Polymorphic differences in alpha- and beta-form crystals of 2R, 4S, 6-fluoro-2-methyl-spiro[chroman-4,4'-imidazoline]-2',5-dione (M79175) as determined by X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry

Polymorphic differences in alpha- and beta-form crystals of 2R, 4S, 6-fluoro-2-methyl-spiro[chroman-4,4'-imidazoline]-2',5-dione (M79175; 1) were studied by X-ray diffractometry, infrared spectroscopy, and differential scanning calorimetry. X-ray powder diffraction indicated the longest spacing of the unit cells to be 14.9 and 12.4 A for the alpha- and beta-form crystals, respectively. The infrared spectra showed the absorption band assigned to NH streching vibration for the alpha-form crystals to be centered at 3250 cm-1 and that for the beta-form crystals to split into two peaks, at 3150 and 3425 cm-1. The enthalpies of fusion were 26.3 kJ/mol at 517.5 K and 31.3 kJ/mol at 501.0 K, respectively. Transformation from the beta- to alpha-form was observed at various heating rates, which were enhanced by the presence of a small amount of alpha-form crystals previously added to the beta-form. The former appeared to serve as a source of nuclei for the growth of both forms. These results confirm that the alpha-form crystal is more stable than the beta-form.     

Polymorphism and crystal structure of 2R,4S,6-fluoro-2-methyl-spiro[chroman-4,4'-imidazoline]-2',5-dione (M79175)

Two polymorphic forms, alpha and beta, of 2R,4S,6-fluoro-2-methyl-spiro-[chroman-4,4'-imidazoline]-2',5-dione (1, M79175) were studied by X-ray crystallography and solid-state infrared spectroscopy. The molecular and crystal structures of the beta-form were determined by single-crystal X-ray diffraction analysis. The molecules in the beta-form crystal are arranged orderly along the b-axis, and the plate-like moieties (chroman ring) of 1 are stacked by van der Waals forces. The molecular packing structure of each crystalline form was investigated by comparing wave numbers of hydantoin rings from which solid-state infrared photoacoustic spectra (FT-IR-PAS) were obtained. From the FT-IR-PAS data of both forms, it became clear that the hydrogen bond in an alpha-form crystal is stronger than that in the beta-form crystal. The cohesion of the polymorphic crystal system is mainly due to hydrogen bonds and van der Waals forces. Based on the polymorphism of 1, it was clarified that thermodynamic stability depends on the mode of hydrogen bonding, while the enthalpy of fusion results from van der Waals forces.     

Phase characterization of indomethacin in binary solid dispersions with PVP VA64 or Myrj 52

In the present study the properties of binary solid dispersions made up of PVP VA64, Myrj 52 and indomethacin (IMC) are studied and characterized. The solid dispersions were prepared by dissolving the materials in dichloromethane, followed by solvent evaporation under reduced pressure at 55 degrees C in a rotavapor. Binary solid dispersions were characterized by standard and modulated temperature differential scanning calorimetry (MTDSC), thermogravimetry (TGA) and X-ray powder diffraction (XRPD). XRPD analysis showed that the initial IMC was in its gamma-form, and that it was transformed to the beta-form (reported to be a solvate) together with an amorphous fraction in the solid dispersions. A mixture of the beta-form and amorphous IMC was also obtained in the binary systems containing less than 30% polymer. IMC without adding polymer was subjected to the same experimental procedures as in the solid dispersions, and used as a model to characterize the solid-state transformations. The following order of transitions was observed: from the initial gamma-form, the beta-form was obtained together with an amorphous component, then the crystalline beta-form transforms into the alpha-form which melts and recrystallizes into the most stable gamma-form.     

Behaviors of crystalline waters of (RS)-7-(2-aminomethylmorpholino)-1- cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid]

Physicochemical characteristics of crystalline water of (RS)-7-(2-aminomethylmorpholino)-1-cyclopropyl-6,8-difluoro-1,4-di hydro-4-oxo-3-quinoline-carboxylic acid were studied by thermal analyses and powder X-ray diffractometry. The dihydrate of the compound was stable under ambient or humidified conditions. The dihydrate converted to a monohydrate on drying under mild conditions. The mono- and dihydrates transformed into alpha-type anhydrate at 110 degrees C. These three kinds of crystals were convertible each other under appropriate conditions. At 165 degrees C, the hydrates and the alpha-anhydrate converted to beta-type anhydrate. The compressed effects on the crystalline waters were also discussed for the dihydrate by kinetic analyses.     

Polymorphism of carbamazepine: solid-state studies on carbamazepine dihydrate.

Carbamazepine dihydrate (CBZ.2H2O) crystallizes in the orthorhombic system, space group Cmca or C2ca. The unit-cell constants are: a = 19.834(7), b = 4.945(1), c = 28.826(9) A. M = 272.27, V = 2827(2) A3, Z = 8, D = 1.280 g.cm-3. Indexed X-ray powerder diffraction pattern is given. Dehydration process was studied by means of thermogravimetry and differential thermal analysis: the enthalpy of dehydration was found at 51 kJ per H2O mole. Thermal dehydration leads to an (anhydrous) gamma-form of CBZ when processed in dry atmosphere. The presence of water vapour induces the formation of the beta-form of CBZ as well as the grinding of CBZ.2H2O at room temperature.     

Assessment of defects and amorphous structure produced in raffinose pentahydrate upon dehydration

The progressive conversion of crystalline raffinose pentahydrate to its amorphous form by dehydration at 60 degrees C, well below its melting temperature, was monitored by X-ray powder diffraction over a period of 72 h. The presence of defects within the crystal structure and any amorphous structure created was determined computationally by a total diffraction method where both coherent long-range crystalline order and incoherent short-range disorder components were modeled as a single system. The data were analyzed using Rietveld, pair distribution function (PDF), and Debye total diffraction methods. Throughout the dehydration process, when crystalline material was observed, the average long-range crystal structure remained isostructural with the original pentahydrate material. Although the space group symmetry remained unchanged by dehydration, the c-axis of the crystal unit cell exhibited an abrupt discontinuity after approximately 2 h of drying (loss of one to two water molecules). Analysis of diffuse X-ray scattering revealed an initial rapid build up of defects during the first 0.5 h with no evidence of any amorphous material. From 1-2 h of drying out to 8 h where the crystalline structure is last observed, the diffuse scattering has both amorphous and defect contributions. After 24 h of drying, there was no evidence of any crystalline material remaining. It is concluded that the removal of the first two waters from raffinose pentahydrate created defects, likely in the form of vacancies, that provided the thermodynamic driving force and disorder for subsequent conversion to the completely amorphous state.     

NMR determination of enantiomers of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo(3,2-b)(1,3)benzoxazin-9-one using chiral shift reagent, tris(3-(heptafluorobutyryl)-d-camphorato)europium(III).

A simple NMR method was developed for the determination of the enantiomers of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo[3,2-b][1,3]benzoxazin-9-one. Chiral shift reagent, tris[3-(heptafluoroburyryl)-d-camphorato]europium(III), causes the doublet assigned to the protons of the 2-methyl group, which normally appears at about 1.5 ppm, to split into two pairs of doublets and to shift downfield to about 2.0-3.5 ppm. The downfield pair of doublets represents the two enantiomers present in one racemate, designated as the beta-form, while the upfield pair represents the enantiomers of the racemate designated as the alpha-form. From the integration of the area under the doublets, the relative concentration of all four enantiomers was determined.     

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: crystal structures and multinuclear solid-state NMR

Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.     

(1R,2S)-2-(3,4-二氟苯基)环丙胺扁桃酸盐单晶的制备及结构解析

目的 制备(1R,2S)-2-(3,4-二氟苯基)环丙胺扁桃酸盐(TCGM3)单晶,并对其空间结构进行解析。方法 通过优化溶剂、温度等结晶工艺参数,制备TCGM3单晶,采用单晶X射线衍射技术对其进行空间结构解析。结果 外形完整的TCGM3单晶可通过甲醇体系室温蒸发4 d得到。单晶X射线衍射结果表明TCGM3该晶胞属于正交晶系,P212121空间群,结构偏离因子R=0.04,分子式为C17H17F2NO3,相对分子质量为321.32 g/mol,立体构型与预测构型一致。结论 通过单晶培养及对其进行单晶X射线衍射分析和结构解析,确证了TCGM3的空间结构。     

(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究

目的　制备(6R,7R) - 7-[2 -呋喃基(甲氧亚氨基)乙酰氨基] - 3-羟甲基- 8-氧代- 5 -硫杂- 1-氮杂二环[4 2 0]辛- 2 -烯- 2 -甲酸。方法　通过7-氨基头孢烷酸的水解,生成去乙酰基7-氨基头孢烷酸,再与2 - (2 -呋喃基)- 2 -甲氧亚胺基乙酸氯反应进行7位氨基的酰化制备上述医药中间体。结果及结论　适宜的反应条件为:7-氨基头孢烷酸在- 2 5℃水解,与2 - (2 -呋喃基) - 2 -甲氧亚胺基乙酰氯在- 10℃反应,二者的摩尔比为1 0∶1. 15,收率可达80 %。     

5-HT_4受体激动剂兼5-HT_3受体阻断剂2-[1-(4-piperonyl)piperazinyl]-benzothiazole致心律失常机制探析

目的观察5-HT4受体激动剂兼5-HT3受体阻断剂2-[1-(4-piperonyl)piperazinyl]benzothiazole对大鼠离体心脏心律的影响,并探析其电生理学机制。方法采用成年健康SD大鼠建立离体心脏Langendorff主动脉逆行灌流系统,观察0.1～10μmol·L-12-[1-(4-piperonyl)piperazinyl]benzothiazole对离体心脏节律的影响,全程记录心电图的变化。应用全细胞膜片钳技术观察2-[1-(4-piperonyl)piperazinyl]benzothiazole对胶原酶分解的大鼠心室肌细胞膜内向整流钾电流(IK1)、瞬时外向钾电流(Ito)、静息膜电位(RMP)及动作电位(AP)的影响。结果在大鼠离体心脏,0.1～10μmol·L-12-[1-(4-piperonyl)piperazinyl]benzothiazole可诱发明显的心律失常。给药15min内,药物(10μmol.L-1)诱发期前收缩(PVB)236±37个,室速(VT)和室颤(VF)发生率分别达到87.5%和62.5%(n=8,P<0.01)。膜片钳记录结果显示,0.1～10μmol·L-12-[1-(4-piperonyl)piperazi-nyl]benzothiazole可浓度依赖性抑制大鼠心室肌IK1(EC50=0.74μmol·L-1)和Ito(EC50=2.16μmol·L-1),降低膜电位,并明显延长动作电位时程(n=6,P<0.01)。结论作为5-HT4受体激动剂和5-HT3受体阻断剂2-[1-(4-pipero-nyl)piperazinyl]benzothiazole致大鼠心律失常风险的电生理学机制为抑制IK1和Ito,降低膜电位,延长动作电位时程。     

Synthesis and antiulcer activity of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo [1,5-a]pyrimidine-7-ones

A series of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo-[1,5-a]pyrimidine-7-ones were synthesized and evaluated for the inhibition of stress-induced gastric ulcers in the rat after oral administration. Several molecules were found to be very active. The particularly interesting compound (E)-1-(3-chlorophenyl)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo[1,5-a]- pyrimidine-7-one was chosen for wider pharmacological investigation.     

Synthesis, partition coefficients and antibacterial activity of 3'-phenyl (substituted)-6'-aryl-2' (1H)-cis-3',3'a-dihydrospiro [3-H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones

Condensation of isatin with primary aryl amines gave a series of Schiff bases (1) which on reaction with thioglycolic acid in 1,4-dioxane afforded the formation of the corresponding 4- thiazolidinones (2). Compound 2 on condensation with substituted benzaldehydes in anhydrous sodium acetate furnished 3-aryl -5'-phenyl (substituted) spiro [3H-indole-3,2'-thiazolidines]-2-(1H), 4'(5'H)-diones (3). The latter (3) on reaction with hydrazine hydrochloride in anhydrous sodium acetate gave 3'-phenyl (substituted) -6'-aryl-2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones] (4). The structure has been established on the basis of spectral data. The partition coefficient for n-octanol/water solvent system and in vitro antibacterial activity of the 2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-one] derivatives have been evaluated.     

Spectrophotometric determination of copper in pharmaceutical and biological samples with 3-[2-[2-(2-hydroxyimino-1-methyl-propylideneamino)-(ethylamino]-ethyl-imino]-butan-2-one oxime).

3-[2-[2-(2-hydroxyimino-1-methyl-propylideneamino)-ethylamino]-ethyl-imino]-butan-2-one oxime, (H(2)mdo) reacts with copper(II) to form a highly stable 1:1 complex in alkaline medium at room temperature. The complex gives a maximum absorption at 570 nm with a molar absorptivity coefficient of 0.16 x 10(4) l mol(-1) cm(-1). A spectrophotometric method using this ligand was developed and optimized in terms of pH, stability of the complex, amount of reagent required, sensitivity, linearity and tolerance limits of various foreign ions. The linear range for copper determination is 0.2-225 mg l(-1). The method is sensitive, accurate and tolerant to many foreign substances, and, all the reagents used are stable under the conditions. Moreover, the method is easy to perform for the determination of copper in pharmaceutical and biological samples.     

Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers.

Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity were prepared by a one-step crystallisation process using varying ratios of acetone/water. The crystals were characterised using image analysis optical microscopy, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The elongation ratio was found to increase with increasing acetone ratio which therefore, appears to accelerate the growth in length rather than width and/or thickness. The crystallinity and polymorphic forms were also acetone-concentration dependent. For example, the crystals formed using 65-80% v/v acetone were almost all of the alpha-form whereas at 85% v/v a small amount of beta-form was precipitated, as detected by a peak at the reflection angle 2 theta=10.4 in the X-ray diffractogram. When 90% v/v acetone was incorporated a mixture of alpha- and beta-forms were produced in almost equal quantity, whereas, with 95% v/v acetone the beta-form predominated. At high acetone concentration (90 and 95% v/v), the crystallisation proceeded rapidly leading to the creation of some amorphous content. The 63-90-microm sieve cut of either commercial grade lactose (CL) or crystallised lactose was mixed with salbutamol sulfate and dispersibility was determined using the twin stage liquid impinger. All the formulations containing carrier particles generated by crystallization from solvent showed higher dispersibility and fine particle fraction (FPF) of the drug compared to the formulation made containing CL. The carrier that showed the highest elongation ratio (produced from an 85% acetone 15% water solution), when mixed with salbutamol sulfate produced the highest dispersibility (38.5%) and highest FPF (29.24%). These parameters were six times higher than the values obtained with the formulation containing CL.     

Synthesis and Crystal Structure of Anhydrous Analog of 1,25-Dihydroxyvitamin D3

As predicted by single crystal X-ray crystallography, and contrary to the reported suggestions, the anhydrous form of calcipotriol, a therapeutically important vitamin D analog, was found stable enough to be used as an active pharmaceutical ingredient. The crystal and molecular structure of calcipotriol anhydrate was solved and refined using single crystal X-ray diffraction. The analog was obtained by a novel convergent synthesis from the vitamin D C-22 sulfone, as an advanced intermediate and a side-chain fragment. The homo-chiral side-chain aldehyde was obtained from cyclopropanecarboxyaldehyde by the chromatographic separation of the intermediate diastereomeric salts with (S)-naproxen. Calcipotriol anhydrate showed a single peak in differential scanning calorimetry and the absence of a peak from a water molecule, typical for the monohydrate. Calcipotriol anhydrate, as the only 1,25-dihydroxylated analog of vitamin D₃, exists as a mixture of both α- and β-forms of the A-ring, present in the asymmetric part of the unit cell of the crystal lattice. The intermolecular hydrogen bonding between both conformers in the crystal lattice indicated that the stability of calcipotriol anhydrate might be at least the same as for the known monohydrate. The usefulness of calcipotriol anhydrate as an active pharmaceutical ingredient was confirmed by the stability study in the standard conditions used for the storage of vitamin D analogs.     

Dehydration behavior of eprosartan mesylate dihydrate.

Eprosartan mesylate (SKF 108566-J; EM) is an antihypertensive agent approved for marketing in the USA. EM dihydrate was prepared by three methods, one of which included suspending the anhydrous drug in an aqueous solution of 1.0 M methanesulfonic acid to form a slurry, followed by filtration. The dehydration kinetics of EM dihydrate were derived by analyzing the fit of the isothermal thermogravimetric analytical (TGA) data to numerous kinetic models. EM dihydrate undergoes dehydration in two distinct steps, each involving the loss of 1 mol of water at 25-70 degrees C and 70-120 degrees C, respectively. Recrystallization of EM occurs at approximately 120-140 degrees C after dehydration to the anhydrous phase. This explanation is supported by variable temperature powder X-ray diffractometry. The mechanism of the dehydration reaction is complex, the dependence of the reaction rate on temperature varying as a function of the particles size. For the dihydrate of sieve fraction <125 microm, the kinetics of the first and second dehydration steps are consistent with the Avrami-Erofeev equation (A3, n = 1/3) over the temperature range studied, corresponding to three-dimensional growth of nuclei. In contrast, for the 125-180-microm and 180-250-microm sieve fractions, the kinetics are best described by the two-dimensional phase boundary reaction (R2) at a lower dehydration temperature (i.e., 28.3 degrees C), and by the Avrami-Erofeev equation (A3, n = 1/3) at a higher dehydration temperature (i.e., 93.7 degrees C). The activation energies (15-40 kcal/mol) and frequency factors of the dehydration of EM dihydrate were determined both by Arrhenius plots of the isothermal rates determined by TGA and by Kissinger plots of the nonisothermal differential scanning calorimetric data. Hot stage microscopy of single crystals of EM dihydrate showed random nucleation at the surface and dehydration with the growth of microcrystals along the needle a axis. Cerius(2) molecular modeling software showed the existence of water channels along the a axis and enabled the observed dehydration behavior of EM dihydrate crystals to be explained in terms of the bonding environment of water molecules in the crystal structure.     

The Structure—Activity Relationship of a New Anti-Arrhythmic Agent 1-[2-Acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one

This paper reports the synthesis of the new compound 1-[2-acetoxy-3-(4-phenyl-1-piperazinyl)propyl]pyrrolidin-2-one (Ac-MG-1). Preliminary pharmacological assessment revealed that Ac-MG-1 possesses anti-arrhythmic activity and a local anesthetic effect. The crystal structure of Ac-MG-1 was determined by X-ray diffraction, and conformational analysis was performed both for Ac-MG-1 and for other derivatives of (arylpiperazinyl)propylpyrrolidin-2-one.     

Effects of Formulation and Process Factors on the Crystal Structure of Freeze-Dried Myo-Inositol

The objective of this study was to elucidate effects of formulation and process variables on the physical forms of freeze-dried myo-inositol. Physical properties of myo-inositol in frozen solutions, freeze-dried solids, and cooled heat-melt solids were characterized by powder X-ray diffraction (PXRD), thermal analysis (differential scanning calorimetry [DSC] and thermogravimetric), and simultaneous PXRD–DSC analysis. Cooling of heat-melt myo-inositol produced two forms of metastable anhydrate crystals that change to stable form (melting point 225°C–228°C) with transition exotherms at around 123°C and 181°C, respectively. Freeze-drying of single-solute aqueous myo-inositol solutions after rapid cooling induced crystallization of myo-inositol as metastable anhydrate (transition at 80°C–125°C) during secondary drying segment. Contrarily, postfreeze heat treatment (i.e., annealing) induced crystallization of myo-inositol dihydrate. Removal of the crystallization water during the secondary drying produced the stable-form myo-inositol anhydrate crystal. Shelf-ramp slow cooling of myo-inositol solutions resulted in the stable and metastable anhydrous crystal solids depending on the solute concentrations and the solution volumes. Colyophilization with phosphate buffer retained myo-inositol in the amorphous state. Crystallization in different process segments varies crystal form of freeze-dried myo-inositol solids. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2347–2355, 2014     

1-(5-硝基吲哚-2-羰基)-4-[3-(1-甲基乙胺基)-2-吡啶基]哌嗪的制备

地拉韦定(delavirdine)是由美国Pharmacia&Upjohn公司研制的非核苷HIV-1逆转录酶抑制剂(NNRTIs),临床与其它抗HIV药联合使用,用于治疗获得性免疫缺陷综合征[1].1-(5-硝基吲哚-2-羰基)-4-[3-(1-甲基乙胺基)-2-吡啶基]哌嗪(1)是其重要中间体.文献[2-4]以5-硝基吲哚-2-羧酸(2)和1-[3-(1-甲基乙胺基)-2-吡啶基]哌嗪(3)为原料,在1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDC)作用下缩合制得.EDC价昂,后处理用氯仿作提取溶剂,且需通过柱色谱纯化,不适于规模化生产.