Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography

Using new solvent room temperature ionic liquid (IL) matrix media, testing of residual solvents in pharmaceutical preparations with static headspace gas chromatographic (SH-GC), is described. The purpose of this work was to demonstrate the feasibility of IL as diluent, six solvents utilized in synthesis of Adefovir Dipivoxil: acetonitrile, dichloromethane, N-methyl-2-pyrrolidone (NMP), toluene, dimethylformamide (DMF), n-butyl ether were dissolved in IL: 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF(4)). The method of external standard was used for quantitative analysis. Its performance was evaluated and validated: all the RSD were lower than 10%, the limits of detection were all of the ppm level and the method was both accurate and linear. And better sensitivities for the six solvents were gained with [bmim]BF(4) as diluent comparing with DMSO.     

Unknown residual solvents identification in drug products by headspace solid phase microextraction gas chromatography-mass spectrometry

Summary A sensitive headspace SPME method for the extraction of residual solvents from pharmaceutical products has been developed and optimized. It was found that minimizing sample and headspace volume has a beneficial effect on extraction efficiency. At the same time the method reproducibility was seriously affected by reducing sample and headspace volume. The added air volume was not found to have any significant influence on method sensitivity. The method showed reproducibilities of less than 10% and detection limits as low as 1 ppb for benzene and dichloromethane. The headspace SPME method is around 1000 times more sensitive than static headspace. The optimized parameters were headspace volume 1.5 mL, sample volume 10 μL, and extraction time 30 min. The method was successfully applied to the identification of unknown residual solvents in three different proprietary active drug substances and was successfully applied to the confirmation of the presence of benzene in a proprietary drug substance. Presented at Balaton Symposium '01 on High-Performance Separation Methods, Siófok, Hungary, September 2–4, 2001     

Spectrophotometric determination of ampicillin sodium in pharmaceutical products using sodium 1,2-naphthoquinone-4-sulfonic as the chromogentic reagent

Spectrophotometric determination of ampicillin sodium is described. The ampicillin sodium reacts with sodium 1,2-naphthoquinone-4-sulfonic in pH 9.00 buffer solution to form a salmon pink compound, and its maximum absorption wavelength is at 463 nm, epsilon463 = 1.14 x 10(4). The absorbance of ampicillin sodium from 2.0-80 microg ml(-1) obeys Beer's law. The linear regression equation of the calibration graph is C = 40.24A - 2.603, with a linear regression correlation coefficient is 0.9997, the detection limit is 1.5 microg ml(-1), recovery is from 97.23 to 104.5%. Effects of pH, surfactant, organic solvents, and foreign ions on the determination of ampicillin sodium have been examined. This method is rapid and simple, and can be used for the determination of ampicillin sodium in the injection solution of ampicillin sodium. The results obtained by this method agreed with those by the official method (HPLC).     

Determination of benzene, toluene, ethylbenzene and xylenes by headspace spectrophotometry with an atomic absorption apparatus.

In this study an atomic absorption spectrophotometer equipped with a selenium hollow-cathode lamp was used for analysis of BTEX (benzene, toluene, ethylbenzene and xylenes) in headspace of aqueous solutions. Initially effective factors on headspace such as volume of solution, stirring time, stirring speed, velocity of carrier gas, temperature, number of strippings, addition of salts and salt concentration were investigated and optimum conditions were selected. By addition of salt in different concentrations, different absorbances were obtained for headspace, therefore, binary mixtures of BTEX were analyzed with simultaneous equations. Obtained results agreed with actual amounts and repeatability was very good (RSD% < 3). Correlation coefficients (r) for calibration curves were about 0.999. This proposed method is comparable with absorbance determination of solution with respect to correlation coefficient, linear dynamic range, limit of detection (LOD) and relative standard deviation (RSD), but this method is less susceptible to interferences and more selective.     

Nondestructive Photoluminescence Read‐Out by Intramolecular Electron Transfer in a Perylene Bisimide‐Diarylethene Dyad

A novel, highly stable photochromic dyad 3 based on a perylene bisimide (PBI) fluorophore and a diarylethene (DAE) photochrome was synthesized and the optical and photophysical properties of this dyad were studied in detail by steady‐state and time‐resolved ultrafast spectroscopy. This photochromic dyad can be switched reversibly by UV‐light irradiation of its ring‐open form 3 o leading to the ring‐closed form 3 c , and back reaction of 3 c to 3 o by irradiation with visible light. Solvent‐dependent fluorescence studies revealed that the emission of ring‐closed form 3 c is drastically quenched in solvents of medium (e.g., chloroform) to high (e.g., acetone) polarities, while the emission of the ring‐open form 3 o is appreciably quenched only in highly polar solvents like DMF. The strong fluorescence quenching of 3 c is attributed to a photoinduced electron‐transfer (PET) process from the excited PBI unit to ring‐closed DAE moiety, as this process is thermodynamically highly favorable with a Gibbs free energy value of ?0.34 eV in dichloromethane. The electron‐transfer mechanism for the fluorescence quenching of ring‐closed 3 c is substantiated by ultrafast transient measurements in dichloromethane and acetone, revealing stabilization of charge‐separated states of 3 c in these solvents. Our results reported here show that the new photochromic dyad 3 has potential for nondestructive read‐out in write/read/erase fluorescent memory systems.     

Use of green alternative solvents in dispersive liquid-liquid microextraction: A review

Dispersive liquid-liquid microextraction is one of the most widely used microextraction techniques currently in the analytical chemistry field, mainly due to its simplicity and rapidity. The operational mode of this approach has been constantly changing since its introduction, adapting to new trends and applications. Most of these changes are related to the nature of the solvent employed for the microextraction. From the classical halogenated solvents (e.g., chloroform or dichloromethane), different alternatives have been proposed in order to obtain safer and non-pollutants microextraction applications. In this sense, low-density solvents, such as alkanols, switchable hydrophobicity solvents, and ionic liquids were the first and most popular replacements for halogenated solvents, which provided similar or better results than these classical dispersive liquid-liquid microextraction solvents. However, despite the good performances obtained with low-density solvents and ionic liquids, researchers have continued investigating in order to obtain even greener solvents for dispersive liquid-liquid microextraction. For that reason, in this review, the evolution over the last five years of the three types of solvents already mentioned and two of the most promising solvent alternatives (i.e., deep eutectic solvents and supramolecular solvents), have been studied in detail with the purpose of discussing which one provides the greenest alternative.     

Temperature-controlled headspace liquid-phase microextraction device using volatile solvents

A novel temperature-controlled headspace liquid-phase microextraction (TC-HS-LPME) device was established in which volatile solvents could be used as extractant. In this device, a PTFE vial cap with a cylindrical cavity was used as the holder of the extraction solvent. Up to 40 μl of extraction solvent could be suspended in the cavity over the headspace of aqueous sample in the vial. A cooling system based on thermoelectric cooler (TEC) was used to lower the temperature of extractant in PTFE vial cap to reduce the loss of volatile solvent during extraction process and increase the extraction efficiency. The selection of solvents for HS-LPME was then extended to volatile solvents, such as dichloromethane, ethyl acetate and acetone. The use of volatile extraction solvents instead of semi-volatile solvent reduced the interference of the large solvent peak to the analytes peaks, and enhanced the compatibility of HS-LPME with gas chromatograph (GC). Moreover, the use of larger volume of extractant solvent increases the extraction capacity and the injection volume of GC after extraction, thus improving detection limits. Several critical parameters of this technique were investigated by using chlorobenzenes (CBs) as the model analytes. High enrichment factors (498–915), low limits of detection (0.004–0.008 μg/L) and precision (3.93–5.27%) were obtained by using TC-HS-LPME/GC-FID. Relative recoveries for real samples were more than 83%.     

Determination of volatile residual solvents in pharmaceutical products by headspace liquid-phase microextraction gas chromatography-flame ionization detector

This paper demonstrates headspace liquid-phase microextraction (HS-LPME) as used for the determination of volatile residual solvents in pharmaceutical products. This method is based on headspace liquid-phase microextraction capillary column gas chromatography. Under optimum conditions, the linerary of the method ranged from 1 to 1,000 mg l⁻¹. The limits of detection are 0.2–2.0 mg l⁻¹ and relative standard deviations (RSD) for most of the volatile solvents were below 10%. This novel method is applied to the analysis of volatile residual solvents in pharmaceutical products with satisfactory results.     

Analysis of class 1 residual solvents in pharmaceuticals using headspace-programmed temperature vaporization-fast gas chromatography-mass spectrometry

A sensitive method is presented for the fast screening and determination of residual class 1 solvents (1,1-dichloroethene, 1,2-dichloroethane, 1,1,1-trichloroethane, carbon tetrachloride and benzene) in pharmaceutical products. The applicability of a headspace (HS) autosampler in combination with GC equipped with a programmed temperature vaporizer (PTV) and a MS detector is explored. Different injection techniques were compared. The benefits of using solvent vent injection instead of split or splitless-hot injection for the measurement of volatile compounds are shown: better peak shapes, better signal-to-noise ratios, and hence better detection limits. The proposed method is extremely sensitive. The limits of detection ranged from 4.9 ppt (benzene) to 7.9 ppt (1,2-dichloroethane) and precision (measured as the relative standard deviation) was equal to or lower than 12% in all cases. The method was applied to the determination of residual solvents in nine different pharmaceutical products. The analytical performance of the method shows that it is appropriate for the determination of residual class 1 solvents and has much lower detection limits than the concentration limits proposed by the International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use. The proposed method achieves a clear improvement in sensitivity with respect to conventional headspace methods due to the use of the PTV.     

Determination of the residual ethanol in hydroalcoholic sealed hard gelatin capsules by static headspace gas chromatography with immiscible binary solvents

Static headspace gas chromatography (HS-GC) with immiscible binary solvents is described to quantitatively determine the residual ethanol used to seal the hard gelatin capsules by liquid encapsulated and microspray sealing (LEMS; cfs 1200, Greenwood, SC, USA). The effects of decane, dodecane, heptane, 0.1 M HCl, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide on the method sensitivity are compared. It is observed that the ethanol headspace concentrations can be increased by fourfolds when aliphatic hydrocarbon solvents are added into the aqueous sample solutions in a HS vial. In addition, a mathematic model based on the concentration equilibriums of liquid–liquid and liquid–gas phases is derived to quantitatively describe the ethanol headspace concentrations versus the volumes of the aliphatic hydrocarbon solvents. The proposed model fits well to the experimental data. The impacts of the oven temperatures and vial equilibration times on the ethanol headspace concentrations are also investigated. Furthermore, the potential interferences of the capsule placebo and hard gelatin capsule shells on the selectivity and quantitation of the method are discussed. The linearity is validated from 5 μg/mL to 500 μg/mL. The limit of quantitation is 5 μg/mL. The accuracy is determined to be 100.8 ± 6%. Finally, this method is successfully used to determine the residual ethanol in the sealed capsules of 5 mg and 10 mg developmental Drug A, and 100 mg and 200 mg developmental Drug B.     

Multiple headspace single-drop microextraction coupled with gas chromatography for direct determination of residual solvents in solid drug product

This paper proposed a multiple headspace single-drop microextraction (MHS-SDME) method coupled to gas chromatography with flame-ionization detection (GC-FID) for direct determination of residual solvents in solid drug product. The MHS-SDME technique is based on extrapolation to an exhaustive extraction of consecutive extractions from the same sample which eliminates the matrix effect on the quantitative analysis of solid samples. The total peak area of analyte is calculated with a beta constant which can be obtained from the slope of the linear regression that related to the peak area of each extraction and the number of extraction times. In this work, a model drug powder was chosen and the amounts of residues of two solvents, methanol and ethanol, were investigated. The factors influencing the extraction process including extraction solvent, microdrop volume, extraction time, sample amount, thermostatting temperature and incubation time were studied. 10 mg of drug powder was incubated for 3 h at 140 °C prior to the first extraction and thermostatted for 15 min at 140 °C between each extraction. Extraction was carried out with 2 μL of dimethyl sulfoxide (DMSO) as the microdrop for 5 min. The features of the method were established using standard solutions. Validation of the proposed method showed good agreement with the traditional dissolution method for analysis of residual solvents in drug product. The results indicated that MHS-SDME has a great potential for the quantitative determination of residual solvents directly from the solid drug products due to its low cost, ease of operation, sensitivity, reliability and environmental protection.     

Simultaneous determination of carvedilol and ampicillin sodium by synchronous fluorimetry

The carvedilol and ampicillin sodium were simultaneously determined by the synchronous fluorimetry. With excitation wavelength at 254 nm, the maximum emission wavelengths of carvedilol and ampicillin sodium were at 357 and 426 nm, respectively. Because the emission spectra of carvedilol and ampicillin sodium were overlapped partially, carvedilol and ampicillin sodium cannot be determined directly by normal fluorimetric method. However, the synchronous fluorimetry can be used for determining both drugs simultaneously without separation procedure. The (Delta)(lambda) = 80 nm was used. Iso-propanol was selected as sensing reagent. Effects of pH, organic solvents and foreign ions on the determination of both drugs were studied. The linear relationship was obtained between the relative fluorescence intensity and concentration of carvedilol and ampicillin sodium in the range of 0.005-0.1 and 5.0-70.0 microg ml(-1), respectively. The linear regression equation of calibration graph for carvedilol is C = 0.000151F - 0.00210, and for ampicillin sodium is C = 0.0770F - 2.62. The correlation coefficient of linear regression equation is 0.9995 for carvedilol and 0.9998 for ampicillin sodium, respectively. The detection limit is 1 ng ml(-1) for carvedilol and 1 microg ml(-1) for ampicillin sodium. The relative standard deviations of carvidelol and ampicillin sodium are 2.47 and 1.61%, respectively. The recovery is from 96.0 to 103.0% for carcvedilol and from 98.0 to 105.0% for ampicillin sodium. This method was rapid, simple and highly sensitive for the determination of carvedilol and ampicillin sodium without pre-separation. The results obtained by this method agreed with those by the official methods. This method can be used for the determination of carvedilol and ampicillin sodium in the medicine dosage.     

Interaction of 2,3-dichloro-1,4-naphthoquinone with n-butylamine in halocarbon solvents

The rapid interaction between 2,3-dichloro-1,4-naphthoquinone (DClNQ) and n-butylamine results in the formation of 2N(n-butylamino)-3-chloro-1,4-naphthoquinone as the final product. The reaction is found to proceed through the initial formation of charge-transfer (CT) complex as an intermediate. The final product of the reaction has been isolated and characterized using FTIR, H1 and C13 NMR spectroscopy, mass spectrometry, and elemental analysis. The rate of formation of product has been measured as a function of time in different halocarbon solvents, viz., chloroform, dichloromethane and 1:1 (v/v) mixture of two solvents. The pseudo first order and second order rate constants at various temperatures for the transformation process were evaluated from the absorbance time data. The activation parameters (E(a), DeltaS#, DeltaH#, and DeltaG#) were obtained from temperature dependence of rate constants. The influence of dielectric constant on the properties of reaction was discussed and the probable course of reaction is presented.     

固相微萃取气相色谱法测定非那雄胺中残留的二氯甲烷和三氯甲烷

利用固相微萃取气相色谱法测定非那雄胺中的溶剂残留,对固相微萃取的萃取温度、萃取时间、解吸时间和溶液的离子强度等分析条件进行了优化.该方法具有较好的线性,相关系数:二氯甲烷为0.997,三氯甲烷为0.998;相对标准偏差:二氯甲烷为2.7%,三氯甲烷为1.8%.     

Hydrogen bond-free flavin redox properties: managing flavins in extreme aprotic solvents

We report a simple, single step reaction that transforms riboflavin, which is insoluble in benzene, to tetraphenylacetyl riboflavin (TPARF), which is soluble in this solvent to over 250 mM. Electrochemical analysis of TPARF both alone and in complexes with two benzene-soluble flavin receptors: dibenzylamidopyridine (DBAP) and monobenzylamidopyridine (MBAP), prove that this model system behaves similarly to other previously studied flavin model systems which were soluble only in more polar solvents such as dichloromethane. Binding titrations in both benzene and dichloromethane show that the association constants of TPARF with its ligands are over an order of magnitude higher in benzene than dichloromethane, a consequence of the fact that benzene does not compete for H-bonds, but dichloromethane does. The alteration induced in the visible spectrum of TPARF in benzene upon the addition of DBAP is very similar to the difference produced by transfer to dichloromethane, further indicating that the flavin head group engages in a similar degree of hydrogen bonding with dichloromethane as with its ligands. This work underlines the importance of using a truly nonpolar solvent for the analysis of the effects of hydrogen bonding on the energetics of any biomimetic host-guest model system.     

Capillary gas chromatographic-mass spectrometric study of the effect of solvents on metoprolol and other aryloxypropanolamines

When metoprolol in methanol was analysed by capillary gas chromatography (GC), an additional peak was observed; mass spectrometry (MS) showed this additional peak to have a molecular weight 12 dalton higher than that of the parent compound. A similar phenomenon was observed with other beta-adrenergic blocking aryloxypropanolamines in methanol or dichloromethane. Capillary GC-MS using deuterated solvents as isotopic markers showed that a methylene group from the solvents was incorporated into the parent molecule. The structure of the observed products and the mechanism of their formation are proposed.     

A generic static headspace gas chromatography method for determination of residual solvents in drug substance

In order to increase productivity of drug analysis in the pharmaceutical industry, an efficient and sensitive generic static headspace gas chromatography (HSGC) method was successfully developed and validated for the determination of 44 classes 2 and 3 solvents of International Conference of Harmonization (ICH) guideline Q3C, as residual solvents in drug substance. In order to increase the method sensitivity and efficiency in sample equilibration, dimethylsulfoxide (DMSO) was selected as the sample diluent based on its high capacity of dissolving drug substance, stability and high boiling point. The HS sample equilibration temperature and equilibration time are assessed in ranges of 125–150 °C and 8–15 min, respectively. The results indicate that the residual solvents in 200 mg of drug substance can be equilibrated efficiently in HS sampler at 140 °C for 10 min. The GC parameters, e.g. sample split ratio, carrier flow rate and oven temperature gradient are manipulated to enhance the method sensitivity and separation efficiency. The two-stage gradient GC run from 35 to 240 °C, using an Agilent DB-624 capillary column (30 m long, 0.32 mm I.D., 1.8 μm film thickness), is suitable to determine 44 ICH classes 2 and 3 solvents in 30 min. The method validation results indicate that the method is accurate, precise, linear and sensitive for solvents assessed. The recoveries of most of these solvents from four drug substances are greater than 80% within the method determination ranges. However, this method is not suitable for the 10 remaining ICH classes 2 and 3 solvents, because they are too polar (e.g. formic acid and acidic acid), or have boiling points higher than 150 °C, (e.g. anisol and cumene). In comparison with the previous published methods, this method has a much shorter sample equilibration time, a better separation for many solvents, a higher sensitivity and a broader concentration range.     

Rapid determination of tannins in tanning baths by adaptation of BSA method

A rapid and reproducible method for the determination of tannins in vegetable tanning baths is proposed as a modification of the BSA method for grain tannins existing in literature. The protein BSA was used instead of leather powder employed in the Filter Method, which is adopted in Italy and various others countries of Central Europe. In this rapid method the tannin contents is determined by means a spectrophotometric reading and not by means a gravimetric analysis of the Filter Method. The BSA method, which belongs to mixed methods (which use both precipitation and complexation of tannins), consists of selective precipitation of tannin from a solution containing also non tannins by BSA, the dissolution of precipitate and the quantification of free tannin amount by its complexation with Fe(III) in hydrochloric solutions. The absorbance values, read at 522 nm, have been expressed in terms of tannic acid concentration by using a calibration curve made with standard solutions of tannic acid; these have been correlated with the results obtained by using the Filter Method.     

Theoretical study on the structures and electronic spectra of TCNE2-.

Investigations into the charge-separated states and electron-transfer transitions in tetracyanoethylene (TCNE) complexes have recently generated much interest. In this work we present theoretical calculations showing that the most stable structure of the dianion TCNE2- has D2d symmetry in vacuum as well as in the solvents dichloromethane and acetonitrile. By means of the coupled cluster linear response, we compute the vertical electronic spectrum in both the gas phase and solution. The theoretical results are compared to the experimental data and good agreement is achieved.     

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.