impact on dissolution/solubility. Here, we demonstrate the use of image-based single-particle analysis (SPA) to consistently monitor the solubility of an amorphous indomethacin sample over time. The results are compared to the XRPD signal of the same sample. For the sample stored at 22 °C/23% relative humidity (RH), full crystallinity as indicated by XRPD was reached around day 40, whereas a solubility corresponding to that of the γ crystalline form was measured with SPA at day 25. For the sample stored at 22 °C/75% RH, the XRPD signal indicated a rapid initial phase of crystallization. However, the sample failed to fully crystallize in 80 days. With SPA, solubility slightly above that of the crystalline γ form was measured already on the second day. To conclude, the solubility measured with SPA directly reflects the solid-state changes occurring on the particle surface. Therefore, it can provide vital information - in a straightforward manner while requiring only minuscule sample amounts - for understanding the effect of storage conditions on the dissolution/solubility of amorphous materials, especially important in pharmaceutical science.

Direct Measurement of Amorphous Solubility.

Amorphous materials exhibit distinct physicochemical properties compared to their respective crystalline counterparts. One of these properties, the increased solubility of amorphous materials, is exploited in the pharmaceutical industry as a way of increasing bioavailability of poorly water-soluble drugs. Despite the increasing interest in drug amorphization, the analytical physicochemical toolbox is lacking a reliable method for direct amorphous solubility assessment. Here, we show, for the first time, a direct approach to measure the amorphous solubility of diverse drugs by combining optics with fluidics, the single particle analysis (SPA) method. Moreover, a comparison was made to a theoretical estimation based on thermal analysis and to a standardized supersaturation and precipitation method. We have found a good level of agreement between the three methods. Importantly, the SPA method allowed for the first experimental measurement of the amorphous solubility for griseofulvin, a fast crystallizing drug, without the use of a crystallization inhibitor. In conclusion, the SPA approach enables rapid and straightforward determination of the supersaturation potential for amorphous materials of less than 0.1 mg, which could prove highly beneficial in the fields of materials science, analytical chemistry, physical chemistry, food science, pharmaceutical science, and others.

Image-Based Investigation: Biorelevant Solubility of α and γ Indomethacin.

Solubility is a physicochemical property highly dependent on the solid-state form of a compound. Thus, alteration of a compound's solid-state form can be undertaken to enhance the solubility of poorly soluble drug compounds. In the Biopharmaceutics Classification System (BCS), drugs are classified on the basis of their aqueous solubility and permeability. However, aqueous solubility does not always correlate best with in vivo solubility and consequently bioavailability. Therefore, the use of biorelevant media is a more suitable approach for mimicking in vivo conditions. Here, assessed with a novel image-based single-particle-analysis (SPA) method, we report a constant ratio of solubility increase of 3.3 ± 0.5 between the α and γ solid-state forms of indomethacin in biorelevant media. The ratio was independent of pH, ionic strength, and surfactant concentration, which all change as the drug passes through the gastrointestinal tract. On the basis of the solubility ratio, a free-energy difference between the two polymorphic forms of 2.9 kJ/mol was estimated. Lastly, the use of the SPA approach to assess solubility has proven to be simple, fast, and both solvent- and sample-sparing, making it an attractive tool for drug development.