title: Single crystal and powder diffraction characterization of three polymorphic forms of Acitretin.
abstract: Acitretin [all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid or 3-methoxy-2-methyl-17-nor-1,2,3,4-tetradehydroretinoic acid], a widely marketed oral synthetic retinoid, introduced for clinical use as effective therapy against psoriasis, was found to crystallize in three polymorphic modifications (hereafter, I, II, and III), the crystal structures of which have been determined by single-crystal diffractometry (form I) or X-ray powder diffraction methods (form II and III) from conventional laboratory data only. In these latter cases, real space techniques (simulated annealing and whole-profile pattern matching) have been employed. Polymorph I crystallizes in space group P2(1), Z = 8, with unit cell parameters a = 7.894(1), b = 58.454(6), c = 8.161(1) angstroms, beta = 102.04(1) degrees, and V = 3682.9(8) angstroms3. Polymorph II crystallizes in space group P2(1)/n, Z = 4, with unit cell parameters a = 13.999(2), b = 10.714(1), c = 12.465(2) angstroms, beta = 98.76(5) degrees, and V = 1847.9(3) angstroms3. Polymorph III crystallizes in space group P2(1)/c, Z = 4, with unit cell parameters a = 3.0751(4), b = 4.0487(4), c = 14.956(2) angstroms, beta = 100.41(7) degrees, and V = 1831.3(4) angstroms3. Polymorph I, found to be identical with that deposited in the European Pharmacopeia, shows four crystallographically independent Acitretin molecules, arranged in pairs through conventional hydrogen-bonded carboxylic dimers; also in form II, carboxylic dimers are observed, located on crystallographic inversion centres, while in form III, a catameric arrangement of the carboxylic residues, winding up about the rather short monoclinic axis, generates one-dimensional chains of hydrogen-bonded Acitretin molecules. Thermal analysis showed that form I can be quantitatively transformed into form II by moderate heating near 200 degrees C, under vacuum. These results show that ab initio structural studies from conventional laboratory X-ray powder diffraction (XRPD) data are fully providing the opportunity to investigate the structural aspects of moderately complex substances also in the absence of single crystals, disclosing the crystal chemistry of a few polymorphs of pharmaceutically relevant species.
authors.affiliation: Dipartimento di Chimica, Materiali ed Ingegneria Chimica G.Natta, Politecnico di Milano, via Mancinelli, 20131, Milano, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Malpezzi
authors.forename: Grato Angelo
authors.initials: GA
authors.lastname: Magnone
authors.forename: Norberto
authors.initials: N
authors.lastname: Masciocchi
authors.forename: Angelo
authors.initials: A
authors.lastname: Sironi
mesh_terms: D017255:Acitretin / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D007536:Isomerism; D007641:Keratolytic Agents / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D033362:Powder Diffraction; D012997:Solvents; D014961:X-Ray Diffraction
chemical_list: D007641:Keratolytic Agents; D012997:Solvents; D017255:Acitretin