One-solvent polymorph screen of carbamazepine

To emphasize the fact that solvents can be either critical or immaterial in crystallizing specific polymorphs, a method for obtaining multiple polymorphs of a compound using only one solvent is demonstrated. By varying the crystallization temperature and level of supersaturation, three of the four polymorphs of carbamazepine (CBZ; 5H-dibenz [b,f]azepine-5-carboxamide) were crystallized from cumene (isopropyl benzene). Form III, also referred to as the primitive monoclinic form, was produced at temperatures below 60 degrees C from supersaturated solutions concentrated at less than twice the solubility of that form. When the supersaturation was increased to twice the solubility of form III at temperatures below 60 degrees C, form II, also referred to as the trigonal form, was produced. Form I, also referred to as the triclinic form, was produced regardless of the level of supersaturation at temperatures above 80 degrees C. Between 60 degrees C and 80 degrees C, mixtures of forms were produced. Competition slurries were employed to establish the transition temperature to be between 79 degrees C and 82 degrees C for the enantiotropically related forms III and I. These results indicate that crystallization of CBZ from cumene can either be under thermodynamic control or affected by the kinetics of crystallization of metastable forms. This raises the question about the importance of solvent diversity when looking for polymorphs, suggesting that a rational experimental design can be used to greatly reduce the number of solvents and crystallization conditions. The results of this one-solvent polymorph screen correlate somewhat with a phase-solubility diagram for CBZ.     

Surfactant-facilitated crystallization of dihydrate carbamazepine during dissolution of anhydrous polymorph

The influence of two structurally different anionic surfactants on the anhydrous-to-dihydrate transformation of carbamazepine (CBZ) was investigated. The surfactants studied were sodium lauryl sulfate (SLS), a surfactant commonly used in compendial dissolution methods, and sodium taurocholate (STC), an important surfactant in the solubilization and absorption of drugs and lipids in the gastrointestinal tract. Results show that both surfactants promoted the crystallization of CBZ dihydrate [CBZ(D)] during dissolution of the anhydrous monoclinic polymorph [CBZ(A)]). Examination of crystal surfaces showed that SLS facilitated the surface-mediated nucleation of CBZ(D) on CBZ(A) crystals at surfactant concentrations below the critical micelle concentration (cmc). Solubilization of a dye and related color changes provided visual evidence for adsorbed SLS assemblies on CBZ(A) crystal faces below the cmc. Above the cmc, both surfactants promoted the transformation by increasing the bulk nucleation of CBZ(D). STC changed the crystal morphology of CBZ(D) from acicular to prismatic, depending on STC concentration. Such morphology changes originate from interactions between STC and molecular structures of CBZ(D) crystal faces that interfere with the formation of a hydrogen-bonded chain of water molecules and carboxamide dimers.     

In situ monitoring of carbamazepine–nicotinamide cocrystal intrinsic dissolution behaviour

Cocrystals have shown huge potential to improve the dissolution rate and absorption of a poorly water soluble drug. However, solution mediated phase transformation of cocrystals could greatly reduce the enhancement of its apparent solubility and dissolution rate. The aim of this study is to gain a deep understanding of the phase transition behaviour of cocrystals during dissolution and to investigate the improvement of dissolution rate. Dissolution and transformation behaviour of carbamazepine–nicotinamide (CBZ–NIC) cocrystal, physical mixture and different forms of carbamazepine: form I (CBZ I), form III (CBZ III) and dihydrate (CBZ DH) were studied by different in situ techniques of UV imaging and Raman spectroscopy. It has been found that compared with CBZ III and I, the rate of intrinsic dissolution rate (IDR) of CBZ–NIC cocrystal decreases slowly during dissolution, indicating the rate of crystallisation of CBZ DH from the solution is slow. In situ solid-state characterisation has shown the evolution of conversion of CBZ–NIC cocrystal and polymorphs to its dihydrate form. The study has shown that in situ UV imaging and Raman spectroscopy with a complementary technique of SEM can provide an in depth understanding during dissolution of cocrystals.     

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.     

A new polymorph of isoimperatorin

Abstract

Isoimperatorin is a naturally occurring furocoumarin and is being considered as a potential chemoprevention. Only one crystal form of isoimperatorin (Form I) was reported during previous research so that an investigation of polymorphism of isoimperatorin was successfully undertaken. A new polymorph of isoimperatorin was discovered through comprehensive polymorph screening experiments. Their structures were elucidated by single-crystal structure analysis and extensively characterized by XRPD, DSC, FT-IR, and SEM. The results showed that the crystal structure and thermal properties of the new polymorph (Form II) were significantly different from those of Form I. Thermodynamic stability and phase transformation were also discussed in detail.     

Synthesis and DNA transfection properties of new head group modified malonic acid diamides

The goals of the current study were to develop and characterize a nanoemulsion of ezetimibe, evaluate its stability, lipid lowering and pharmacokinetic profile. Solubility of the drug was estimated in various oils and surfactants. Existence of nanoemulsion region was confirmed by plotting phase diagrams. Various thermodynamic stability and dispersibility tests were performed on the formulations chosen from phase diagram. Percentage transmittance, refractive index, viscosity, droplet size and zeta potential of the optimized formulations were determined. Dialysis bag method was employed to study the release rate. The formulation selected for bioavailability estimation contained Capryol 90 (10%, v/v), Crempophor EL (11.25%, v/v), Transcutol^® P (33.75%, v/v), and double distilled water (45%, v/v). The release rate from the nanoemulsion was highly significant (p < 0.001) in contrast to the drug suspension. The level of total cholesterol in the group receiving nanoemulsion CF1 was found to be highly significant (p < 0.001) in comparison to the group receiving drug suspension. Bioavailability studies in rats revealed superior absorption of ezetimibe from nanoemulsion as compared to the marketed formulation and drug suspension. The shelf life of the nanoemulsion was estimated to be 18.53 months. The present study corroborated nanoemulsion to be a promising choice to improve the bioavailability of ezetimibe.     

杨梅素-咖啡因共晶在不同有机溶剂中的形成热力学特征

目的考察了杨梅素-咖啡因共晶在甲醇、乙醇、丙酮中的形成热力学特征。方法通过测定杨梅素、咖啡因、杨梅素-咖啡因共晶在甲醇、乙醇、丙酮中的溶解度,探讨杨梅素-咖啡因共晶的溶液络合模型,计算相关热力学参数,并绘制3种溶剂的共晶三元相图。结果杨梅素-咖啡因共晶在3种溶剂中均符合1∶1溶液络合模型;共晶形成反应为热力学自发反应(ΔG°<0),随着温度升高,溶度积(Ksp)逐渐增大,络合常数(K11)逐渐减小,反应自发程度减弱,低温有利于共晶的形成;共晶的溶解为吸热过程(Δ_(sol)H_m>0),升高温度有利于共晶的溶解。杨梅素-咖啡因-溶剂(甲醇、乙醇和丙酮)三元体系的三相图为对称相图,共晶形成区域在乙醇和丙酮中较甲醇中大,共晶更易形成。结论利用热力学研究方法为选择共晶制备用溶剂及优化共晶制备条件奠定了理论和应用基础。     

The antihypoxic action of malonic acid]

Malonic acid showed a protective action on rats in acute hypoxic hypoxia. The antihypoxic effect of this compound is unassociated with its action on succinate dehydrogenase and may be mediated through the changes in hormonal metabolic regulation.     

Photo-induced cytotoxicity of malonic acid [C(60)]fullerene derivatives and its mechanism.

The biological activities of fullerenes have attracted extensive attention in recent years. The aim of this paper is to study the relation of the photo-induced cytotoxicity of fullerene derivatives to their chemical structures as well as the possible cellular mechanism involved in the photocytotoxicity. Three C(60) derivatives with two to four malonic acid groups (DMA C(60), TMA C(60) and QMA C(60)) were prepared and the cytotoxicity of these compounds against HeLa cells was determined by MTT. Cell cycle was measured by flow cytometry. The results showed that the cytotoxicity of the malonic acid C(60) derivatives was irradiation- and dose-dependent. The sequence of their photo-induced growth inhibition was DMA C(60)>TMA C(60)>QMA C(60). Hydroxyl radical quencher mannitol (10mM) was not able to prevent cells from the damage induced by irradiated DMA C(60). DMA C(60), together with irradiation, was found to have an ability of inducing a decrease in the number of G(1) cells from 63 to 42% and a rise in that of G(2)+M cells from 6 to 26%. These data indicated that the number of malonic acid molecules added to C(60) played an important role in the phototoxicity, and the blockage of cell cycle might be a mechanism of this activity.     

Evaluation of a new Seralyzer assay for carbamazepine

The performance of a new dry-phase, strip immunoassay technique for the analysis of serum carbamazepine concentrations (Seralyzer), was compared to a standard high performance liquid chromatography (HPLC) method. One hundred blood samples were collected from 87 patients and analysed using both techniques. There was no significant difference between the concentrations measured by either technique, and the results were highly correlated (r = 0.97). The Seralyzer is a rapid and accurate method for use in carbamazepine therapeutic drug monitoring.     

Evaluation of a new polymorph azlocillin sodium by its antibacterial activity

The polymorph azlocillin sodium (obtained by us from acetonitril as recrystallized solvent), has been examined in order to evaluate the influence of the crystal form (state) on its antibacterial activity. Differences in minimal inhibitory concentrations (MIC) values have shown differences in the antibacterial properties of azlocillin sodium (AZ) and its polymorph AZ. These data illustrate the dependance of antibacterial activity on drug crystallinity.     

The antioxidizing activity of malonic acid derivatives]

Nine newly synthesized malonic acid derivatives were shown to have antioxidizing activity which makes up from 30 to 60% of the antioxidizing activity of ionol and vitamin E in vitro and does not yield to the activity of the latter substances in vivo. It is suggested that malonic acid derivatives may influence the antioxidizing enzymes--catalase, glucose-6-phosphate dehydrogenase and superoxide dismutase.     

Contingent tolerance to carbamazepine: a peripheral-type benzodiazepine mechanism.

Rats were tested for anticonvulsant responsivity to agents active at central and peripheral-type benzodiazepine receptors before and after they were made tolerant to the anticonvulsant effects of carbamazepine on amygdala-kindled seizures. Tolerance to carbamazepine in this paradigm is a contingent process; it occurs when the drug is administered prior to, but not following the kindled seizure. In animals tolerant to carbamazepine, cross-tolerance was observed to the anticonvulsant effects of PK11195, which is active at peripheral-type benzodiazepine receptors, but not to diazepam, which affects central-type benzodiazepine receptors. In animals treated with carbamazepine after the kindled seizure (not tolerant), no alteration in the anticonvulsant effect of PK11195 was observed. These data extend previous biochemical and pharmacological findings suggesting the importance of peripheral-type benzodiazepine receptor mechanisms in the anticonvulsant effects of carbamazepine and suggest a role for this site in the process of contingent tolerance development.     

Heat of fusion measurement of a low melting polymorph of carbamazepine that undergoes multiple-phase changes during differential scanning calorimetry analysis.

Two polymorphs of carbamazepine that melt at 176 and 189 degrees C and are known to be enantiotropic have been characterized more fully than in previous reports. For the first time, a value for the heat of fusion (29.3 kJ/mol) of the lower melting form is estimated, even though single melting DSC endotherms were not obtained. A method is described for summing the heat flows of intermediate transitions that occur when low melting carbamazepine is heated to a temperature where it will remain melted. The method should have general applicability in studies of polymorphs. Other characteristics of the carbamazepine enantiotropic pair are reported, including the transition temperature (71 degrees C).     

Supercritical carbon dioxide treatment as a method for polymorph preparation of deoxycholic acid

A new polymorph of deoxycholic acid (DCA) was formed by using a supercritical carbon dioxide treatment. Deoxycholic acid crystals were stored in a pressure vessel purged with carbon dioxide at 12MPa, 60 degrees C for definite intervals. After storage for 1h in supercritical carbon dioxide (SC-CO2), new X-ray diffraction (XRD) peaks, not found in the bulk DCA crystal, were observed at 2theta = 7.4 degrees, 9.7 degrees and 14.0 degrees. The intensities of the new diffraction peaks increased with an increase in storage time, whereas the intensities of the diffraction peaks due to bulk DCA crystal decreased. On the DSC curves, the crystals obtained showed an exothermic peak at around 155 degrees C followed by the melting peak of bulk DCA crystal at 175 degrees C. By the temperature-controlled powder XRD measurement, the crystals obtained were found to be a metastable form of DCA. The polymorphs of DCA have not been reported; therefore, the SC-CO2 treatment would be a peculiar method to obtain a DCA polymorph.     

2-(3-噻吩基)丙二酸的合成

3-甲基噻吩经溴代、氰基取代制得3-噻吩乙腈，再经醇解、与碳酸二乙酯反应和碱性水解制得合成青霉素类抗生素的中间体2-（3-噻吩基）丙二酸，总收率36％。     

Formation of dihydrate from carbamazepine anhydrate in aqueous conditions

According to our observations, carbamazepine dihydrate crystals grow by the whisker mechanism (or mechanisms). The habit, the dimensions of the crystals and their rapid growth indicate this. Also the strong orientation in the X-ray diffractogram is in harmony with the whisker theory. The whisker growth explains also the rapid transition from the anhydrous form to the dihydrate one in water.

Dihydrate whiskers which are loosely in the solution as well as ones fastened to the surface of the anhydrous mother crystal has been observed. The oriented crystal structure of carbamazepine dihydrate may be at least one important factor in the growth mechanism of carbamazepine dihydrate whiskers.