A Structural Powder Diffraction Study of Two Polymorphic Forms of Nortriptyline Hydrochloride

Nortriptyline hydrochloride, a tricyclic antidepressant, appears in two different polymorphic forms, only one of which (hereafter, form β) has been previously characterized by single‐crystal analysis. Form β is monoclinic, P21/c, with a = 5.070(2), b = 34.088(5), c = 9.976(1) Å, and β = 90.74(2)°. A second crystalline form (the α form) has now been characterized by structural powder diffraction methods (using both laboratory and synchrotron radiation diffraction data). Form α crystallizes in the monoclinic P2/c space group, a = 9.99126(6), b = 5.10021(3), c = 34.1636(1) Å, and β = 98.684(6)°. The thermodynamic relationship between the two forms has been determined by differential scanning calorimetry analysis and variable‐temperature thermodiffractometric experiments, revealing that the two forms are monotropically related and form α is more stable. Both phases are characterized by a sequence of hydrogen‐bonded N‐protonated molecules, which, in the two crystalline environments, adopt the same conformation. The difference between the two crystals can be traced back to the supramolecular arrangement characterized by one‐dimensional chains, built by homochiral molecules (for conformationally driven chirality) in the α form, and by enantiomeric ones in the β form. This observation nicely explains why, upon heating, solid‐solid interconversion between the two forms does not occur.