(M1230-02-13) Preparation and Evaluation of Co-Amorphous Formulations of Telmisartan - Amino Acids as a Potential Method for Solubility and Dissolution Enhancement

Purpose: Telmisartan (TLM) is a potent antihypertensive drug with pH-dependent aqueous solubility. This work aimed to improve the solubility and dissolution rate of TLM by the co-amorphous method using three different types of Amino acids namely: Aspartic acid (ASP)( acidic), Proline (PRO) (neutral) and Arginine(ARG)(basic) . Moreover, the prepared co-amorphous mixture was characterized in terms of FTIR,DSC,SEM, and XRPD. Stability study was conducted for the best obtained co-amorphous formulation.

Methods: The co-amorphous blends of Telmesartan-amino acids were prepared by mixing and freeze dryingTelmesartan with three different types of amino acids ( acidic, basic and neutral ) in different ratios.Solid state characterization were investigated including solubility, dissolution rate, FTIR , DSC , X-ray andstability studies

Results: Among the prepared co-amorphous formulations, Telmesartan-Arginine ( TLM-ARG) exhibited the greatest enhancement on solubility with increasing the molar ration of ARG. The ( TLM-ARG) at 1:2 ratio showed about 57 fold increase in solubility of TLM, and the highest dissolution precentage in phosphate buffer (pH 7.5) (100% release )in 20 minutes compared with both crystalline TLM (20% in 60 minutes ) and physical mixtures. Powder X-ray analysis, FTIR , DSC and SEM demonstrated the formation of amorphous form with the co-amorphous formulation. Only (TLM:ARG) (1:0.5 ) were stable at 40ºC /75% RH for minimum of 90 days.

Conclusion: From this research, it can be concluded that co-amorphous formulations between TLM and AAs provide an approach for dissolution rate enhancement and consequently improved the bioavailability of TLM. Acidity and basicity of the AA is a crucial factor for improving aqueous solubility of TLM; basic AA alkalizer greatly enhanced the aqueous solubility and improved the dissolution rate, while acidic AA did not give any enhancement effect. The solid-state characterization results of FTIR, PXRD, DSC, SEM, showed that there were intermolecular interactions between TLM and ARG in the binary combinations which led to improved dissolution rate compared with pure crystalline TLM or amorphous TLM. Data obtained from X-ray diffraction and DSC of (TLM-ARG) formulations showed that TLM was present in the amorphous form in all prepared dispersions.ARG was able to stabilize the amorphous form of TLM and enhance its aqueuos solublity and dissolution. The ( 1:2 ) of TLM: ARG co-amorphous showed the best solubility and dissolution rate while ( 1:0.5) showed the best stability.

PH- Solubility profile of TLM, F7, F8, F9 and F10 in phosphate buffers at different pH values (1,3, 5, 7.5and9) (mean ± SD, n = 3).

Dissolution profiles of TLM, F1, F2, F3, F4, F5, F6 F7, F8, F9, F10, and the physical mixture PM, PM7andPM8 (mean ± SD, n = 3), in phosphate buffer at pH 7.5

Composition of (TLM-AA) co-amorphous formulations, % drug content, practical yield, and equilibriumsolubility results (n=3)