Thermally-prepared polymorphic forms of cilostazol.
Prior to this study, cilostazol, an antithrombotic drug, was thought to exist as a single crystalline phase with a melting point of approximately 159 degrees C (Form A). On cooling, melts often form a glass that, when heated, may crystallize as additional crystalline polymorphic forms. Cilostazol, when reheated, subsequently forms polymorphs that melt at approximately 136 degrees C (Form B) and 146 degrees C (Form C). Free-energy temperature diagrams estimated from calorimetry data reveal that each pair of the cilostazol polymorphs (A-B, B-C, and A-C) is monotropic. Essentially pure samples of suitable crystalline shape and size permitted single crystal structural analysis of Forms A and C. Theoretical solubility ratios calculated using calorimetry data indicate that at 37 degrees C, Form B should be more than four times more soluble and Form C should be more than two times more soluble than Form A. Forms B and C could not be crystallized from solvents. Metastable forms from super cooled melts analyzed by intrinsic dissolution and Fourier transform-Raman experiments demonstrated that Forms B and C undergo a rapid, solvent-mediated recrystallization to Form A, making dissolution rate measurements difficult.
Stowell
Grayson W
GW
aaiResearch, Inc., 2320 Scientific Park Drive, Wilmington, North Carolina 28405, USA.
Behme
Robert J
RJ
Denton
Stacy M
SM
Pfeiffer
Inigo
I
Sancilio
Frederick D
FD
Whittall
Linda B
LB
Whittle
Robert R
RR
D002151:Calorimetry / Q000379:methods; D002626:Chemistry, Pharmaceutical; D000077407:Cilostazol; D004055:Differential Thermal Analysis / Q000379:methods; D006358:Hot Temperature; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry
D013777:Tetrazoles; D000077407:Cilostazol