Mino R. Caira

Crystalline Polymorphism of Organic Compounds

Crystal polymorphism is encountered in all areas of research involving solid substances. Its occurrence introduces complications during manufacturing processes and adds another dimension to the complexity of designing materials with specific properties. Research on polymorphism is fraught with unique difficulties due to the subtlety of polymorphic transformations and the inadvertent formation of pseudopolymorphs. In this report, a summary of thermodynamic, kinetic and structural considerations of polymorphism is presented. A wide variety of techniques appropriate to the study of organic crystalline polymorphism and pseu-dopolymorphism is then surveyed, ranging from simple crystal density measurement to observation of polymorphic transformations using variable-temperature synchrotron X-ray diffraction methods. Application of newer methodology described in this report is yielding fresh insights into the nature of the crystallization process, holding promise for a deeper understanding of the phenomenon of polymorphism and its practical control.

Design of Organic Solids

Directional Aspects of Intermolecular Interactions.- Supramolecular Synthons and Pattern Recognition.- Hydrogen-Bonded Ribbons, Tapes and Sheets as Motifs for Crystal Engineering.- Functional Organic Zeolite Analogues.- Crystalline Polymorphism of Organic Compounds.

Structure and solid-state chemistry of anhydrous and hydrated crystal forms of the trimethoprim-sulfamethoxypyridazine 1:1 molecular complex

The crystal structure of the equimolar trimethoprim (TMP) and sulfamethoxypyridazine (SMPD) complex in the anhydrous form (TMP. SMPD) and that of the species with 1.5 molecules of water of crystallization (TMP.SMPD.W) are reported in this article. X-ray powder diffraction patterns (both computer generated and experimental) and thermal analytical data from differential scanning calorimetry (DSC) and thermogravimetry useful for the characterization of TMP.SMPD and TMP.SMPD.W are provided. The stability of TMP.SMPD.W, which retains its crystallographic order under 0% relative humidity (RH) conditions at room temperature (22 degrees C) and 20 mmHg, is accounted for in terms of crystal structure and hydrogen bonding. Transformation of TMP.SMPD to the hydrate complex by exposure to approximately 100% RH, suspension in water, and wet granulation, and dehydration of TMP.SMPD.W by thermal treatment and by desiccation with methanol were investigated and tentatively interpreted in terms of crystal properties. Interactions in the physical mixture of TMP and SMPD by grinding, compression, heating, and contact with water were also studied. Water-mediated formation of TMP.SMPD.W by wetting and metastable eutectic melting-mediated formation of TMP.SMPD by heating was demonstrated. Mechanical activation by milling makes the physical mixture prone to solid-state transformation into dimorphic anhydrous cocrystals by supply of thermal energy during a DSC scan.

Molecular complexes of sulfonamides. 2.1:1 complexes between drug molecules: sulfadimidine-acetylsalicylic acid and sulfadimidine-4-aminosalicylic acid

The preparation and crystal structures of the 1:1 complexes sulfadimidine-acetylsalicylic acid (I) and sulfadimidine-4-aminosalicylic acid (II) are described. Each complex unit is maintained by two intermolecular hydrogen bonds, namely N-H⋯O=C and N⋯H-O, involving the N atom of the sulfonamide group and one pyrimidine N atom of the sulfonamide and the carboxylic group of the acid. Molecular parameters for protonated complexed aspirin, as found in I, are reported for the first time and reveal a significantly different conformation from that of the uncomplexed aspirin molecule. The structure of the 4-aminosalicylic acid molecule does not change significantly on complexation with sulfadimidine. Variation in the hydrogen bonded N⋯O distances in these complexes and their analogs is discussed.

A study of adduct formation between bis(acetylacetonato)oxovanadium(IV) and substituted pyridines

Abstract The reaction of several variously substituted pyridines with bis(acetylacetonato)oxovanadium(IV), VO(ACA)2, has been studied. The complexes were isolated in the solid form, and it appears from their i.r. spectra that, depending on the pyridine substituent, the complexes exist as either cis- or trans-isomers (with reference to the acetylacetone rings). This structural isomerism has been confirmed by an X-ray crystallographic study.

Polymorphs of nitrofurantoin. I. Preparation and X-ray crystal structures of two monohydrated forms of nitrofurantoin

The preparation and X-ray crystal structures of two monohydrates of the antibacterial drug nitro furantoin are reported. MonohydrateI crystallizes in the monoclinic space groupP21n and monohydrateII in the orthorhombic space group Pbca. The nitrofurantoin molecule maintains the same, planar conformation in both crystals. The molecular packing arrangements inI andII are distinctly different,I possessing a layer structure while inII the packing is based on a herring bone motif. Hydrogen bonds of the type O-H⋯O, N-H⋯O, O-H⋯N and C-H⋯O stabilize the crystal structures.

Polymorphism and Pseudopolymorphism of the Antibacterial Nitrofurantoin

Abstract A physicochemical study of six crystalline modifications of the drug nitrofurantoin is presented. These forms comprise two polymorphs, two monohydrates, a DMF solvate and a DMSO solvate. The clathrate nature of the solvates as well as their thermal decompositions are described. The results of dissolution rate measurements for the polymorphs and monohydrates are discussed in relation to the formulation of the drug.

Enantiotropically related albendazole polymorphs.

In the present study we report the solid-state properties of albendazole (ABZ) re-crystallized from different solvents for comparison with the commercially available form. Crystalline phases were characterized as to thermal behavior, X-ray diffractometry, both on powder and single crystal, and solubility in methanol or 0.1 N HCl. The relevant thermodynamic parameters were calculated from solubility measurements at different temperatures. The re-crystallization of ABZ both from methanol and N,N-dimethylformamide afforded a new stable polymorph form (Form II) enantiotropically related to the commercially available ABZ (Form I), the latter being the metastable form at ambient temperature. Both forms proved to be physically quite stable, likely due to a high-energy barrier for the activation of the interconversion. ABZ in the solid state represents a rather complex system in which the molecular structural differences that could be associated with the polymorphism are of at least four possible types, or combinations of these: (a) tautomeric; (b) different conformations of either or both of the side-chains attached to the bicyclic ring system; (c) the occurrence of molecular disorder or its absence; (d) no essential difference in molecular structure but different hydrogen bonding arrangements in the two polymorphs.

Unusual 1C4 conformation of a methylglucose residue in crystalline permethyl-β-cyclodextrin monohydrate

The severely distorted conformation adopted by the uncomplexed TRIMEB molecule in the solid state is attended by ring-inversion of one of the seven methylglucose residues.

Structures of two conformational polymorphs of the cholesterol-lowering drug probucol

Two polymorphic forms of the drug probucol, (4,4′-[(1-Methylethylidene)-bis(thio)]bis-[2,6-bis (1, 1-dimethylethyl)phenol]), have been isolated and characterized by thermal analysis, X-ray powder diffraction and single crystal X-ray analyses. Form I, with onset melting point 125°C, is monoclinic, space groupP21c witha=16.972(5),b=10.534(4),c=19.03(1)Å,β=113.66(3)°,Z=4. Form II, with onset melting temperature 116°C, is monoclinic, space groupP21/n witha=11.226(2),b=15.981(2),c=18.800(3)Å,β=104.04(1)°,Z=4. The probucol molecule adopts different conformations in the two polymorphs. In Form II, the C-S-C-S-C chain is extended and the molecular symmetry approximates C2v whereas in Form I, the two S-C-S-C torsion angles are approximately 80° and 165°. Molecular mechanics calculations show that the less symmetrical conformer of Form I is more stable than the conformer in Form II by approximately 26 kJ mol−1. Crystal packing in both polymorphs is determined by van der Waals interactions only. X-ray powder diffraction indicates that Form II converts to Form I on grinding.