Multicomponent Amorphous Solid Forms of Telmisartan: Insights into Mechanochemical Activation and Physicochemical...

Area of Science:

• Pharmaceutical Science
• Materials Science
• Solid-State Chemistry

Background:

• Telmisartan (TEL) is an angiotensin II receptor blocker with poor physicochemical properties.
• Developing new solid forms is crucial for improving drug solubility and bioavailability.
• Mechanochemistry offers a solvent-minimized approach for solid-state drug formulation.

Purpose of the Study:

• To explore new solid forms of telmisartan (TEL) using alpha-ketoglutaric acid (KGA) and glutamic acid (GA) as coformers.
• To investigate the role of mechanochemically prepared solid forms in augmenting physicochemical parameters.
• To understand the mechanism of amorphous-mediated cocrystallization.

Main Methods:

• Mechanochemical synthesis using a 1:1 stoichiometric ratio of TEL and coformers with catalytic ethanol.
• Characterization via Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Fourier-Transform Infrared Spectroscopy (FTIR).
• Evaluation of apparent solubility, intrinsic dissolution, and physical stability; FESEM and EDX mapping for surface analysis.

Main Results:

• Mechanochemical synthesis resulted in amorphous solid forms (TEL-KGA and TEL-GA) via amorphous-mediated cocrystallization.
• Significant augmentation in apparent solubility (8-10-fold) and intrinsic dissolution release (6-9-fold) compared to pure TEL.
• Demonstrated amorphous-mediated cocrystallization involving molecular recognition, intermediate amorphous phase, and product nucleation.

Conclusions:

• Amorphous phases prepared via mechanochemistry are promising for cocrystal investigation through amorphous-mediated cocrystallization.
• These amorphous forms offer substantial improvements in solubility and dissolution kinetics.
• The metastable cocrystal phase can prevent rapid precipitation, enhancing overall physicochemical properties.