Solid forms of amlodipine besylate: Physiochemical, structural, and thermodynamic characterization

TY - JOUR

T1 - Solid forms of amlodipine besylate

T2 - Physiochemical, structural, and thermodynamic characterization

AU - Koradia, Vishal Shamji

AU - Lopez de Diego, Heidi

AU - Frydenvang, Karla Andrea

AU - Ringkjøbing-Elema, Michiel

AU - Müllertz, Anette

AU - Bond, Andrew D

AU - Rantanen, Jukka

PY - 2010/12/1

Y1 - 2010/12/1

N2 - Amlodipine besylate, a calcium channel antagonist widely used in the treatment of hypertension and coronary artery disease, has been found to exist in four solid forms: anhydrate, monohydrate, dihydrate, and amorphous. A comprehensive characterization of these forms is provided, based on single-crystal and powder X-ray diffraction, thermal, spectroscopic, microscopic and solubility measurements. The crystal structure of the dihydrate is reported at both 25 and -150 °C. The crystal lattices of both the dihydrate and the stable monohydrate collapse upon removal of water molecules to create melt, from which the anhydrate subsequently crystallizes. Rapid cooling of the dehydration induced melt from any of the hydrates produces the amorphous form. Spectroscopic analysis in conjunction with the crystal structure analysis shows differences in the hydrogen bond networks in the different solid forms. The kinetic solubility rank order at 37 °C in water is found to be anhydrate > monohydrate > dihydrate. In these conditions, the dihydrate is found to be the most stable form, and other forms undergo solvent-mediated transformation (SMT) to yield the dihydrate. Consistent with the SMT results, vant Hoff analysis indicates anhydrate and dihydrate to be the stable phase above and below 71 °C, respectively.

AB - Amlodipine besylate, a calcium channel antagonist widely used in the treatment of hypertension and coronary artery disease, has been found to exist in four solid forms: anhydrate, monohydrate, dihydrate, and amorphous. A comprehensive characterization of these forms is provided, based on single-crystal and powder X-ray diffraction, thermal, spectroscopic, microscopic and solubility measurements. The crystal structure of the dihydrate is reported at both 25 and -150 °C. The crystal lattices of both the dihydrate and the stable monohydrate collapse upon removal of water molecules to create melt, from which the anhydrate subsequently crystallizes. Rapid cooling of the dehydration induced melt from any of the hydrates produces the amorphous form. Spectroscopic analysis in conjunction with the crystal structure analysis shows differences in the hydrogen bond networks in the different solid forms. The kinetic solubility rank order at 37 °C in water is found to be anhydrate > monohydrate > dihydrate. In these conditions, the dihydrate is found to be the most stable form, and other forms undergo solvent-mediated transformation (SMT) to yield the dihydrate. Consistent with the SMT results, vant Hoff analysis indicates anhydrate and dihydrate to be the stable phase above and below 71 °C, respectively.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/cg101127z

DO - 10.1021/cg101127z

M3 - Journal article

SN - 1528-7483

VL - 10

SP - 5279

EP - 5290

JO - Crystal Growth & Design

JF - Crystal Growth & Design

IS - 12

ER -