Solvent residues direct injection

Gas chromatography is commonly used to analyse mixtures for quantification. A wide variety of special detectors with adequate linear response ranges are available for quantification of various classes of compounds (cf. Table 4.14). Quantification by direct injection may be used to determine additives, residual monomers and solvents in product formulations, coated films, and solid materials [109]. On the other hand, reliable quantification by means of solid-injection PTV-GC, HS-GC and PyGC techniques is not always trivial. 

Liquid samples, other than those that are inherently liquid, can arise from the solid sample extraction techniques described above. As mentioned previously, sometimes a simple dilute-and-shoot approach can be utilized, i.e., add solvent to the sample and then inject directly into the instrument. Other times, evaporation of residual liquid can be utilized—then the sample is either directly injected, or if the sample is evaporated to dryness, a new solvent can be added. Often, however, the residual matrix causes interference and the following techniques can be employed for further sample cleanup. 

The current BP methods for determination of solvent residues in pharmaceuticals remaining from the manufacturing process rely on direct injection of the sample dissolved in a suitable solvent (often water) and are based on packed column GC. Some examples are given in Table 11.4. 

The most useful method for solvent residue analysis is GC. It can be performed by direct injection technique, or by headspace, solid phase microextraction (SPME), or single-drop microextraction (SOME) techniques [96]. GC has high selectivity, good specificity, is easy to perform, and involves simple sample preparation. Modem capillary GC allows separation of many compounds, together with their identification and quantification [96]. GC uses different detector systems, which are presented in Table 8.7. 

There are four types of sample preparation methods for residual solvents head-space sampling, extraction, direct injection, and solid-phase microextraction. 

The preferred sample preparation method for residual solvent analysis of pharmaceuticals is direct injection of the dissolved sample (11,60). With this technique, the recovery is most reliable because there is no opportunity for recovery loss due to adsorption or entrapment. The other techniques involve a separation of the volatiles before the GC injection and there is a risk that the volatile will be trapped. Typical solvents for this analysis are water, dimethyl sulfoxide, benzyl alcohol, and dimethylformamide (11,12,61). The three latter solvents are chosen because they are higher-boiling than commonly used pharmaceutical solvents and thus elute after them and do not interfere with the analysis. Water offers the advantage that it contributes little interference with a flame ionization detector. 

Liquid samples can be directly injected onto the system, while tissue samples require a crude extraction and sedimentation prior to analysis. TFC is also effective at separating residues that are bound to sample proteins. The use of TFC eliminates time-consuming sample cleanup in the laboratory and results in a much shorter analysis time, higher productivity, and reduced solvent consumption without sacrificing sensitivity or reproducibility. 

Residual solvents are typically analyzed using a gas chromatograph (GC) outfitted with a flame ionization detector (FID). The sample is introduced either by direct injection or by headspace injection. Headspace injection has grown in popularity in recent years, since it eliminates many of the interferences originating from nonvolatile components of the API/excipient. The typical GC column used for residual solvents is a capillary column with a 6% cyanophenyl, 94% dimethylpolysiloxane-phase film, which is referred to as a G43 column by USP, with a unique suffix given by column manufacturers. Certain methods will also use the G16 or Carbowax 20M columns depending on what solvents are being analyzed. 

Often interference effects from either solvents [74] or other components in sample matrices can cause significant problems especially with direct injection of such solutions. Headspace analysis has been shown to be of great value for residual solvent analysis in drug substance [75] and dmg product [76] because the drag itself is not introduced into the system. Similarly, residual solvent analysis in pharmaceuticals using thermal desorption [77] and solid phase microexttaction (SPME) [78] has been shown to be of benefit. For more con ilex matrices such as... 

Evaporate the reaction mixture to dryness and dissolve the residue in a suitable solvent for chromatography. Alternatively, add hydrochloric acid (1M), agitate, separate the organic layer, and wash it with sodium hydroxide (1 M, 1 ml). Analyse the organic phase by direct injection GC or dilute with methanol (I ml) prior to analysis by HPLC. 

Kawamura et al. [81] have surveyed nonylphenol by GC-MS (with quantification by GC-SIM-MS) in 207 samples of food contact plastics and baby toys. Crompton [43] has described the quantitative GC analysis of residual vinylchloride, butadiene, acrylonitrile, styrene and 2-ethyIhexylacrylate in polymers by solution headspace analysis. Considerably greater sensitivities and shorter analysis times were obtained using the headspace analysis methods than were possible by direct injection of polymer solutions into a GC. Similarly, various residual hydrocarbons (10 ppm of isobutane, n- and isopentane, iso- and neohexane) in expanded PS were determined by GC analysis of a solution of the sample with hydrocarbon internal standards accuracies of 5 to 10% were reported [82]. Residual n- and isopentane (0.001%) in expandable and expanded PS were also determined by a solvent-free procedure consisting of heating the polymer at 240°C in a sealed tube, followed by HS-GC calibration against known blends of n- and isopentane and n-undecane internal standard [82]. 

Split injection is used for volatile to semi-volatile compounds, and is one of the easiest injection techniques. With this technique, the flow of carrier gas is split between the capillary column and the atmosphere. This split does not occur in case of splitless injection. Splitless injection is used in case residual solvents remain in the sample at low eon-centrations, due to increased sensitivity compared to split injection. Other possibilities of direct injection are on-column injection and Programmed Temperature Vaporisation (PTV) injection. Both techniques allow detection limits to achieve put levels but are large volxune injection techniques. In on-column injection systems, the sample is injected on a pre-colmnn and then the solvent is vented, leaving only the analytes to be injected on the coltunn. In PTV, after the sample injection, the solvent is evaporated at a low temperature in a packed chamber and then removed. This leaves the solutes on the packing. When the injection port is heated the analytes are transferred to the analytical column. ... 

The flow of droplets is directed through a small orifice (Skimmer 1 Figure 12.1) and across a small region that is kept under vacuum by rotary pumps. In this region, approximately 90% of solvent and injected helium is removed from the incipient particle beam. Because the rate of diffusion of a substance is inversely proportional to its molecular mass, the lighter helium and solvent molecules diffuse away from the beam and are pumped away. The heavier solute molecules diffuse more slowly and pass through the first skimmer before they have time to leave the beam the solute is accompanied by residual solvent and helium. 

Hollander and co-workers [303—305] dealt with the problem in detail and developed a method for the isolation of hormones from blood, using Bio-Rad AG 50W-X2 (100—120 mesh) ion-exchange resin. Acylation with pivalic anhydride—methanol—triethylamine (20 1 1) was performed at 70°C for 10 min. The derivatives were purified with the aid of Amberlite IR-45 resin and benzene as a solvent. The dry residue was dissolved in 100 jul of benzene and 5 /il were injected directly on to a 60 cm X 4 mm I.D. column packed with 5% OV-1 on Chromosorb W HP after an isothermal period at 220°C for 12 min, the temperature was increased at 3°C/min up to 300°C. Calibration standards were injected immediately after the sample. Almost identical results were obtained for T3 by GC and radioimmunoassay [304], Other workers [306] applied the same procedure to the seeds and analysed pivalyl methyl esters of T3 and T4 on an 81 cm column packed with 3% of Dexsil on Chromosorb W HP at 305°C. 

Three standard solutions were prepared—one containing 1 mg. of DDT and 1 mg. of DDD per 10 ml. of solvent the second containing 1 mg. of diazinon per 10 ml. of solvent and the other containing 1 mg. of ethion per 10 ml. of solvent (benzene). The retention time (time required after injection of the sample for the component to reach its maximum peak height) was used as a qualitative measure to identify the component. Quantitative information was obtained from the direct relationship of the concentration of insecticide to the maximum peak height. Standards were analyzed periodically during the analysis of the residues. 

Solid-phase microextraction (SPME) is a technique that was first reported by Louch et al. in 1991 (35). This is a sample preparation technique that has been applied to trace analysis methods such as the analysis of flavor components, residual solvents, pesticides, leaching packaging components, or any other volatile organic compounds. It is limited to gas chromatography methods because the sample must be desorbed by thermal means. A fused silica fiber that was previously coated with a liquid polymer film is exposed to an aqueous sample. After adsorption of the analyte onto the coated fiber is allowed to come to equilibrium, the fiber is withdrawn from the sample and placed directly into the heated injection port of a gas chromatograph. The heat causes desorption of the analyte and other components from the fiber and the mixture is quantitatively or qualitatively analyzed by GC. This preparation technique allows for selective and solventless GC injections. Selectivity and time to equilibration can be altered by changing the characteristics of the film coat. 

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