Malpezzi Luciana, Magnone Grato Angelo, Masciocchi Norberto, Sironi Angelo
Dipartimento di Chimica, Materiali ed Ingegneria Chimica G.Natta, Politecnico di Milano, via Mancinelli, 20131, Milano, Italy.
J Pharm Sci. 2005 May;94(5):1067-78. doi: 10.1002/jps.20330.
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.
阿维A [全反式-9-(4-甲氧基-2,3,6-三甲基苯基)-3,7-二甲基-2,4,6,8-壬四烯酸或3-甲氧基-2-甲基-17-去甲-1,2,3,4-四脱氢视黄酸] 是一种广泛上市的口服合成维甲酸，作为治疗银屑病的有效疗法引入临床使用，已发现它以三种多晶型变体（以下简称I、II和III）结晶，其晶体结构已仅通过常规实验室数据用单晶衍射法（I型）或X射线粉末衍射法（II型和III型）确定。在后一种情况下，采用了实空间技术（模拟退火和全谱图匹配）。I型多晶型体结晶于空间群P2(1)，Z = 8，晶胞参数a = 7.894(1)、b = 58.454(6)、c = 8.161(1) 埃，β = 102.04(1)°，V = 3682.9(8) 埃³。II型多晶型体结晶于空间群P2(1)/n，Z = 4，晶胞参数a = 13.999(2)、b = 10.714(1)、c = 12.465(2) 埃，β = 98.76(5)°，V = 1847.9(3) 埃³。III型多晶型体结晶于空间群P2(1)/c，Z = 4，晶胞参数a = 3.0751(4)、b = 4.0487(4)、c = 14.956(2) 埃，β = 100.41(7)°，V = 1831.3(4) 埃³。发现I型与欧洲药典中保存的晶型相同，显示有四个晶体学独立的阿维A分子，通过常规氢键连接的羧基二聚体成对排列；在II型中也观察到羧基二聚体，位于晶体学反演中心，而在III型中，羧基残基的四聚体排列围绕相当短的单斜轴缠绕，形成氢键连接的阿维A分子的一维链。热分析表明，在真空中，通过在200℃附近适度加热，I型可以定量转化为II型。这些结果表明，仅从常规实验室X射线粉末衍射（XRPD）数据进行的从头结构研究完全有机会在没有单晶的情况下研究中等复杂物质的结构方面，揭示了一些药学相关物种多晶型体的晶体化学。
