Polymorphism of Alprazolam (Xanax®): A Review of its Crystalline Phases and Identification, Crystallographic Characterization, and Crystal Structure of a New Polymorph (Form III)

• Published in: Journal of pharmaceutical sciences Vol. 96; no. 5; pp. 1114 - 1130
• Main Authors: de Armas, Héctor Novoa, Peeters, Oswald M., Van den Mooter, Guy, Blaton, Norbert
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.05.2007; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: alprazolam; Alprazolam - chemistry; Anti-Anxiety Agents - chemistry; Biological and medical sciences; Calorimetry, Differential Scanning; Crystallization; crystallography; Crystallography, X-Ray; differential scanning calorimetry (DSC); General pharmacology; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Structure; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; phase transformations; Phase Transition; polymorphism; Powder Diffraction; Rietveld refinement; solid state; Technology, Pharmaceutical - methods; Temperature; Water - chemistry; X-ray powder diffractometry; alprazolam; differential scanning calorimetry (DSC); crystallography; Rietveld refinement; X-ray powder diffractometry; polymorphism; phase transformations; solid state; Differential scanning calorimetry; Pharmaceutical technology; Psychotropic; Identification; Review; Powder; Alprazolam; Characterization; Solid state; Tranquillizer; Benzodiazepine derivatives; X ray diffractometry; Polymorphism; Crystalline structure
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20930

A new polymorphic form of Alprazolam (Xanax®), 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo-[4,3-α][1,4]benzodiazepine, C17H13ClN4, has been investigated by means of X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and differential scanning calorimetry (DSC). This polymorphic form (form III) was obtained during DSC experiments after the exothermic recrystallization of the melt of form I. The crystal unit cell dimensions for form III were determined from diffractometer methods. The monoclinic unit cell found for this polymorph using XRPD after indexing the powder diffractogram was confirmed by the cell parameters obtained from single crystal X-ray diffractometry on a crystal isolated from the DSC pans. The single crystal unit cell parameters are: a = 28.929(9), b = 13.844(8), c = 7.361(3) Å, β = 92.82(3)°, V = 2944(2) Å3, Z = 8, space group P21 (No.4), Dx = 1.393 Mg/m3. The structure obtained from single crystal X-ray diffraction was used as initial model for Rietveld refinement on the powder diffraction data of form III. The temperature phase transformations of alprazolam were also studied using high temperature XRPD. A review of the different phases available in the Powder Diffraction File (PDF) database for this drug is described bringing some clarification and corrections.