Solvents In Drug Substances Research Articles

Development and validation of residual solvent determination by headspace gas chromatography in Imatinib Mesylate API

An accurate, precise, robust and sensitive method was developed for residual solvents determination by fast static headspace gas chromatography (HSGC) with flame ionization detector in Imatinib Mesylate API. Residual solvents in drug substances are quantified using gas chromatography with headspace. As per regulatory guidelines, residual solvents must be controlled for release any batches of active pharmaceutical ingredients (API). This paper includes the development and validation of HSGC method for the determination of residual solvents specifically methanol, acetone, dichloromethane, n-hexane, ethyl acetate and pyridine in Imatinib Mesylate API. Imatinib Mesylate is a specific inhibitor of BCR-ABL tyrosine kinase. DB-624 capillary column, 30 m long × 0.53 mm internal diameter, the 3 µm film thickness was used for analysis. To minimize degradation, injector temperature was set at 170 °C. The initial oven temperature was kept at 35 °C for 2 min and used ramp 1 at a rate of 4 °C min−1 to temperature of 80 °C hold for 0 min and used ramp 2 at a rate of 40 °C min−1 to a final temperature of 230 °C for 12 min hold time. Nitrogen was selected as a carrier gas. 1-Methyl-2-Pyrrolidinone (NMP) was used as a sample solvent. The method can be readily used to determine defined residual solvents present in a various range of APIs, intermediates, excipients and drug products.

A Validated RP-HPLC Method for the Simultaneous Determination of Six High-Boiling Residual Solvents in Drug Substances and Its Implementation in Apis

A new method using high-performance liquid chromatography coupled with ultra violet detection was developed and validated for the simultaneous quantification of six high-boiling residual solvents-Acetic acid, N,N-dimethylformamide, Dimethyl sulfoxide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and Benzyl alcohol in drug substances. This paper describes the development and validation of a simple and efficient RP-HPLC method for the determination of these high boiling residual solvents. Quantitation limits for Acetic Acid is 1000ppm (1000 μg/g of API), for Dimethylsulfoxide is 400 ppm (400 μg/g of API), for N, N dimethylformamide is 70 ppm (70 μg/g of API), for Dimethylacetamide is 80 ppm (80 μg/g of API), for N-methyl-2-pyrrolidone is 40 ppm (40 μg/g of API) and for Benzyl Alcohol is 60 ppm (60 μg/g of API) by this method. Several Active Pharmaceutical Ingredients were analyzed using the conditions of this method to evaluate and assess its versatility for the purpose of residual solvents analysis for a wide range of Active Pharmaceutical Ingredients. The results of this evaluation strongly indicate that this method can be readily used (as-is or with minor modifications) to determine high boiling residual solvents present in a wide range of Active Pharmaceutical Ingredients and other drug substances.

Use of ionic liquids as headspace gas chromatography diluents for the analysis of residual solvents in pharmaceuticals

In this study, two ionic liquids (ILs), 1-butyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([BMIM][NTf2]) and trihexyltetradecylphosphonium bis[(trifluoromethyl)sulfonyl]imide ([P66614][NTf2]) were examined as contemporary diluents for residual solvent analysis using static headspace gas chromatography (SHS-GC) coupled with flame ionization detection (FID). ILs are a class of non-molecular solvents featuring negligible vapor pressure and high thermal stabilities. Owing to these favorable properties, ILs have potential to enable superior sensitivity and reduced interference, compared to conventional organic diluents, at high headspace incubation temperatures. By employing the [BMIM][NTf2] IL as a diluent, a 25-fold improvement in limit of detection (LOD) was observed with respect to traditional HS-GC diluents, such as N-methylpyrrolidone (NMP). The established IL-based method demonstrated LODs ranging from 5.8 parts-per-million (ppm) to 20ppm of residual solvents in drug substances. The optimization of headspace extraction conditions was performed prior to method validation. An incubation temperature of 140°C and a 15min incubation time provided the best sensitivity for the analysis. Under optimized experimental conditions, the mass of residual solvents partitioned in the headspace was higher when using [BMIM][NTf2] than NMP as a diluent. The analytical performance was demonstrated by determining the repeatability, accuracy, and linearity of the method. Linear ranges of up to two orders of magnitude were obtained for class 3 solvents. Excellent analyte recoveries were obtained in the presence of three different active pharmaceutical ingredients. Owing to its robustness, high throughput, and superior sensitivity, the HS-GC IL-based method can be used as an alternative to existing residual solvent methods.

Development and Validation of Static HS-GC Method for the Determination and Quantification of Residual Solvents of Bromhexine Hydrochloride (BHX)

The determination of residual solvents in drug substances is the mandatory requirement by various health authorities in the world. There are no analytical methods available in the literature that can simultaneously separate and quantitate residual solvents in bromhexine hydrochloride (BHX) active pharmaceutical ingredient (API). This paper describes the development and validation of a simple, efficient, accurate, and robust static headspace gas chromatography method for the determination of residual solvents, namely methanol, ethanol, ethyl acetate, monochlorobenzene, and benzene, in BHXAPI. This new method has been demonstrated to be accurate, linear, precise, reproducible, specific, and robust for its intended purpose. The method gives very good sensitivities viz. detection limits for benzene is 0.4 ppm, ethyl acetate 2 ppm and for others solvents 5 ppm and precision (below 9.0 % RSD) for all solvents. The results of this evaluation strongly indicate that this method can be readily used to determine residual solvents in BHX.

ChemInform Abstract: Ionic Liquids: A New Strategy in Pharmaceutical Synthesis

AbstractReview: 33 refs.

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.

Static headspace gas chromatographic method for quantitative determination of residual solvents in pharmaceutical drug substances according to European Pharmacopoeia requirements

A static headspace (HS) gas chromatographic method for quantitative determination of residual solvents in a drug substance has been developed according to European Pharmacopoeia general procedure. A water–dimethylformamide mixture is proposed as sample solvent to obtain good sensitivity and recovery. The standard addition technique with internal standard quantitation was used for ethanol, tetrahydrofuran and toluene determination. Validation was performed within the requirements of ICH validation guidelines Q2A and Q2B. Selectivity was tested for 36 solvents, and system suitability requirements described in the European Pharmacopoeia were checked. Limits of detection and quantitation, precision, linearity, accuracy, intermediate precision and robustness were determined, and excellent results were obtained.

Validation of a generic analytical procedure for determination of residual solvents in drug substances

A generic analytical procedure for determination of residual solvents in drug substances is described and validated. The procedure is based on methods described in the European and United States parmacopeias, but is faster than the compendial procedures. It is applicable both during drug development and for quality control in commercial manufacture. The method is accurate, linear and shows a satisfactory level of precision. The solvents included in the validation comprise the five class 1 solvents, 17 out of 27 class 2 solvents, 17 out of 27 class 3 solvents and three unclassified solvents according to ICH guideline Q3C. The solvents can be detected and quantified at levels at or below the ppm limits given in the guideline. In most cases the quantification limit is in the lower ppm range. A strategy is proposed to choose between water or N, N-dimethyl formamide as a diluent. The need for re-validation of the method, mandatory for quantitative procedures according to the European Pharmacopeia, is minimised when using the generic procedure.

High-speed gas chromatographic analysis of solvents in pharmaceuticals using solid phase microextraction

A simple, inexpensive and rapid analytical approach for the determination of organic volatile impurities in pharmaceutical drug substances is developed, where sample preparation step was conducted using solid phase microextraction (SPME), followed by a fast GC separation. With an extraction time between 3 and 5 min and separation of 13 solvents in less than 3 min employing fast temperature programming using resistively heated column, organic volatile impurities can be analyzed within a total analysis time of 6–9 min. Various SPME phases were evaluated towards sensitivity and selectivity for the extraction of 13 commonly found solvents in drug substances dissolved in dimethyl sulfoxide and water. A 2-cm Carboxen/polydimethyl siloxane/divinylbenzene (Carboxen/PDMS/DVB) phase and a 65-μm DVB/PDMS phase showed better sensitivity towards these solvents when extracted from organic and aqueous matrix in comparison with the sensitivity obtained with direct injection approach. Extraction parameters such as extraction time, extraction stir rate, etc. are discussed. %RSD of peak area of replicate extraction was between 2 and 10% when 100 μm PDMS was used for extracting solvents from aqueous matrix. When DVB/PDMS fiber was evaluated for precision, %RSD of peak area from replicate extractions of solvents from organic matrix was between 2 and 8%. One-hundred micrometer PDMS showed excellent linearity from 10 to 500 μg/ml for analytes extracted from water solutions. On the other hand, DVB/PDMS phase showed better linearity than Carboxen/PDMS/DVB fiber when it was used to extract analytes in the concentration range of 10–5000 μg/ml from organic matrix.

Analysis of residual solvents by fast gas chromatography

Using a 10 m×0.1 mm I.D. DB-624 capillary column, fast separation of 40 commonly used solvents can be achieved in a single analysis in less than 4.9 min. For typical determination of trace solvents in drug substance, the analysis time can further be shortened to less than 1.5 min using combined temperature and pressure programming. The technique was illustrated for sample introduction by both direct injection and via headspace.

Determination of Residual Solvents in Drug Substances by Gas Chromatography with Thermal Desorption Cold Trap Injection.

A simple and reliable method has been developed for the determination of residual solvents in drug substances by gas chromatography with thermal desorption cold trap injection. Residual solvents in a sample were desorbed by heating at a temperature higher than the melting point of the sample, then trapped in a cold trap cooled at -130°C. After the cold trap was heated, solvents were injected into an analytical column. These operations were performed automatically by the control unit of the injector. This method is useful for the determination of residual solvents in drug substances because of its high sensitivity without the interference of drug substances. As an example of the application of the method, residual solvents in five drug substances were determined.