Crystalline polymorphism and molecular structure of sodium pravastatin

In this work different crystallization processes of sodium pravastatin are explored and a new polymorph is obtained. The analytical results of powder X-ray diffraction (PXRD) and thermal analysis for this new polymorph indicate that it is different from the polymorphs previously reported. This new crystal form shows different physical-chemical properties than the previous forms, such as crystallographic structure, thermal behavior, and melting point, 181.5 degrees C. Besides, all crystallization processes previously reported use an aprotic solvent as antisolvent. However, we propose a new crystallization process for sodium pravastatin that uses only protic solvents, overcoming industrial scaling and environmental problems. Variable-temperature PXRD experiments show a transformation between different crystal forms in the range of 80-120 degrees C. Solid-state 13C NMR, reported in this work for the first time, and Fourier transform infrared (FT-IR) studies of some polymorphs show some differences in intermolecular interactions, especially with carboxylate and hydroxyl groups. Quantum mechanical calculations of the pravastatin molecule are also presented for the first time, obtaining a molecular structure similar to the experimental structure existing within the crystal lattice of the tert-octylamonium salt of pravastatin.     

Tautomeric polymorphism of the neuroactive inhibitor kynurenic acid

Kynurenic acid (KYN; systematic name: 4‐hydroxyquinoline‐2‐carboxylic acid, C₁₀H₇NO₃) displays a therapeutic effect in the treatment of some neurological diseases and is used as a broad‐spectrum neuroprotective agent. However, it is understudied with respect to its solid‐state chemistry and only one crystal form (α‐KYN·H₂O) has been reported up to now. Therefore, an attempt to synthesize alternative solid‐state forms of KYN was undertaken and six new species were obtained: five solvates and one salt. One of them is a new polymorph, β‐KYN·H₂O, of the already known KYN monohydrate. All crystal species were further studied by single‐crystal and powder X‐ray diffraction, thermal and spectroscopic methods. In addition to the above methods, differential scanning calorimetry (DSC), in‐situ variable‐temperature powder X‐ray diffraction and Raman microscopy were applied to characterize the phase behaviour of the new forms. All the compounds display a zwitterionic form of KYN and two different enol–keto tautomers are observed depending on the crystallization solvent used.     

Crystallization products of risedronate with carbohydrates and their substituted derivatives

The gastrointestinal absorption of bisphosphonates is in general only about 1%. To address this problem mixtures of risedronate monosodium salt with twelve varied sugar alcohols, furanoses, pyranoses and eight gluco-, manno- and galactopyranoside derivatives as counterions were designed in an effort to prepare co-crystals/new entities with improved intestinal absorption. Crystalline forms were generated by means of kinetically and/or thermodynamically controlled crystallization processes. One hundred and fifty-two prepared samples were screened by means of FT-NIR and FT-Raman spectroscopy. No co-crystal was prepared, but noteworthy results were obtained. A new solid phase of risedronate monosodium salt generated in the presence of phenyl-β-d-galactopyranoside under thermodynamically controlled crystallization conditions was found and also characterized using solid state NMR spectroscopy, X-ray powder diffraction and differential scanning calorimetry. This new polymorph was named as form P. Interactions between risedronate monosodium salt and both carbohydrates were confirmed by means of molecular dynamics simulation. In the present study the relationships between the chemical structures of the studied compounds required for crystalline form change are discussed.     

Calorimetric determinations and theoretical calculations of polymorphs of thalidomide

The analysis of the thermograms of thalidomide obtained for the two reported polymorphs and β by differential scanning calorimetry (DSC) shows some inconsistencies that are discussed in the present work. The conception of a new polymorph form, named β^*, allowed us to explain the observed thermal behavior more satisfactorily. This new polymorph shows enantiotropy with both and β polymorphs, reflected in the unique endotherm obtained in the DSC-thermograms, when a heating rate of 10 °C/min is applied. Several additional experiments, such as re-melting of both polymorph forms, showed that there is indeed a new polymorph with an endotherm located between the endotherms of and β. IR, Raman, and powder X-ray permit us to characterize the isolated compound, resulting from the re-melting of both polymorph forms. Mechanical calculations were performed to elucidate the conformations of each polymorph, and ab initio quantum chemical calculations were performed to determine the energy of the more stable conformers and the spatial cell energy for both polymorphs and β. These results suggested a possible conformation for the newly discovered polymorph β^*.     

Some Physico-chemical Properties of Doxazosin Mesylate Polymorphic Forms and its Amorphous State

Seven polymorphic modifications of doxazosin mesylate, designed as forms A, D, E, F, G, H, I, and the amorphous state were studied by thermal methods (TG and DSC), temperature resolved X-ray powder diffractometry, hot stage and scanning electron microscopy and by FT-IR spectroscopy. Amorphous form was obtained either by fast evaporation of the solvent or by fast cooling of the melt in the DSC. Polymorphs A and F were found to be stable in the temperature range from room temperature to their melting points at 277.9 and 276.5°C, respectively. Form G, which melts at 270.8°C, was found to be hygroscopic. Polymorph D undergoes irreversible solid–liquid–solid phase transition at 235.5°C to polymorph I which melts at 274.9°C. Form H, which melts at 258.0°C, was found to be unstable at high temperatures. DSC examinations revealed that form H is irreversibly transformed to polymorph F during heating above the temperature of about 240°C. The amorphous state was found to be stable at room temperature but when heating above the glass transition (T _g=144.1°C) it crystallizes at 221.6°C, what leads into a mixture of polymorphic forms. The new polymorphic form designed as E was identified in the mixture. The polymorph E is converted by heating to the more stable form F. The solubilities at 25°C for forms A, and F in methanol are 3.5 and 7.7 mg mL⁻¹and in water they are 3.8 and 6.2 mg mL⁻¹, respectively. This revised version was published online in August 2006 with corrections to the Cover Date.     

Polymorphism in Polyamide of Dytek®-A and Dodecanedioic Acid

Our X-ray work of Dytek®-A, 2-methyl-pentamethylenediamine, containing polyamides shows polymorphism, whereas the polyamides with linear diamines do not. The polyamide of Dytek®-A and dodecanedioic acid, MPMD-12, is singled out for discussion and compared with the unbranched analogs of polyamides 6,12 and 5,12. Due to the presence of the -CH₃ side group in the 2-position of the diamine, the polyamide MPMD-12 exhibits two stable crystal conformations. The new δ polymorph is not seen in linear polyamides 6,12 and 5,12. Studies by DSC polyamide MPMD-12 clearly illustrates at least two crystal forms, γ and δ, coexisting over a wide temperature range, and the isolation of each phase is possible by controlling temperature and time. The DMA modulus in the temperature region between the glass transition (or alpha relaxation) and melting transition shows strong dependence on the thermal history as demonstrated in a study of crystallization kinetics.     

Polymorphism and phase transition behavior of 6,6′‐bis(chloromethyl)‐1,1′,4,4′‐tetramethyl‐3,3′‐(p‐phenylenedimethylene)bis(piperazine‐2,5‐dione)

A crystallographic investigation of the title compound, C₂₂H₂₈Cl₂N₄O₄, using crystals obtained under different crystallization conditions, revealed the presence of two distinct polymorphic forms. The molecular conformation in the two polymorphs is very different: one adopts a `C' shape, whereas the other adopts an `S' shape. In the latter, the molecule lies across a crystallographic twofold axis. The `S'‐shaped polymorph undergoes a reversible orthorhombic‐to‐monoclinic phase transition on cooling, whereas the structure of the `C'‐shaped polymorph is temperature insensitive.     

Evaluation of the physical stability and local crystallization of amorphous terfenadine using XRD-DSC and micro-TA

It is very difficult to follow rapid changes in polymorphic transformation and crystallization and to estimate the species recrystallized from the amorphous form. The aim of this study was to clarify the structural changes of amorphous terfenadine and to evaluate the polymorphs crystallized from amorphous samples using XRD-DSC and an atomic force microscope with a thermal probe (micro-TA). Amorphous samples were prepared by grinding or rapid cooling of the melt. The rapid structural transitions of samples were followed by the XRD-DSC system. On the DSC trace of the quenched terfenadine, two exotherms were observed, while only one exothermic peak was observed in the DSC scan of a ground sample. From the in situ data obtained by the XRD-DSC system, the stable form of terfenadine was recrystallized during heating of the ground amorphous sample, whereas the metastable form was recrystallized from the quenched amorphous sample and the crystallized polymorph changed to the stable form. Obtained data suggested that recrystallized species could be related to the homogeneity of samples. When the stored sample surface was scanned by atomic force microscopy (AFM), heterogeneous crystallization was observed. By using micro-TA, melting temperatures at various points were measured, and polymorph forms I and II were crystallized in each region. The percentages of the crystallized form I stored at 120 and 135 °C were 47 and 79%, respectively. This result suggested that increasing the storage temperature increased the crystallization of form I, the stable form, confirming the temperature dependency of the crystallized form. The crystallization behavior of amorphous drug was affected by the annealing temperature. Micro-TA would be useful for detecting the inhomogeneities in polymorphs crystallized from amorphous drug.     

Oxygen redistribution in ZrO<Subscript>2</Subscript>-Y<Subscript>2</Subscript>O<Subscript>3</Subscript> system

This work represents the results of oxygen redistribution studies at quantitative and isotopic levels in synthesis and thermal treatment of ZrO - (0 to 35 mol %) Y₂O₃ solid solution crystals. The crystals were grown by directed melt crystallization method in a cold container using direct high-frequency heating. The crystal oxygen content and isotopic composition data was collected with respect to stabilizer concentration and technological conditions of synthesis. The temperature and frequency relationships of crystal electroconductivity were also studied. Some strength and tribological characteristics of the given materials were represented. The solid state formation by directional melt crystallization was shown to involve oxygen isotopic exchange interaction between the melt, growing crystal, and gas phase.     

Disappearing and reappearing polymorphs. The benzocaine:picric acid system.

The low-melting polymorphic modification of the 1:1 complex of benzocaine (BC) and picric acid (PA) had earlier been reported to be an example of a "disappearing polymorph". The BC:PA system has been reinvestigated by thermomicroscopy, calorimetry, solid-state NMR, and X-ray crystallography. The phase diagram has been derived, and robust procedures for the crystallization of the two 1:1 complexes, a hydrate of the 1:1 complex, and a 2:1 complex have been devised. The structures of all four phases have been determined and compared using graph set analysis to characterize the hydrogen-bonding patterns. It is shown that the thorough microscopic investigation of the thermal behavior, combined with calorimetric methods, can lead to the development of strategies to crystallize metastable polymorphic forms which may be difficult to obtain once their stable congeners have been obtained.     

Polymorphs and Polymorphic Cocrystals of Temozolomide

Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4′‐bipyridine‐N,N′‐dioxide (BPNO), and solid‐state stability were studied. Apart from a known X‐ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3‐hydroxypyridine‐N‐oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N? H???N_imidazole and N? H???N_tetrazine interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZ?BPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen‐bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N–H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C?O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen‐bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen‐bond reorganization.     

Polymorphic phase transformations of 3‐chloro‐trans‐cinnamic acid and its solid solution with 3‐bromo‐trans‐cinnamic acid

We have investigated the polymorphic phase transformations above ambient temperature for 3‐chloro‐trans‐cinnamic acid (3‐ClCA, C₉H₇ClO₂) and a solid solution of 3‐ClCA and 3‐bromo‐trans‐cinnamic acid (3‐BrCA, C₉H₇BrO₂). At 413 K, the γ polymorph of 3‐ClCA transforms to the β polymorph. Interestingly, the structure of the β polymorph of 3‐ClCA obtained in this transformation is different from the structure of the β polymorph of 3‐BrCA obtained in the corresponding polymorphic transformation from the γ polymorph of 3‐BrCA, even though the γ polymorphs of 3‐ClCA and 3‐BrCA are isostructural. We also report a high‐temperature phase transformation from a γ‐type structure to a β‐type structure for a solid solution of 3‐ClCA and 3‐BrCA (with a molar ratio close to 1:1). The γ polymorph of the solid solution is isostructural with the γ polymorphs of pure 3‐ClCA and pure 3‐BrCA, while the β‐type structure produced in the phase transformation is structurally similar to the β polymorph of pure 3‐BrCA.     

Re-investigations of thermal decomposition of gadolinium sulfate octahydrate

The crystals of Gd₂(SO₄)₃·8H₂O were obtained by slow crystallization from a saturated solution previously received by dissolving Gd₂O₃ in an aqueous solution of sulfuric acid. The thermal behavior of this salt was studied using simultaneous DTA–TG technique under a nitrogen and air, in the temperature range of 298–1773 K. It was found that the dehydration of gadolinium sulfate octahydrate as well as thermal decomposition of anhydrous Gd₂(SO₄)₃ undergo in two steps. The existence of two polymorphic modification of anhydrous gadolinium sulfate has been confirmed. The new XRD data for high-temperature polymorph of Gd₂(SO₄)₃ were given. All intermediate products of dehydration and thermal decomposition were characterized by EPR method.     

Hetero‐Seeding and Solid Mixture to Obtain New Crystalline Forms

Para‐methyl benzyl alcohol (p‐MeBA II) and para‐chloro benzyl alcohol (p‐ClBA) are quasi‐isostructural and share the same hydrogen‐bond patterns, but their crystals are not isomorphous. No new polymorphs could be obtained by conventional polymorph screening based on different solvents and different crystallization conditions. Formation of a new polymorph of p‐MeBA named p‐MeBA I, isomorphous with the crystal of p‐ClBA, was induced by hetero‐seeding with a small quantity of powdered p‐ClBA added to a supersaturated solution of p‐MeBA in hexane, while seeding of p‐ClBA with p‐MeBA II failed to give a new phase of p‐ClBA isomorphous with known crystalline p‐MeBA II. Mixed crystals of p‐MeBA and p‐ClBA were also prepared with different p‐MeBA/p‐ClBA ratios to understand the role of the different functional groups in the crystal structure. Crystal phases were characterized by combined use of single‐crystal and powder X‐ray diffraction, differential scanning calorimetry, and solid‐state NMR spectroscopy.     

Two‐phase crystallization kinetics of syndiotactic polystyrene

In this work, a two phase crystallization model based on the extension of the Kolmogoroff approach was proposed and verified by comparison with experimental isothermal and nonisothermal crystallization data of Syndiotactic Polystyrene (sPS) in a very wide range of cooling rates, up to 600 °C/s. To investigate the effects of high cooling rate on the sPS crystalline structure, a homemade apparatus was adopted. The morphology in solid samples was analyzed by densitometry, IR spectroscopy, and X‐rays diffraction. The coupling of these techniques allows the determination of the fractions of different crystalline phases. In agreement with melt‐crystallization studies of sPS proposed by different authors, either α and β forms could be produced depending on the thermal history of the sample. Results show that the stable β form is favored for specimens solidified at higher temperature or under low cooling rates, whereas α and mesomorphic forms are favoured at low temperature or high cooling rates. The proposed multiphase crystallization kinetics model successfully described all the range of experimental data. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 48: 1757–1766, 2010     

Polymerization of elemental sulfur with various divinyl and diallyl monomers and properties of the copolymers

Abstract

Polymeric sulfur generated from thermal ROP forms a semi crystalline, intractable solid with poor mechanical properties and is not easy to melt and resists solid processing. Stabilization of diradical polymeric sulfur form can be achieved by reaction with dienes which stabilizes the polymeric sulfur (depolymerization of polymeric sulfur by polymerization with diene co-monomer). The present work demonstrates how the physical properties of the sulfur based copolymer can be tuned by varying the vinylic and allylic modifier. These particular new structurally modified sulfur based copolymers could act as efficient polymer binders for making concrete materials.     

Molecular dynamics studies of the kinetics of phase changes in clusters III: structures, properties, and crystal nucleation of iron nanoparticle Fe331

Molecular dynamics (MD) computer simulations have been carried out to study the structures, properties, and crystal nucleation of iron nanoparticles with 331 Fe atoms or with diameter around 2 nm. Structure information for the nanoparticles was analyzed from the MD simulations. Three crystalline phases and one amorphous phase were obtained by cooling the nanoparticles from their molten droplets at different cooling rates or with different lengths of cooling time periods. Molten droplets froze into three different solid phases and a solid-solid transition from a disordered body-centered cubic (BCC) phase to an ordered BCC phase were observed during the slow cooling and the quenching processes. Properties of nanoparticle Fe₃₃₁, such as melting point, freezing temperature, heat capacity, heat of fusion, heat of crystallization, molar volume, thermal expansion coefficient, and diffusion coefficient, have been estimated. Nucleation rates of crystallization to two solid phases for Fe₃₃₁ at temperatures of 750, 800, and 850 K are presented. Both classical nucleation theory and diffuse interface theory are used to interpret our observed nucleation results. The interfacial free energy and the diffuse interface thickness between the liquid phase and two different solid phases are estimated from these nucleation theories.     

A形体过量β沸石的晶化过程

以四乙基氢氧化铵(TEAOH)为结构导向剂,在超浓水热条件下合成了手性多形体A(简称A形体)过量的β沸石,对初始凝胶的性质及晶化过程进行了深入研究,测定了相应的晶化曲线.研究结果表明,与晶化出A形体含量低于50%的普通β沸石的合成体系相比,晶化出A形体过量的β沸石的合成体系中含水量极低,凝胶中过量的水必须在晶化之前通过加热去除,但过度去除初始凝胶中的水则会显著延长晶化时间.在晶化初期,产物中己出现A形体过量特征,随着晶化的进行,A形体的过量程度无显著变化.     

Characterization of polymorphs of a novel quinolinone derivative, TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone)

The polymorphic forms and amorphous form of TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), a newly developed antiallergenic compound, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy and solid state 13C-NMR. The intrinsic dissolution rates of polymorphic forms were measured using the rotating disk method at 37 degrees C. The dissolution rates correlated well with the thermodynamic stability of each polymorphic form. These dissolution properties were clearly reflected in the oral bioavailability of TA-270 in rats. The transition behavior for each polymorph and for the amorphous form was studied under the high temperature and humidity conditions. The beta- and delta-forms were transformed into the alpha-form by heating. The amorphous form was also easily crystallized into alpha-form by heating, however it was relatively stable under humidified conditions. The internal molecular packing of each polymorph was estimated from IR and solid state NMR spectral analysis.