Understanding the polymorphic behavior of sibenadet hydrochloride through detailed studies integrating structural and dynamical assessment.
Three polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan) have been shown to exist at ambient temperature and have been characterized. Each undergoes a solid-state transition to a common high temperature form, which melts at approximately 220 degrees C. X-ray powder diffraction (XRPD) indicates that Polymorphs I and II share a similar layered structure not exhibited by Polymorph III. All three ambient temperature polymorphs show evidence of varying degrees of dynamic disorder of the terminal phenyl group as shown by solid-state NMR spectroscopy. Furthermore, the carbons alpha to the ether link also undergo different rates of mobility in Polymorphs I and II. This variation in the extent of dynamic disorder results in an alteration in the short-range structure resulting in distinct polymorphs. Polymorph I is the thermodynamically stable form at room temperature as indicated by solution calorimetry and assessment by thermodynamically driven solution mediated phase transition studies. The present study aims to address the types of discriminatory data required to make a clear distinction between physical forms and define, unequivocally, the presence of polymorphism.
Cosgrove
S D
SD
Preformulation and Biopharmaceutics, Pharmaceutical and Analytical Research and Development, AstraZeneca R and D Charnwood, Bakewell Road, Loughborough, LE11 5RH, United Kingdom. steve.cosgrove@astrazeneca.com
Steele
G
G
Austin
T K
TK
Plumb
A P
AP
Stensland
B
B
Ferrari
E
E
Roberts
K J
KJ
D058666:Adrenergic beta-2 Receptor Agonists; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008855:Microscopy, Electron, Scanning; D011208:Powders; D017448:Receptors, Dopamine D2 / Q000819:agonists; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013499:Surface Properties; D013696:Temperature; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D014961:X-Ray Diffraction
D058666:Adrenergic beta-2 Receptor Agonists; D011208:Powders; D017448:Receptors, Dopamine D2; D013844:Thiazoles; C116267:sibenadet