Analysis Of Organic Residual Solvents In Pharmaceuticals With High Sensitivity Based On Static Headspace Gas Chromatography Technology

Residual solvents in pharmaceuticals are defined as organic volatile chemicals thatare used or produced in the manufacture of active substances or excipients, or in thepreparation of medicinal products. Generally, many of these volatile organic chemicalscan not be completely removed by standard manufacturing processes or techniques andare left behind, preferably at low levels. Residual solvent analysis of bulk drugsubstances and finished pharmaceutical products is necessary for a number of reasons.High levels of residual organic solvents represent a risk to human health because oftheir toxicity. RS analysis is described in all Pharmacopoeias, among which EuropeanPharmacopoeia has strictest rules, however, method from Ph. Eur. fails to detect lowevapor pressure and high boiling point RS. Sensitivity of RS determination is alsoreduced with pure organic solvents as media. So, the development of the new method todetect high boiling point RS has significant academic value and application prospective.A static headspace gas chromatography analysis method was used in the study toanalyze residual solvent in this study. However, the sensitivity of the analytical methoddescribed in the Ph. Eur. is not sufficient for those solvents with high boiling point, lowvapour pressures and non volatile like dimethylsulfoxide, N, N-Dimethylformamide, N,N-Dimethylacetamide and Benzyl alcohol. The research started from the shortcomingsof Eur. Ph. that fails to identify the high boiling point residual solvents. A new staticheadspace chromatography analysis method was developed based on sHS-GC analysis.The research also investigated the increase of sHS-GC analysis sensitivity fordetermination of residual solvents which are often used in pharmaceuticals. The mainconclusions and results are as following:①Based on principles of headspace gas chromatography, the concentration ofvolatile compounds in the gas phase can be expressed as Cg=Cs0/(K+β). In order toyield higher concentrations of volatile analytes in the gas phase and better sensitivity,influence of phase ratio on sensitivity was investigated. The difference between ourstudy and traditional phase ratio was that the amout of analytes in the vial was constant.The liquid volume in the vial was set to be1mL to12mL with interval of1mL. It wasclear that the highest sensitivity was obtained using only1.0mL of liquid phase in thevial. The response with1.0mL total volume is almost5times higher than the responsewith6.0mL total volume. The result shows that the lower liquid volume the higher concentration of analytes.②Concerning the partition of analyte in two phases and high boiling point ofdimethylsulfoxide of189°C, liquid paraffin was introduced as the new dilution solventto solve high boiling point residual solvents. With settings described in Ph. Eur., Water,N, N-dimethylformamide, N, N-dimethylacetamide, Benzyl alcohol,1-octnal and liquidparaffin were investigated as dilution. Only liquid paraffin as dilution successfullydetected solvent peak at the limit described in ICH. However, other dilutions were notable to detect the dimethylsulfoxide peak. Introduction of liquid paraffin provided a newway to determine the high boiling points residual solvents.③Keep liquid paraffin as dilution and1ml of liquid volume in the vial,parameters of static headspace combine gas chromatography analysis were optimized.The experimental parameters such as headspace vial equilibration temperature,headspace vial equilibration time, autosampler injection time, headspace vial pressurizetime were optimized to be160°C,10min,0.08min and1.0min respectively. GC oventemperature programs were optimized, maintaining the temperature at140°C for5min,then raising the temperature at a rate of6°C/min to165°C and maintaining it for10min. New developed method was used to analyze DMSO of250ppm in liquid paraffin,the peak area of DMSO is10times higher than initial parameters in Ph. Eur.. Analysistime was shortened to1/6of initial one; sensitivity and efficiency were improvedsignificantly.④A new developed method must be validated before use in pharmaceuticalanalysis to ensure that the obtained result is reliable. Results show that the linearity isgood with r of0.9996. The repeatability was checked by calculating the relativestandard deviation (RSD) values at each concentration point, RSD (n=4) of sixconcentrations are less than10%. Acurracy was determined by recovery ratio to bebetween95％and105％. The limits of detection (LOD) and quantitation (LOQ) of thestandard solutions were determined to be around1.0ppm and3.0ppm respectively.Linear range from25ppm to300ppm was obtained with a correlation coefficient of0.9996. New method gives higher sensitivity for the determination of DMSO comparingPh. Eur. The application of this new method was demonstrated successfully bydetermining residual DMSO in drug coating materials Kollicoat IR samples. Theamounts of DMSO in samples were determined to be4640ppm and4750ppm withexternal calibration and standard addition respectively.⑤The method was applied using another s HS-GC instrument to determine the DMF, DMA and BA as RS, the specificity and selectivity was good. The linearity wasgood with r higher than0.996, RSD (%) cvalues of RT and peak area precision andaccuracy were found to be0.5and4.0respectively which shows good precision.Recovery values were between95-105%presents good accuracy. LOD and LOQ ofDMF and DMA were determined to be0.3and1.0ppm, LOD and LOQ of BA was1.0and3.0ppm respectively.⑥Analysis of18residual solvents often used in pharmaceuticals wereinvestigated. Influences of organic media DMF, DMA and BA mixed with water asdilution media on analysis sensitivity were studied. Influences of liquid phase volumeand ionic strength of the dilution media on analysis sensitivity were also investigated. Itwas concluded that mixed media, high ionic strength and lower liquid volume increasedanalysis significantly. The determination of18residual solvents was evaluated on termsof linearity, range and precision. Conclusions could save drugs samples and organicsolvents, which is good for environment and saving analysis cost.This work focused on the determination of RS in pharmaceuticals, aimed toincrease the sHS-GC analysis sensitivity. sHS-GC analysis of high boiling point, lowvapour pressures and non volatile residual solvents and regular organic solvent oftenused in pharmaceuticals were investigated. Research conculsions have high theoreticalsignificance and application value on analysis of RS in pharmaceuticals.