Development of a residual solvent test for bulk alpha-phenyl-1-(2-phenylethyl)-piperine methanol using headspace sampling

An automated static headspace gas chromatographic method for the determination of residual solvents in the bulk drug substance alpha-phenyl-1-(2-phenylethyl)-piperine methanol, a serotonin 5-HT2 receptor antagonist, is evaluated. The method includes the use of 1-propanol as an internal standard. The gas chromatographic conditions utilize a dimethylpolysiloxane phase (SPB-1) capillary column and a flame ionization detector. Validation of this test method includes a recovery study of known levels of acetone, ethyl acetate, methanol, and methyl ethyl ketone in the range of 0.05% to 1.0% (weight-per-weight or w/w) to verify the accuracy of this method; these four solvents are the most likely residual volatiles used in the production of the drug substance. These data and other aspects of the development of this test method are discussed.     

四苯硼钾由单-到不同混合溶剂的迁移自由能

KBPh4作为一种典型的大阴离子电解质 ,在研究与计算大分子电解质的迁移热力学性质中起着重要的作用 .讨论大分子电解质与不同溶剂间的作用 ,还可以为萃取、色谱及表面活性剂的研究提供理论依据 .一些文献及我们前文曾对四苯硼盐由水到一些纯溶剂 [1,2]及从水到某些水-有机混合溶剂中的标准迁移自由能进行了研究 [3],但对四苯硼盐在有机-有机混合溶剂中的研究报导极少 .本文对 KBPh4由水到水-异丙醇和由甲醇到甲醇-异丙醇混合溶剂的标准迁移自由能进行了研究和探讨 .1实验部分 1.1实验仪器及方法 　　用 CS501型超级恒温槽恒温 ;用 WF…     

Solubility of anthracene in binary toluene + alcohol solvent mixtures at 298.15 K

Experimental solubilities are reported for anthracene in eight binary toluene?+?alcohol solvent mixtures at 298.15?K. The alcohol solvents studied were 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 2-propanol, 2-butanol, 2-methyl-1-propanol and 3-methyl-1-butanol. Results of these measurements were used to test a mathematical representation based on the combined nearly ideal binary solvent (NIBS)/Redlich–Kister equation. For the eight systems studied, the combined NIBS/Redlich–Kister equation was found to accurately describe the experimental data, with an average absolute deviation between the measured and back-calculated values being approximately ±0.4%.     

Solvolysis of 4-methylcyclohexylidenemethyliodonium salt: chirality probe approach to a primary vinyl cation intermediate

Optically active 4-methylcyclohexylidenemethyl(aryl)iodonium tetrafluoroborate (1.BF(4)(-)) was prepared and its solvolysis was carried out at 60 degrees C in various solvents. The main product is optically active 4-methylcycloheptanone (or its enol derivative) in unbuffered solvents, accompanied by the iodoarene. The rearranged product always maintains the optical purity of the starting 1. Its stereochemistry conforms to a mechanism involving the rearrangement via the sigma-bond participation in departure of the nucleofuge, followed by trapping of the resulting chiral 5-methylcyclohept-1-enyl cation with a nucleophilic solvent. That is, the achiral, primary vinyl cation is not involved during the reaction. The unrearranged substitution product is also obtained in a minor fraction in unbuffered methanol, ethanol, and acetic acid, but not in trifluoroethanol or hexafluoro-2-propanol: the methoxy product from methanolysis is largely racemized, but the acetolysis product is obtained mainly via retention of configuration. Reactions of 1 with bromide, acetate, and trifluoroacetate in chloroform give unrearranged substitution products in different degrees of inversion. These unrearranged products are concluded to be formed via the direct nucleophilic substitutions. Added bases such as sodium acetate in methanol lead to the unrearranged methoxy products of complete racemization, which is ascribed to the alpha elimination (to give an alkylidenecarbene) followed by the solvent insertion.     

Solubility and solution thermodynamics of 2, 6-bis (4-hydroybenzylidene) cyclohexanone in pure and binary solvents at various temperatures

Solubility of 2, 6-bis (4-hydroxybenzylidene) cyclohexanone (BHBC) in pure solvents such as 1,4-dioxane, methanol, 1-butanol, 1-propanol, ethyl acetate, acetone, tetrahydrofuran (THF), glacial acetic acid, dimethyl sulphoxide (DMSO) and binary solvents dimethyl formamide (DMF) and (1-Propanol + Tetrahydrofuran) were investigated by gravimetric method at different temperature range. The experiment solubility increases with increase in temperature in both pure and binary solvents. The Maximum solubility is found in DMF at 328.15 K and for binary solvent mixture i.e. 1-propanol and THF (0.9 mol fraction) it was maximum at 318.15 K. Further modified Apelblate and Buchowski-Ksiazczak models were used for the theoretical calculation of solubility of BHBC in pure as well binary solvents. A satisfactory correlation of these models with experimental data was observed. The solution thermodynamics parameters like enthalpies, Gibb's free energy of dissolution and entropy of solutions were calculated using Van't Hoff and Gibb's equation, which reveals the solvation mechanism is non-spontaneous and entropy driven.     

Competitive surface adsorption of solvent molecules and compactness of agglomeration in calcium hydroxide nanoparticles

Calcium hydroxide forms unstable reactive nanoparticles that are stabilized when they are dispersed in ethylene glycol or 2-propanol. The aggregation behavior of these particles was investigated by contrast-variation small-angle neutron scattering (SANS), combined with small-angle X-ray scattering (SAXS). Nanoparticles on the order of 100 nm were found to aggregate into mass-fractal superstructures in 2-propanol, while forming more compact agglomerated aggregates with surface fractal behavior in ethylene glycol. Commensurate specific surface areas evaluated at the Porod limit were more than an order of magnitude greater in 2-propanol (approximately 200 m2.g(-1)) than in ethylene glycol (approximately 7 m2.g(-1)). This profound microstructural evolution, observed in similar solvents, is shown to arise from competitive solvent adsorption. The composition of the first solvent layer on the particles is determined over the full range of mixed solvent compositions and is shown to follow a quantifiable thermodynamic equilibrium, determined via contrast-variation SANS, that favors ethylene glycol over 2-propanol in the surface layer by about 1.4 kJ.mol(-1) with respect to the bulk solvent composition.     

顶空采样-毛细管气相色谱法分析格列美脲原料药中的溶剂残留

建立了顶空采样-毛细管气相色谱检测格列美脲原料药中溶剂残留的分析方法。对产自国内8个生产厂家的格列美脲样品中有机溶剂的残留状况进行了系统评价,结合药品生产工艺信息,确定了丙酮、乙酸乙酯、甲醇、异丙醇、乙醇、氯仿、甲苯、1,4-二氧六环、吡啶、氯苯、乙醚、二氯甲烷、正己烷和苯等14种有机溶剂为残留检测对象。根据被测组分在色谱柱上的保留性质将其分为两类,以实现基线分离。用Supelco-Wax极性色谱柱,以乙腈为内标物,分离检测了丙酮、乙酸乙酯、甲醇、异丙醇、乙醇、氯仿、甲苯、1,4-二氧六环、吡啶和氯苯的残留量;用Supelco OVI-G43弱极性色谱柱,以丁酮为内标,分离检测了乙醚、二氯甲烷、正己烷和苯的残留量。14种残留组分在各自的浓度范围内呈良好的线性关系(r=0.99167～0.99997,n=8),最低检出限范围为0.2～13.5 μg/g;14种残留组分检测的日间重复性(以相对标准偏差(RSD)计)为0.6%～9.2%(n=3),3种加标浓度的平均添加回收率为86.3%～104.1%(RSD为0.2%～5.3%,n=16)。实验结果表明,该方法简单、灵敏、可靠,适用于格列美脲中残留溶剂的分析确证。     

Temperature dependence of unperturbed dimensions for isotactic poly(2-hydroxyethyl methacrylate)

The unperturbed dimensions of isotactic poly(2-hydroxyethyl methacrylate) (PHEMA) were evaluated from intrinsic viscosity measurements in water, ethanol, 1-propanol, 2-propanol, and 2-butanol under θ conditions over the temperature range of 3.7–32.1°C. The smallest value of unperturbed dimensions (K_θ) and the largest negative temperature dependence of unperturbed dimensions and the polymer–solvent interaction parameter (B) were obtained in aqueous θ solvent relative to the corresponding organic θ solvents. These results were interpreted by the hydrophobic interaction between the hydrophobic groups of isotactic PHEMA and water solvent. The temperature coefficient of the unperturbed dimensions, d ln〈r〉/dT, obtained in this study has a negative value of ?1.44 × 10^?3 deg^?1 under chemically similar θ solvents such as ethanol, 1-propanol, 2-propanol, and 2-butanol where specific solvent effects are eliminated or minimized. In order to obtain the thermodynamic parameters for mixing between isotactic PHEMA and solvents, the plots of the polymer–solvent interaction parameter versus reciprocal absolute temperature (1/T) were carried out. Both the entropy of dilution and enthalpy of dilution show the negative values for water, methanol, and t-butanol, whereas the positive ones for ethanol, 1-propanol, 2-propanol, and 2-butanol. This result indicates that the solution of isotactic PHEMA behave as exothermal systems in the former class of solvents and endothermal ones in the latter class of solvents.     

Characterization of the non-stoichiometric and isomorphic hydration and solvation in FK041 clathrate

FK041 crystallizes as a non-stoichiometric hydrate or as solvated hydrates which were characterized as isomorphic clathrates by powder X-ray diffractometry. Moisture and organic solvent vapor sorption studies, differential scanning calorimetry and thermogravimetric analysis revealed that FK041 monohydrate forms a physically stable host crystal, which has lattice channels for guest water and/or organic solvent molecules. The hydration state varies non-stoichiometrically between dihydrate and tetrahydrate depending on the relative humidity and the mol content of the co-existing organic solvent, that is 2-propanol, ethanol, or acetone. These organic solvents are thought to replace a part of originally present water with a mol ratio of 1:3. 2-Propanol exhibited the most stable solvation, indicating that the size and shape of 2-propanol are the most preferable to the lattice channels.     

Nonaqueous capillary electrophoresis: application possibilities and suitability of various solvents for the separation of basic analytes

Eleven organic solvents were tested for their suitability in the use of capillary electrophoresis (CE). In all cases, 25 mM ammonium acetate and 1 M acetic acid were used as electrolytes. Three basic therapeutical agents, propranolol, carteolol and imipramine, were used as analytes. Four solvents (2-propanol, ethylene glycol, propylene glycol, dichloromethane) were not suitable for use with CE under our conditions. Depending on the other solvents used, the analytes showed very different behavior. We observed that the epsilon/eta quotient alone is not sufficient for a characterization of the solvents. Further investigations with all the solvents as 1:1 mixtures with methanol were carried out. As a result some principal changes occurred compared to the pure solvents. Working with mixtures of different solvents proved to be advantageous because of the possibility to influence properties like high viscosity or low ionizing abilities by the addition of a suitable second solvent.     

Synthesis and characterization of NiSn colloids and active solids prepared in organic solvents by CLD

Bimetallic colloidal dispersions were obtained by simultaneous cocondensation of nickel and tin atoms with organic solvents at 77 K using the chemical liquid deposition (CLD) method. The atoms in a 1:1 ratio were produced by resistive heating and were reacted with 2-propanol, 2-methoxyethanol, and acetone to produce colloids.The kinetic stability of the colloid dispersions was related to the solvation effect of organic molecules, e.g., low stability for acetone, higher for 2-propanol, and the highest for 2-methoxyethanol. The colloidal particles were characterized by UV-Vis measurements showing absorption bands at 204 and 270 nm. A 3-day study in which samples were taken every hour showed that the absorption bands decrease probably due to clustering. Electrophoretic measurements revealed that the particles are weakly positively charged. Transmission electron microscopy studies revealed an average particle size distribution ranging from 6 to 10 nm depending on the solvent. Most of the colloids exhibit a spherical shape with some degree of agglomeration.After solvent evaporation several active solids were obtained. The FTIR spectra show the presence of the solvent incorporated in the active solids/films, e.g., for acetone the carbonyl stretching is observed at 1723 cm^–1. The thermal stability of these bimetal powders/films was studied by TGA up to 550 °C. Their maximum decomposition temperatures are 350, 415, and 429 °C for NiSn–2-methoxyethanol, –2-propanol, and –acetone, respectively.     

Effects of the molecular properties of mixed solvents on the elution of alkyl benzoates in RPLC.

The retention behavior and mechanism of methyl, ethyl, propyl, isopropyl, buthyl and isobuthyl benzoates have been studied at different eluent compositions of aqueous mixtures with water-soluble organic solvents (methanol, ethanol, 1-propanol, 2-propanol, acetonitrile (AN), 1,4-dioxane and tetrahydrofuran (THF)) in RPLC. The retention of the solutes is discussed based on the solvent composition, solvent polarity (ETN value), preferential solvation, hydrogen bonding and solvent clusters of the eluents. The smaller ETN values and the larger preferential solvation of the mixed solvent eluted the solutes faster. The IR spectra of HDO suggested that the solvents, except for methanol and ethanol, break the hydrogen bonding between water molecules, resulting in fast elution of the solutes. Based upon the results, we chose an optimum solvent composition for the separation of benzoates and applied it to the determination of the benzoates in clove.     

2-Methyl-2-propanol as solvent for o-iodoxybenzoic acid (IBX) oxidation of 1? alcohols to aldehydes

2-Methyl-2-propanol has been demonstrated to be an effective solvent for IBX oxidation of 1? alcohols to the corresponding aldehydes. IBX has a measurable, but low, solubility in 2-methyl-2-propanol and thus partially avoids the drawbacks inherent in the solubility problems associated with IBX without resorting to less desirable solvents. This may be particularly useful where solubility of the alcohol is also at issue.     

Thermosolvatochromism of merocyanine polarity indicators in pure and aqueous solvents: relevance of solvent lipophilicity

The following novel solvatochromic probes were synthesized: 2,6-dibromo-4-[(E)-2-(1-alkylpyridinium-4-yl)ethenyl] phenolate, where the alkyl groups are methyl, n-butyl, n-hexyl, and n-octyl, respectively. Solvatochromism of three of these probes (C(1), C(4), and C(8)) was studied in 36 protic and aprotic solvents. A modified linear solvation energy relationship has been applied to the data obtained at 25 degrees C. Correlation of (empirical) polarities with other solvent properties showed more dependence on lipophilicity than on basicity. A similar conclusion has been reached for a series of other solvatochromic indicators. Exceptions are those that carry acidic hydrogens, being biased toward solvent basicity. Thermosolvatochromism has been studied in mixtures of water with methanol, 1-propanol, acetonitrile, and DMSO. Thermosolvatochromic data have been treated according to a model that explicitly considers the presence in bulk solution of three "species": water, organic component, and solvent-water hydrogen-bonded aggregate. Solvation by the latter is favored over solvation by either of the two precursor solvents (aqueous DMSO is an exception). Temperature increase resulted in desolvation of the probes, due to concomitant decrease of the structures of the component solvents. The above-mentioned modified solvation equation has been successfully applied to solvatochromism in aqueous methanol and aqueous 1-propanol.     

Preferential Solvation in Aqueous–Organic Mixed Solvents Using Solvatochromic Indicators

Solvatochromism of the twisted intramolecular charge-transfer (TICT) fluorescence of 4-(N,N-dimethylamino)benzonitrile (DMABN) in pure water, methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, and in the corresponding aqueous–organic binary mixed solvents was systematically studied and an empirical solvent polarity scale (F _B) based on the DMABN solvatochromism was defined. The F _B parameters of the explored binary mixed solvents as a function of solvent composition were analyzed by a stepwise solvent-exchange (SSE) model to clarify the preferential solvation (PS) of the probe dye in these binary mixed solvents. Solvation diagrams toward DMABN in the mixed solvents, i.e., the local solvent composition in the solvation shell of DMABN molecules was depicted as a function of bulk solvent composition to visualize the PS in these mixed solvents. For comparison, a similar PS analysis was applied to the solvatochromism of 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1- yl)phenolate (ET-30) and pyrene (Py) in these mixed solvents; the responsive PS pattern of the mixed solvents toward the specific indicator dye of DMABN, ET-30, and Py was then discussed in terms of the chemical properties of the probe dye, the properties of the mixed solvents, and the solute–solvent and solvent–solvent interactions.     

Evaluation of a headspace-GC method for residual solvents in a serotonin 5-HT3 antagonist compound

A static headspace gas chromatographic method is developed and evaluated for the quantitation of residual 2-propanol, methanol, and toluene in bulk (2alpha, 6alpha, 8alpha, 9alpha beta)-octahydro-3-oxo-2,6-methanon-2H-quinolizin-8-yl-1H-indole-3-caboxylate methanesufonate hydrate, a serotonin 5-HT3 receptor antagonist drug compound. This method is accurate and precise, and it includes the use of 1-propanol as an internal standard. The gas chromatographic conditions utilize a dimethylpolysiloxane phase (SPB-1) capillary column and a flame ionization detector. Validation of this test method includes a recovery study of known levels of the three target analyte solvents to verify the accuracy of this method, because these solvents were used in the recrystallization and synthesis of all current and future lots of the bulk drug. The tested range is 0.05% to 1.0% (w/w) for 2-propanol and methanol and 0.01% to 0.10% (w/w) for toluene. Mean recovery of all spikes is 107% (w/w) of theory for methanol (n = 15) and 101% (w/w) for 2-propanol. Toluene mean recovery of all spikes is 98% (w/w) of theory within the tested range (n = 6). These data and other facets of the development of this headspace method are discussed.     

Stability-indicating high-performance liquid chromatographic assay method and photostability of carprofen

A rapid, sensitive, and accurate stability-indicating high-performance liquid chromatographic assay method for determining the degradation of carprofen (CPF) is developed and validated under acidic, basic, or photo-irradiated conditions. The analysis is monitored with a Cosmosil 5C18-AR column using a mobile phase of CH3CN-H2O-AcOH (50:49:1, v/v/v) at 260 nm. The developed method satisfies the system suitability criteria, peak integrity, and resolution among the parent drug and its degradation products. The results indicate that the established assay method shows good selectivity and specificity suitable for stability measurements of CPF. CPF is found to be more sensitive to exposure to light and in acidic conditions, but it is stable in a basic medium. The kinetic study of the photodegradation of CPF follows an apparent first-order reaction in a variety of solvents. The solvent effects on the rates of degradation are in the decreasing order of chloroform > dichloromethane > methanol > ethanol > 2-propanol, which is irrelevant to the dielectric constant epsilon. However, the hydrogen-donating ability of the solvents is essential to the photochemical decomposition of CPF. A plot of log k versus the Kirkwood function exhibits a linear relationship in aqueous ethanolic solutions, which implies that degradation proceeds via an ionic mechanism.     

Acrylate ester-based monolithic columns for capillary electrochromatography separation of triacylglycerols in vegetable oils

A simple and reliable method for the evaluation of triacylglycerols (TAGs) in vegetable oils by capillary electrochromatography (CEC) with UV-Vis detection, using octadecyl acrylate (ODA) ester-based monolithic columns, has been developed. The percentages of the porogenic solvents in the polymerization mixture, and the mobile phase composition, were optimized. The optimum monolith was obtained at the following ratios: 40:60% (wt/wt) monomers/porogens, 60:40% (wt/wt) ODA/1,3-butanediol diacrylate and 23:77% (wt/wt) 1,4-butanediol/1-propanol (14 wt% 1,4-butanediol in the polymerization mixture). A satisfactory resolution between TAGs was achieved in less than 12 min with a 65:35 (v/v) acetonitrile/2-propanol mixture containing 5 mM ammonium acetate. The method was applied to the analysis of TAGs of vegetable oil samples. Using linear discriminant analysis of the CEC TAG profiles, the vegetable oils belonging to six different botanical origins (corn, extra virgin olive, hazelnut, peanut, soybean and sunflower) were correctly classified with an excellent resolution among all the categories.     

Solubility,crystallization and oiling-out behavior of PEGDME: 1. Pure-solvent systems

Oiling out denotes a (metastable) liquid–liquid demixing during cooling crystallization prior to formation of the first crystals. This in most cases unwanted effect deteriorates the properties of the desired solid product. On the basis of the crystallization of the model substance polyethylenglycoldimethylether (PEGDME) from pure solvents, the influence of the molecular size of the solute and the type of solvent on the oiling-out behavior was systematically investigated. In this study the solubility data were determined gravimetrically as well as by using differential scanning calorimetry. The crystallization and oiling-out temperatures were detected visually in batch crystallization experiments. Oiling out was observed during the crystallization of PEGDME with a molar mass of 2000 g/mol (PEGDME2000) from diethylketone, ethyl acetate and 2-propanol, whereas no oiling out was detected during the cooling process of PEGDME with a molar mass of 1000 g/mol (PEGDME1000) from all solvents considered. Furthermore the oiling-out temperature for PEGDME2000 was not significantly influenced by the chosen solvents diethylketone, ethyl acetate and 2-propanol. In the second part of this study, it is shown that the appearance and absence of oiling out in all considered solvents can be qualitatively predicted by the pertubed chain statistical association theory (PC-SAFT) only using solubility data.