PhD Scientific Days 2024

Poster Session R - Pharmaceutical Sciences and Health Technologies 2.

Comparison of Evaluation Methods for Measuring Amorphous and Kinetic Solubility

Text of the abstract

The bioavailability of a drug is greatly influenced by its solubility, therefore it is important to know the solubility of a drug in an early state of drug development.
Nowadays, as the proportion of amorphous solid dispersions (ASD) and other pharmaceutical forms that rely on nanonization, amorphous active ingredient formulations, or other methods to achieve supersaturation is increasing, more and more emphasis is being placed on determining kinetic and amorphous solubility.
Kinetic solubility is the concentration that can be measured when a precipitate first appears in the solution. Amorphous solubility is the maximum concentration a solution of the substance can reach, it is the maximum degree of supersaturation. There are different methods for its theoretical estimation and experimental determination. By exceeding amorphous solubility, a new phase rich in active substance can be created, called liquid-liquid phase separation (LLPS).
Kinetic solubility can be determined by using an auxiliary solvent, changing pH, and dissolving ASDs. There are also different methods for interpreting the data, which can lead to different results to varying degrees, thereby questioning the validity.
Our aim was to investigate the effect of using different evaluation methods on the same data, to check, which could be the most precise, best suited to get the results. Molecules of different acid-base characteristics were chosen as model compunds. The pH was always set to values where the molecule is in neutral form. Measurements were carried out at 37 °C, aliquots of stock solution were added to a continuously stirred glass vial containing the buffer, and the absorbance was measured with in-line UV probes. We carried out three to six paralel measurements for each substance. Three different evaluation methods were chosen: detection based on the 2nd derivate of the spectra, baseline elevation, and Zero Intercept Method (ZIM).
In all cases, ZIM produced the lowest results. The results evaluated based on the second derivative and the baseline elevation are significantly higher than those calculated with ZIM. The degree of discrepancies were different for each molecule.
Choosing the right type of method to evaluate our data can be crucial in determining solubility values. These results show, how important it is to know how different evaluation methods can influence our results.