Crystal form conversion of nevirapine solvates subjected to elevated temperature and humidity: a qualitative study.

Some known nevirapine solvates have been reported to undergo solvent exchange in aqueous media to form a stable hemihydrate. This study aimed to determine the effects of atmospheric moisture on said nevirapine solvates and to gain insight into which factors determine the end product of transformation. Solvates were prepared by solvent recrystallisation and stored, together with the anhydrous and hemihydrate forms, in a climate chamber at 40 °C and 75% RH for a period of 28 days. Samples were analyzed using DSC, TGA, FT-IR, PXRD and Karl Fischer titration. Some solvates were observed to undergo desolvation to the anhydrous form of nevirapine (Form I), whilst others converted to the hemihydrate. It was found that water miscibility of the guest solvent determined the stable form of nevirapine, anhydrous or hemihydrate, to which each solvate eventually transformed. Transformation to the hemihydrate only occurred if the guest solvent was sufficiently water soluble to allow water molecules to enter solvent channels and displace the original guest. Solvates with hydrophobic guests desolvated to the anhydrous form. We concluded that, in the absence of a guest, solvent channels are lost during transformation to the monoclinic crystal system and space group P21/c (Form I) so that water cannot enter after desolvation.

Clathrates of TETROL: selective inclusion of methylcyclohexanones in their energetically unfavorable axial methyl conformations.

3- and 4-Methylcyclohexanone have been isolated exclusively as their energetically disfavoured axial conformers in the host-guest complexes formed upon recrystallization of the novel optically pure host compound, (+)-(2R,3R)-1,1,4,4-tetraphenylbutane-1,2,3,4-tetraol (TETROL), from these cycloalkanones.

Ethyl-paraben and nicotinamide mixtures: apparent solubility, thermal behavior and X-ray structure of the 1:1 co-crystal.

This work aims at investigating the nicotinamide (NA)-ethyl-paraben (EP) binary system both in solution and in the solid state. In particular, the apparent EP solubility in water was studied in the presence of different NA concentrations (between 0.28 and 1.64 M). It was found that the apparent EP solubility increase (nearly twofold) observed at the highest NA concentration tested can be ascribed to a change in the polarity of the solvent mixture, rather than to a direct effect of NA on EP. The effect of fusion and re-crystallization from water or ethanol solutions on EP and NA mixtures was investigated by means of differential scanning calorimetry, elemental analysis and X-ray diffraction both on powder and single crystal. It was discovered that EP and NA form a co-crystal having a 1:1 molar composition that can be easily crystallized from ethanol. Single crystal X-ray analysis of this species revealed that the NA and EP molecules form corrugated layers within which the two components are intimately associated by a dense network of hydrogen bonds. In the presence of an excess NA in solution, the EP-NA co-crystal has lower water solubility with respect to both the single co-crystal formers and precipitates in aqueous solutions at ambient temperature.

1,3-Dipolar cycloaddition reactions of 1-(4-phenylphenacyl)-1,10-phenanthrolinium N-ylide with activated alkynes and alkenes.

The 3+2 cycloaddition reaction of 1-(4-phenylphenacyl)-1,10-phenanthrolinium ylide 4 with activated alkynes gave pyrrolo[1,2- 4a][1,10]phenanthrolines 6a-d. The "one pot" synthesis of 6a,b,d from 4, activated alkenes, Et(3)N and tetrakis-pyridine cobalt (II) dichromate (TPCD) is described. The helical chirality of pyrrolophenanthrolines 6b-d was put in evidence by NMR spectroscopy.

Polymorphism of NCX4016, an NO-releasing derivative of acetylsalicylic acid.

NCX4016 [2-acetoxybenzoic acid 3'-(nitrooxymethyl)phenyl ester] is a recently developed nitrooxy-derivative of aspirin with improved antiinflammatory, analgesic, and antithrombotic activity as well as increased gastrointestinal safety. Systematic polymorphic screening performed with different solvents and preparation methods resulted in the identification of two polymorphs, designated Forms I and II. They were characterized by scanning electron microscopy, powder X-ray diffraction, thermal analyses, and infrared spectroscopy; the crystal structure of polymorph I was solved by single-crystal X-ray analysis and compared with that of aspirin. Finally, intrinsic dissolution rate studies and calculations according to the melting data method were performed to assess the thermodynamic relationship between the two polymorphs.

Triclinic polymorph of sulfasalazine.

In this modification of the title compound, 5-(4-[(2-pyridylamino)sulfonyl]phenyldiazenyl)salicylic acid, C(18)H(14)N(4)O(5)S, the molecule is present in the amide tautomeric form. Two azo-bridged phenyl rings render the bulk of the molecule planar, with the carboxylic acid group at one terminal and the pyridylamino residue at the other. The repeating unit in the crystal is a centrosymmetric dimer containing two identical R-2/2-(8) hydrogen-bonded ring systems, each involving the carboxylic acid and pyridylamino moieties. Additional stabilization is due to an intramolecular hydrogen bond between the 2-hydroxyl group and the carbonyl O atom of the carboxylic acid group, as well as intermolecular pi-pi stacking.

Tunable clathrates.

Investigation of the selectivity of a diol organic host for mixtures of DMF and DMSO, showed the formation of five inclusion compounds in which the stoichiometry varies in discrete steps and is determined by the composition of the liquid guest mixture; the structures of these compounds are described.

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.

Physical properties of parabens and their mixtures: solubility in water, thermal behavior, and crystal structures.

The peculiar solubility behavior of propylparaben (propyl ester of 4-hydroxybenzoic acid) in aqueous solution, when tested separately and together with methyl-, ethyl-, and butyl-parabens, has been investigated in detail. The results clearly indicate that the decrease in solubility (approximately 50% compared to the solubility value of propylparaben alone) is typical of those mixtures containing also ethylparaben, as demonstrated by solubility experiments on binary, ternary, and quaternary mixtures of the parabens. Phase diagrams of all the six binaries show that propylparaben and ethylparaben are the only pair that form almost ideal solid solutions near the melting temperatures. Moreover, phase-solubility analysis shows that propylparaben and ethylparaben, at room temperature, can also form solid solutions whose solubility is related to the composition of the solid phase at equilibrium. To achieve an independent confirmation of the possible solid solution formation that supports the above interpretation of the solubility behavior, the crystal structures of the four parabens have been examined and isostructurality has been found to exist only between ethylparaben and propylparaben. Powder X-ray diffraction has also been performed on ethylparaben, propylparaben, and their solid solutions obtained by recrystallization from water. The progressive shift of distinctive diffraction peaks with phase composition clearly indicates that propylparaben and ethylparaben form substitutional solid solutions. The small value (<1) of the disruption index provides thermodynamic support for substitutional solid solutions based on isostructural crystals.

Structural characterization of two polymorphic forms of piroxicam pivalate.

The crystal and molecular structures of two polymorphs of piroxicam pivalate are presented and discussed. A peculiarity of the high melting (154 degrees C) polymorph is the association of piroxicam pivalate molecules as centrosymmetric dimers by hydrogen bonding. Two centrosymmetrically related N-H...N hydrogen bonds maintain the dimer structure involving the amido nitrogen atom as donor and the pyridine nitrogen atom as acceptor. Molecular association of this type does not occur in the crystal structures of drugs belonging to the oxicam class of nonsteroidal antiinflammatory drugs. Two distinct conformations coexist in the crystal of the low melting polymorph (136 degrees C) with differing hydrogen bonding arrangements within domains of the crystallographically independent molecules. The occurrence of different molecular conformations (conformational polymorphism) associated with different hydrogen bonding schemes in discrete domains is an unusual structural feature. Structural data for the two polymorphs are also correlated with the relevant infrared spectra. Computer-generated X-ray powder diffraction patterns for the two polymorphs of piroxicam pivalate are in very good agreement with the experimental ones, thus confirming the validity of the single-crystal X-ray models.

Structure and thermal stability of alprazolam and selected solvates.

Five forms of the drug alprazolam have been identified by thermal analysis and X-ray powder diffraction (XRD). The single crystal X-ray structures of two of these species, a polymorph 1 and a dihydrate 2, were determined. The dihydrate crystallized from a solution of alprazolam in methanol containing traces of water. Species 3 and 4 are nonstoichiometric solvates with ethanol and acetonitrile, respectively. The differential scanning calorimetric curves for the solvates 2-4 are similar, showing a desolvation endotherm, followed by an exotherm associated with recrystallization, and a final endotherm for the fusion of alprazolam. The solvates 3 and 4 were shown to be isomorphous by XRD. The products of desolvation of 2-4 were identified by their XRD traces. Solvates 2 and 3 yield polymorph 1 on desolvation, whereas solvate 4 yields a different polymorph.

Solid state characterization of dehydroepiandrosterone.

Three polymorphs (forms I-III), a monohydrate (form S2), and three new solvates [4:1 hydrate (form S1), monohydrate (form S3), and methanol half-solvate (form S4)] were isolated and characterized by X-ray powder diffractometry (XRPD), IR spectroscopy, differential scanning calorimetry (DSC), hot stage microscopy, solution calorimetry, and their dissolution rates. A new polymorph, designated as form V, melting at 146.5-148 degrees C, was observed by hot stage microscopy. Our results indicate that only forms I and S4 exhibit reproducible DSC thermograms. Five of the isolated modifications undergo phase transformation on heating, and their DSC thermograms are not reproducible. Interpretation of DSC thermograms was facilitated by use of hot stage microscopy. The identification of each modification is based on XRPD patterns (except forms S3 and S4, for which the XRPD patterns are indistinguishable) and IR spectra. In the IR spectra, a significant difference was observed in the OH stretching region of all seven modifications. In a purity determination study, 5% of a contaminant modification in binary mixtures of several modifications could be detected by use of XRPD. To obtain a better understanding of the thermodynamic properties of these modifications, a series of increasing heating rates and different pan types were used in DSC. According to Burger's rule, forms I-III are monotropic polymorphs with decreasing stability in the order form I > form II > form III. The melting onsets and heats of fusion for forms I-III are 149.1 degrees C, 25.5 kJ/mol; 140.8 degrees C, 24.6 kJ/mol; and 137.8 degrees C, 24.0 kJ/mol, respectively. For form III the heat of fusion was calculated from heat of solution and DSC data. In the case of form S1 the melting point, 127.2 degrees C, was obtained by DSC using a hermetically sealed pan. The relative stabilities of the six modifications stored under high humidity conditions were predicted to be, on the basis of the heat of solution and thermal analysis data, from S2 > form S3 > form S1 > form I > form II > form III. However, the results of the dissolution rate determination were inconsistent with the heat of solution data. The stable form I shows a higher initial dissolution rate than the metastable form II and unstable form III. All modifications were converted into the stable monohydrate, form S2, during the dissolution study, suggesting that the moisture level in solid formulations should be carefully controlled.

Zwitterionic nature of tenoxicam: crystal structures and thermal analyses of a polymorph of tenoxicam and a 1:1 tenoxicam:acetonitrile solvate.

The products of recrystallization of tenoxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3- carboxamide 1,1-dioxide) from ethanol and acetonitrile were investigated by thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. Recrystallization from ethanol yielded a polymorph designated 1, and recrystallization from acetonitrile gave a solvate 2 with 1:1 stoichiometry. The structures of 1 and 2 were determined by single-crystal X-ray methods. Polymorph 1 is triclinic, space group P1, with Z = 4; solvate 2 is monoclinic, space group P2(1)/n, with Z = 4. In both crystal structures, the tenoxicam molecule exists in the zwitterionic form, adopting a planar conformation that is stabilized by two intramolecular hydrogen bonds (N(+)-H...O and N-H...O-). Tenoxicam molecules associate by N(+)-H...O and C-H...N hydrogen bonding in both crystal structures. Desolvation of 2 yields a polymorph of tenoxicam that is different from polymorph 1. A study of the kinetics of the desolvation of 2 by dynamic thermogravimetry yielded estimates of the activation energy in the range 69-72 kJ.mol-1. From a comparison of experimental and simulated X-ray powder diffraction patterns, neither 1 nor 2 undergoes a polymorphic transition upon grinding. X-ray patterns based on the single-crystal X-ray data for 1 and 2 are presented as reliable references for their identification.

X-ray structural studies and physicochemical characterization of the 1-butanol, 1-pentanol, and 1,4-dioxane solvates of succinylsulfathiazole.

The crystal structures and thermal decomposition of three solvated forms of the antibacterial drug succinylsulfathiazole (SST) have been studied. The solvates, with 1:1 host-guest stoichiometry, are SST x 1-butanol (1) SST x 1-pentanol (2), and SST x 1,4-dioxane (3). Solvates 1 and 2 crystallize in the triclinic system, space group P1, with two formula units per cell, and are nearly isostructural. The OH groups of the guest molecules in both solvates engage in hydrogen bonding to the host SST and occupy cavities in the crystals. Solvate 3 is triclinic, space group P1, with two formula units per cell, but the two independent solvent molecules are located in crystallographically distinct channels. In one channel, solvent molecules are hydrogen bonded to the host while, in the other, they are held by van der Waals interactions only. The structural results are in accord with thermogravimetric and differential scanning calorimetric data which indicate one-step desolvation for 1 and 2 but two-step desolvation for 3. X-ray powder diffraction was used to attempt identification of the polymorphic forms of SST resulting from desolvation of 1-3. Desolvation of 1 and 3 appears to yield pure polymorphs of SST while 2 yields a mixture of polymorphs. The activation energies for the desolvation of the nearly isomorphous solvates 1 and 2 were found by dynamic thermogravimetry to be 155 and 149 kJ mol(-1), respectively.

X-ray structural characterization of anhydrous metronidazole benzoate and metronidazole benzoate monohydrate.

Single crystals of anhydrous metronidazole benzoate and its monohydrate were isolated from the same aqueous solution and studied by X-ray diffraction. Anhydrous metronidazole benzoate gives crystals belonging to the triclinic space group P1 and, at ambient temperature, a = 6.649 (2), b = 8.666(1), c = 11.940(3) A, alpha = 76.70(2)degrees, beta = 76.72(2)degrees, gamma = 87.56(2)degrees, V = 651.6(3) A3, Z = 2, and Rw(F) = 0.053. Metronidazole benzoate monohydrate gives crystals belonging to the triclinic space group P1 and, at ambient temperature, a = 7.544(1), b = 7.990(1), c = 12.329(4) A, alpha = 94.33(2)degrees, beta = 97.40(2)degrees, gamma = 101.36(1)degrees, V = 718.6(3) A3, Z = 2, and Rw(F) = 0.041. Thermomicroscopy, differential scanning calorimetry, and thermogravimetry were used for initial characterization of the title species and to investigate possible phase changes on heating. The crystal structure analyses revealed that the metronidazole benzoate molecule adopts different conformations in the two crystal forms. Crystal cohesion in the anhydrous form is due to van der Waals interactions only, whereas in the monohydrate, there is strong intermolecular hydrogen bonding mediated by water molecules. Computer-generated X-ray powder patterns for the two species are distinctly different and serve as reference for their identification.

Physical and structural comparison of oxyphenbutazone monohydrate and anhydrate.

Two crystal forms of oxyphenbutazone (a monohydrate and an anhydrate) were prepared by recrystallization. The forms were characterized by means of differential scanning calorimetry, thermogravimetry, infrared spectrophotometry, X-ray powder diffraction patterns, thermomicroscopy, scanning electron microscopy, as well as powder and intrinsic dissolution rates. The crystal structure of the anhydrate has been elucidated and compared with that of the monohydrate.

Physical characterization of the methanol solvate of urapidil.

The methanol solvate of urapidil was prepared and characterized by means of differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, X-ray powder diffraction, intrinsic dissolution rate, and solution calorimetry. The stoichiometry of the urapidil:methanol solvate was found to be 1:1. The crystal and molecular structures were determined from three-dimensional X-ray data. The stability of the solvate under different storage conditions was also determined.

Physical characterization of the hydrates of urapidil.

Three hydrates of urapidil were prepared and characterized by means of differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, X-ray powder diffraction, intrinsic dissolution rates, and solution calorimetry. The stoichiometry of the urapidil hydrates was found to be 1:5, 1:3, and 1:1 (urapidil:water). The crystal and molecular structures of urapidil pentahydrate were determined from three-dimensional X-ray data. The stability of the pentahydrate and monohydrate under different storage conditions was also determined.

Physicochemical properties and X-ray structural studies of the trigonal polymorph of carbamazepine.

The trigonal polymorph of carbamazepine (alpha-carbamazepine) was obtained by crystallization from a number of solvents. It was characterized by means of differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, X-ray power diffraction, thermal microscopy, and powder and intrinsic dissolution rates. The crystal and molecular structures were determined by single-crystal, three-dimensional X-ray analysis. A comparison is drawn between the physicochemical properties of the monoclinic (beta) and trigonal (alpha) forms. Structural features of carbamazepine occurring in these forms and in the acetone solvate are compared. Substantial differences were detected between the two polymorphic forms with regard to infrared and differential scanning calorimetry data, thermomicroscopical behavior, morphology, and molecular conformation.