IDENTIFICATION聽ANDCONTROLOFRESIDUALSOLVENTS
The聽test聽procedures聽described聽in聽this聽general聽method聽may
be聽used:
i.聽for聽the聽identification聽of聽the聽majority聽of聽Class聽1聽and聽Class
2residualsolventsinanactive聽substance,聽excipient聽or
medicinal聽product聽when聽the聽residual聽solvents聽are聽unknown;
ii.聽as聽a聽limit聽test聽for聽Class聽1聽and聽Class聽2聽solvents聽when聽present
in聽an聽active聽substance,聽excipient聽or聽medicinal聽product聽;
iii.聽for聽the聽quantification聽of聽Class聽2聽solvents聽when聽the
limits聽are聽greater聽than聽1000聽ppm聽(0.1聽per聽cent)聽or聽for聽the
quantification聽of聽Class聽3聽solvents聽when聽required.
Class聽1,聽Class聽2聽and聽Class聽3聽residual聽solvents聽are聽listed聽in
general聽chapter聽5.4.聽Residual聽solvents.
Three聽diluents聽are聽described聽for聽sample聽preparation聽and
the聽conditions聽to聽be聽applied聽for聽head-space聽injection聽of
the聽gaseous聽sample聽onto聽the聽chromatographic聽system.
Two聽chromatographic聽systems聽are聽prescribed聽but聽System
A聽is聽preferred聽whilst聽System聽B聽is聽employed聽normally聽for
confirmation聽of聽identity.聽The聽choice聽of聽sample聽preparation
procedure聽depends聽on聽the聽solubility聽of聽the聽substance聽to聽be
examined聽and聽in聽certain聽cases聽the聽residual聽solvents聽to聽be
controlled.
The聽following聽residual聽solvents聽are聽not聽readily聽detected聽by
the聽head-space聽injection聽conditions聽described:聽formamide,
2-ethoxyethanol,聽2-methoxyethanol,聽ethylene聽glycol,
N-methylpyrrolidone聽and聽sulfolane.聽Other聽appropriate
procedures聽should聽be聽employed聽for聽the聽control聽of聽these
residual聽solvents.
When聽the聽test聽procedure聽is聽applied聽quantitatively聽to聽control
residual聽solvents聽in聽a聽substance,聽then聽it聽must聽be聽validated.
PROCEDURE
Examine聽by聽gas聽chromatography聽with聽static聽head-space
injection聽(2.2.28).
Sample聽preparation聽1.聽This聽is聽intended聽for聽the聽control聽of
residual聽solvents聽in聽water-soluble聽substances.
Sample聽solution聽(1).Dissolve0.200gofthesubstancetobe
examined聽in聽water聽R聽and聽dilute聽to聽20.0聽ml聽with聽the聽same
solvent.
Sample聽preparation聽2.聽This聽is聽intended聽for聽the聽control聽of
residual聽solvents聽in聽water-insoluble聽substances.
Sample聽solution聽(2).Dissolve0.200gofthesubstancetobe
examined聽in聽N,N-dimethylformamide聽R聽(DMF)聽and聽dilute聽to
20.0聽ml聽with聽the聽same聽solvent.
Sample聽preparation聽3.聽This聽is聽intended聽for聽the聽control聽of
N,N-dimethylacetamide聽and/or聽N,N-dimethylformamide,
when聽it聽is聽known聽or聽suspected聽that聽one聽or聽both聽of聽these
substances聽are聽present聽in聽the聽substance聽to聽be聽examined.
Sample聽solution聽(3).Dissolve0.200gofthesubstancetobe
examined聽in聽1,3-dimethyl-2-imidazolidinone聽R聽(DMI)聽and
dilute聽to聽20.0聽ml聽with聽the聽same聽solvent.
Insomecasesnoneoftheabovesamplepreparation
procedures聽are聽appropriate,聽in聽which聽case聽the聽diluent聽to聽be
used聽for聽the聽preparation聽of聽the聽sample聽solution聽and聽the聽static
head-space聽conditions聽to聽be聽employed聽must聽be聽demonstrated
to聽be聽suitable.
Solvent聽solution聽(a).To1.0mlof聽Class聽1聽residual聽solvent
solution聽CRS,add9mlof聽dimethyl聽sulphoxide聽R聽and聽dilute
to聽100.0聽ml聽with聽water聽R.聽Dilute聽1.0聽ml聽of聽this聽solution聽to
100聽ml聽with聽water聽R.聽Dilute聽1.0聽ml聽of聽this聽solution聽to聽10.0聽ml
with聽water聽R.
The聽reference聽solutions聽correspond聽to聽the聽following聽limits聽:
—benzene:2ppm,
—聽carbon聽tetrachloride:聽4聽ppm,
—聽1,2-dichloroethane:聽5聽ppm,
—聽1,1-dichloroethene:聽8聽ppm,
—聽1,1,1-trichloroethane:聽10聽ppm.
olvent聽solution聽(b).聽Dissolve聽appropriate聽quantities聽of聽the
Class聽2聽residual聽solvents聽in聽dimethyl聽sulphoxide聽R聽and聽dilute
to聽100.0聽ml聽with聽water聽R.聽Dilute聽to聽give聽a聽concentration
of聽1/20聽of聽the聽limits聽stated聽in聽Table聽2聽(see聽5.4.聽Residual
solvents).
Solvent聽solution聽(c).聽Dissolve聽1.00聽g聽of聽the聽solvent聽or
solvents聽present聽in聽the聽substance聽to聽be聽examined聽in聽dimethyl
sulphoxide聽R聽or聽water聽R,聽if聽appropriate,聽and聽dilute聽to
100.0聽ml聽with聽water聽R.聽Dilute聽to聽give聽a聽concentration聽of
1/20聽of聽the聽limit(s)聽stated聽in聽Table聽1聽or聽2聽(see聽5.4.聽Residual
solvents).
Blank聽solution.聽Prepare聽as聽described聽for聽solvent聽solution聽(c)
but聽without聽the聽addition聽of聽solvent(s)聽(used聽to聽verify聽the
absence聽of聽interfering聽peaks).
Test聽solution.聽Introduce聽5.0聽ml聽of聽the聽sample聽solution聽and
1.0mloftheblanksolutionintoaninjectionvial.
Reference聽solution聽(a)聽(Class聽1).聽Introduce聽1.0聽ml聽of聽solvent
solution聽(a)聽and聽5.0聽ml聽of聽the聽appropriate聽diluent聽into聽an
injection聽vial.
Reference聽solution聽(a1)(Class1).Introduce5.0mlofthe
sample聽solution聽and聽1.0聽ml聽of聽solvent聽solution聽(a)聽into聽an
injection聽vial.
Reference聽solution聽(b)聽(Class聽2).聽Introduce聽1.0聽ml聽of聽solvent
solution聽(b)聽and聽5.0聽ml聽of聽the聽appropriate聽diluent聽into聽an
injection聽vial.
Reference聽solution聽(c).Introduce5.0mlofthesample
solution聽and聽1.0聽ml聽of聽solvent聽solution聽(c)聽into聽an聽injection
vial.
Reference聽solution聽(d).聽Introduce聽1.0聽ml聽of聽the聽blank
solution聽and聽5.0聽ml聽of聽the聽appropriate聽diluent聽into聽an
injection聽vial.
Close聽the聽vials聽with聽a聽tight聽rubber聽membrane聽stopper
coated聽with聽polytetrafluoroethylene聽and聽secure聽with聽an
aluminium聽crimped聽cap.聽Shake聽to聽obtain聽a聽homogeneous
solution
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