Understanding the pH Dependence of Supersaturation State—A Case Study of Telmisartan

Abstract

Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work aimed to investigate and better understand the pH dependence of supersaturation of telmisartan (TEL) at a molecular level and find a connection between the physicochemical properties of the active pharmaceutical ingredient (API) and the ability to form supersaturated solutions of the API. Therefore, the main focus of the work was the pH-dependent thermodynamic and kinetic solubility of the model API, TEL. Based on kinetic solubility results, TEL was observed to form a supersaturated solution only in the pH range 3–8. The experimental thermodynamic solubility-pH profile shows a slight deviation from the theoretical Henderson–Hasselbalch curve, which indicates the presence of zwitterionic aggregates in the solution. Based on pKa values and the refined solubility constants and distribution of macrospecies, the pH range where high supersaturation-capacity is observed is the same where the zwitterionic form of TEL is present. The existence of zwitterionic aggregation was confirmed experimentally in the pH range of 3 to 8 by mass spectrometry.

The Effect of the Particle Size Reduction on the Biorelevant Solubility and Dissolution of Poorly Soluble Drugs with Different Acid-Base Character

“…In the case of the nanonized samples, the amorphous character is also observable at the end of the measurements in all media; however, the characteristic peaks are appearing on the diffractogram but with low intensity. Therefore, the higher equilibrium solubility results can be attributable to the combined effect of the particle size reduction and the amorphous character [ 28 , 29 ].…”

Prediction of Liquid–Liquid Phase Separation at the Dissolving Drug Salt Particle Surface

“…The pH– S pH LLPS profiles of CPH, DCF, and PRF followed the HH equation, whereas that of PAP did not (Figure C). Previously, the pH–crystalline solubility profile of PAP was reported to deviate from the HH equation owing to the formation of cationic aggregates. , Therefore, the formation of cationic aggregates would also be the reason for the deviation of the pH– S pH LLPS profile from the HH equation . Fuguet et al used mass spectrometry to confirm that CPH formed aggregates in the pH–crystalline solubility profile .…”

“…23,38 Therefore, the formation of cationic aggregates would also be the reason for the deviation of the pH−S pH LLPS profile from the HH equation. 39 Fuguet et al used mass spectrometry to confirm that CPH formed aggregates in the pH−crystalline solubility profile. 24 However, the pH−S pH LLPS profile of CPH followed the HH equation.…”