TY - JOUR
T1 - Molecular Insights from Spectral and Computational Studies on Crystalline and Amorphous Telmisartan
AU - Singh, Mahendra
AU - Murugan, Natarajan Arul
AU - Kongsted, Jacob
AU - Zhan, Peng
AU - Banerjee, Uttam Chand
AU - Poongavanam, Vasanthanathan
PY - 2024/7/25
Y1 - 2024/7/25
N2 - Suboptimal aqueous solubility of drugs is one of the key challenges in early pharmaceutical development. To overcome this issue, alternative solid-state forms, including polymorphs, salts, cocrystals, and amorphous solids, are explored to enhance aqueous solubility. Despite the advantages of amorphous solids, their pharmaceutical application is limited due to the thermodynamic instability, unpredictability of the crystallization potential, and a lack of comprehensive molecular-level understanding. Herein, we explore the differential molecular interactions between the crystalline and amorphous forms of telmisartan, a nonpeptide angiotensin II receptor antagonist and a BCS class II drug, using spectroscopies and computational simulations. The amorphous phase of telmisartan was prepared through the quench cooling of the melt. From spectral techniques and computational tools, we observed the altered behavior in the molecular interactions of amorphous telmisartan compared to its crystalline counterpart. Through molecular dynamics simulations of both amorphous and crystalline forms, we identified that the amorphous structure maintained some of its molecular interactions within the disordered molecular arrangement. Notably, the amorphous form exhibited a relatively weaker (indicated by an increase in bond length) yet less extensive (constituting only 2.6% of the total population) hydrogen bonding network when contrasted with the crystalline counterpart, where the hydrogen bonding network constituted up to 76% of the total population with stronger hydrogen bonds.
AB - Suboptimal aqueous solubility of drugs is one of the key challenges in early pharmaceutical development. To overcome this issue, alternative solid-state forms, including polymorphs, salts, cocrystals, and amorphous solids, are explored to enhance aqueous solubility. Despite the advantages of amorphous solids, their pharmaceutical application is limited due to the thermodynamic instability, unpredictability of the crystallization potential, and a lack of comprehensive molecular-level understanding. Herein, we explore the differential molecular interactions between the crystalline and amorphous forms of telmisartan, a nonpeptide angiotensin II receptor antagonist and a BCS class II drug, using spectroscopies and computational simulations. The amorphous phase of telmisartan was prepared through the quench cooling of the melt. From spectral techniques and computational tools, we observed the altered behavior in the molecular interactions of amorphous telmisartan compared to its crystalline counterpart. Through molecular dynamics simulations of both amorphous and crystalline forms, we identified that the amorphous structure maintained some of its molecular interactions within the disordered molecular arrangement. Notably, the amorphous form exhibited a relatively weaker (indicated by an increase in bond length) yet less extensive (constituting only 2.6% of the total population) hydrogen bonding network when contrasted with the crystalline counterpart, where the hydrogen bonding network constituted up to 76% of the total population with stronger hydrogen bonds.
U2 - 10.1021/acs.cgd.4c00608
DO - 10.1021/acs.cgd.4c00608
M3 - Journal article
AN - SCOPUS:85199711095
SN - 1528-7483
VL - 24
SP - 6354
EP - 6363
JO - Crystal Growth & Design
JF - Crystal Growth & Design
IS - 15
ER -