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

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.