Pressure-Balanced Headspace For The Determination Of . - PerkinElmer

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a p p l i c at i o n N o t eGas ChromatographyAuthorPadmaja PrabhuPerkinElmer, Inc.Shelton, CT 06484 USAPressure-Balanced Headspacefor the Determination ofClass I, II and III ResidualSolvents in Pharmaceuticalsby USP Chapter 467 MethodologyIntroductionResidual solvents are used in the manufactureof active pharmaceutical ingredients (APIs),excipients, or in preparation of drug productsand are not removed during the purificationprocesses. Residual solvents are one of thethree main impurities in pharmaceutical materials;the other two are organic and inorganic impurities.Solvents have a number of uses in the pharmaceutical manufacturing process, may sometimesbe critical in the synthesis and can determine characteristics like crystalform, purity and solubility. Residual solvents do not provide any therapeuticbenefit and should be removed to the extent possible, fulfilling qualitybased requirements as per International Conference on Harmonization(ICH) guidelines – this is one of the standards to control the quality andthe purity of the pharmaceutical substances, excipients, or drug products.

Both the ICH and the United States Pharmacopoeia (USP)have guidelines for limiting the amounts of solvents usedin pharmaceuticals. The ICH lists three classes of solventsbased on their toxicity to humans and environmental health.Until 2008, the USP limited and tested for only chloroform,dioxane, methylene chloride and trichloroethylene. In harmonization with the ICH, the USP has changed the generalchapter 467 , which became effective July 1st, 2008. Thechapter now includes a comprehensive listing of the Class I, IIand III solvents and their control limits, with procedures foridentification, confirmation and quantification (ProcedureA, B and C, respectively). This chapter is applicable to allthe articles that use or produce residual solvents and to allthe manufacturers who produce official excipients, APIs anddrug products.USP chapter 467 suggests analysis of residual solventsusing a gas chromatograph (GC) equipped with a flame ionization detector (FID) and an automated headspace sampler(HS). The new chapter employs three testing procedureswhich are used to screen and identify (Procedure A), confirm(Procedure B) and quantitatively determine (Procedure C) theresidual solvents in the sample. When the user has informationabout the specific solvents utilized during the manufacturing ofthe article, only Procedure C needs to be performed. If thesolvents used are unknown, all three procedures are neededfor identification and quantitation. If only Class III solventsare used in the manufacture of an article, an alternativeloss-on-drying method is permitted, however, if Class IIand III solvents are also present, it is advisable to analyzeby chromatographic techniques.This paper will demonstrate the analysis of all three classesof residual solvents by pressure-balanced headspace sampleintroduction and GC-FID analysis. In addition to a discussionof the instrumental technique, the choice of the diluent willalso be studied; two diluents will be used throughout.ExperimentalA PerkinElmer Clarus 600 GC equipped with FID detectorand a PerkinElmer TurboMatrix HS-40 Headspace Sampleris the instrumental platform for this application. TheTurboMatrix HS is a pressure-balanced headspace sampler;the basis of sample collection in this system is a calculationof sample volume, allowing gas at a known flow rate toenter the analytical column for a specific time.2When compared to other headspace technology, thepressure-balanced sampling of the TurboMatrix HS providessuperior precision and inertness as a result of the simple,inert sample path. This technology does not require gassampling valves or other moving parts, reducing the samplecontact with hot metal loops and the maintenance associated with moving parts. The TurboMatrix HS-40 includes amulti-position vial oven with overlapped vial thermostattingcapability. Overlapped thermostatting automatically optimizesthe use of the multi-position oven – this allows the nextsample to inject as soon as the GC oven becomes ready,providing unparalleled sample throughput. Completeheadspace parameters are described in Table 1.Table 1. Detailed Headspace Analytical Conditions.Headspace Unit:PerkinElmer TurboMatrix HS-40Headspace Mode:ConstantNeedle Temperature:105 CTransfer Line Temperature: 110 COven Temperature:80 CThermostat Time:20 minVial Pressurization Time:2.0 minWithdraw Time:0.1 minInjection Time:0.12 minColumn Pressure:48 psigInjection Pressure:48 psigVial Pressure:48 psigVial Vent:OnTransfer Line:Fused Silica (0.53 mm)

Table 2. Detailed Gas Chromatographic Analytical Conditions.Gas ChromatographPerkinElmer Clarus 600 GC with FIDAnalytical Column (G43)PerkinElmer Elite-624 (30 m x 0.53 mm i.d. x 3.0 µm df)Analytical Column (G16)PerkinElmer Elite-Wax (30 m x 0.32 mm i.d. x 0.5 µm df)Injection Port TypeProgrammable Split/SplitlessInjector Temperature (or Program)200 CInjection TypeHS-ControlInjector Temperature140 CCarrier Gas TypeHeliumFlow Rate (G43)3.0 mL/minFlow Rate (G16)1.0 mL/minSplit Ratio1:5FID Temperature250 CClass I and IIIOven Temperature Program (G43)Oven Temperature Program (G16)Class IITemperatureHold TimeRateTemperatureHold TimeRate40 C20 min10 C/min40 C17 min40 C/min240 C10 minEnd240 C2 minEnd40 C20 min6 C/min50 C19 min40 C/min165 C1 min25 C/min220 C1 minEnd220 C2 minEndBuilding upon the throughput of the TurboMatrix HS, theClarus 600 GC features a best-in-class oven with high-speedcooling, resulting in a shorter period between the end ofone run and the beginning of the next. This becomes especiallyuseful in methods when the initial oven temperature is closeto ambient. Complete gas chromatographic conditions arepresented in Table 2.DiscussionIn this application note, a comprehensive list of solvents isanalyzed, with a method optimized for chromatographicresolution and run time. The analysis of each solvent isperformed on both the G16 and G43 phases to providecomplete resolution of all solvents included in chapter 467 . In addition to separation on multiple phases, twodiluents are used in each class of solvents. The diluentchoice is an important variable in method development. Thematerial and analyte solubility, boiling point, as well as thesolvents used in manufacture, need to be considered. Theresponse for each analyte changes with the diluent used,thus care should be exercised when selecting the diluent sothat sensitivity and resolution can be optimized. Some solvents,typically non-polar, show very good response with water as adiluent, while the others, typically polar, in organic diluents.3

1. 1,1,-Dichloroethene2. 1,1,1-Trichloroethane3. Carbon tetrachloride1. 1,1,-Dichloroethene2. 1,1,1-TrichloroethaneFigure 1. The analysis of Class I solvents in water using a G43 aneTrans ePyridineToluene2-HexanoneChlorobenzeneEthyl benzeneFigure 3. The analysis of Class II in 1,3-Dimethyl-2-Imidazolidinone using a G43 phase.1.2.3.4.5.6.n-HexaneCyclohexane eMethylene chloride1,1,2 trichlorthethene7.8.9.10.11.12.Toluene1,4 e 4. The analysis of Class II in solvents in water using a G16 phase.1.2.3.4.5.6.PentaneEthyl etherEthanolAcetoneEthyl formateI-propanol7.8.9.10.11.12.13.Methyl ethyl ketone2-Methyl 1-propanolEthyl acetatePropyl acetateMethyl isobutyl ketone3-Methyl 1-butanolIsobutyl acetateFigure 2. The analysis of Class I solvents in N,N-Dimethylacetamide using a G16 phase.Procedure A & B –Identification and Confirmationof Materials for SolventsProcedure A is used to identifythe residual solvents in a pharmaceutical sample. In this, allsolvents were initially analyzedusing the G43 column and associated GC conditions. Multiplediluents are used in Figures 1, 3and 5.The residual solvents were confirmed using Procedure B on aG16 column. The elution order isdifferent between the G43 andG16 phases, allowing confirmation of the analyte identificationby retention time on 2 orthogonalcolumn phases. In addition, severalco-eluting compounds onProcedure A are now resolved,while other compounds nowco-elute. Figures 2, 4 and 6demonstrate the results of theanalysis with a G16 phase.Procedure C – QuantificationFigure 5. The analysis of Class III solvents in N-Methyl-2-Pyrrolidone using a G43 phase.1.2.3.4.5.6.7.PentaneEthyl ethern-Heptanetert-butyl methylMethyl acetateEthyl acetateIsopropyl acetate8.9.10.11.12.13.14.Methyl ethylPropyl acetateMethyl isobutyl ketoneIsobutyl acetate2-Methyl 1-propanolI-ButanolCumeneFigure 6. The analysis of Class III solvents in water using a G16 phase.4After identification and confirmation of residual solventsin pharmaceutical materials byProcedures A and B, the analytesare quantified by the procedurewhich provides the optimal separation of solvents present in thesample. The exact analytical procedure chosen for quantificationis based on the optimal separation conditions for the analytesof interest.

ConclusionThe revised chapter 467 aligns the USP methodology for theanalysis of residual solvents with that set by the InternationalConference on Harmonization. In this paper, we have presenteda comprehensive analysis for the identification, confirmationand quantitation of Class I, II, and III solvents. The full suite ofanalytes is separated while maintaining an efficient analysis.The overlapping thermostatting of the TurboMatrix HS assuredthat the system was ready to inject as soon as the GC achievedits starting conditions. Furthermore, the fast-cooling capabilityof the Clarus 600 GC oven was used to reduce the injectionto-injection time of this application, increasing productivity.The full list of typically-analyzed solvents was presented withtwo different diluents, on both the G43 and G16 phases. Thechoice of diluent is based on both the solubility of the materialunder test and the boiling point of the least-volatile solventexpected. A combination of column selectivities provided theseparation for all of the solvents in Class I, II, and III.PerkinElmer, Inc.940 Winter StreetWaltham, MA 02451 USAP: (800) 762-4000 or( 1) 203-925-4602www.perkinelmer.comFor a complete listing of our global offices, visit www.perkinelmer.com/ContactUsCopyright 2009, PerkinElmer, Inc. All rights reserved. PerkinElmer is a registered trademark of PerkinElmer, Inc. All other trademarks are the property of their respective owners.008723 01

the articles that use or produce residual solvents and to all the manufacturers who produce official excipients, APIs and drug products. USP chapter 467 suggests analysis of residual solvents using a gas chromatograph (GC) equipped with a flame ion-ization detector (FID) and an automated headspace sampler (HS).

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