pharmaceutical
Applications
note
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#59577C
4
min. 2 3 4 5 6 7 8 9
1
2
3
5
1. methylene chloride 600ppm
2. chloroform
60ppm
3. benzene*
2ppm
4. trichloroethylene
80ppm
5. 1,4-dioxane
380ppm
GCAnalysis of OrganicVolatile ImpuritiesAccording toUSP <467>
SupplementTwo of USP 25-NF 20, effective January, 2002
Sample Preparation:
1:10 dilution of cat.# 36007 in distilledwater
(this deviation from the 1:50 dilution in themethodwas needed to obtain a
detectable benzene peak).
30m, 0.53mm ID, 5.0µmRtx
®
-G27with 5m phenylmethyl Integra-Guard
™
(cat.# 10279-126).
Oven temp.:
35°C (hold 5min.) to 175°C@ 8°C/min., to 260°C@
35°C/min. (hold 16min.);
Inj. port:
Uniliner
®
direct injection sleeve 70°C;
Inj. size:
1µL;
Det. temp.:
260°C;
FID sensitivity:
1 x 10
-12
AFS;
Carrier gas:
helium, 4.1psi constant pressure, 35cm/sec. set@ 35°C.
Aminormodification of the dilution concentration forMethod I allows analysis of 2ppm benzene, using anRtx
®
-G27 column.
A new test for the gas chromatographic (GC) analysis of Organic
Volatile Impurities (OVI) in pharmaceutical products was published
in the Third Supplement to the US Pharmacopoeia (USP) XXII-NF
XVII, which became effectiveNovember 15, 1990. Since its original
appearance in theUSP, this testing protocol has undergonemany re-
visions and additions.
1-6
The most recent change was published as
USP 25, effective January 1, 2002.
13
The biggest prior changewas to
the limit test concentrations, which nowmatch European Pharmaco-
poeia (EP) concentrations and ICH guidelines for the five USP
<467>-regulated solvents (Table I).
8, 9
The January 2002 revision
makes no significant changes.
USP has officially removed the limit test requirements for benzene
from any article specified to be tested by <467> for organic volatile
impurities, except where a specific limit for benzene is in the individ-
ual monograph.
10
The revision was needed because Methods I andV
were unable to detect benzene at 2ppm. Method IV, the onlymethod
that detects benzene at 2ppm, became official in Supplement Two of
USP 24-NF 19.
11
Figure 1
shows an analysis usingUSP<467>Method I on aG27 ana-
lytical columnwith aphenylmethyl guard column.Note that the sample
preparation used in this analysis deviates from the method-specified
1:50 dilution in distilled water. A 1:10 dilution in distilled water was
used to obtain a detectable amount of benzene by direct injection.
USP also has clarified that a 5m phenylmethyl guard column is not
needed for the Method IV headspace analysis.
10
Figure 2
shows an
analysis usingMethod IV at the revised concentrations, the method-
specified sample preparation procedure, aG43 analytical column, and
no guard column.
*Testing for benzene only requiredwhen specified in the individual monograph.
*Testing for benzene only requiredwhen specified in the individual monograph.
benzene*
2ppm
chloroform
60ppm
1,4-dioxane
380ppm
methylene chloride
600ppm
trichloroethene
80ppm
Limit Test Concentrations forUSP<467>
Figure 1
Table II
USP<467>Methods and corresponding
chromatographic systems
Table I
Method I
G27with 5m phenylmethyl guard column (5% phenyl/95%methyl polysiloxane)
30m, 0.53mm ID, 5.0µm, (Rtx
®
-G27 column, cat.# 10279-126)
Sample Introduction:
direct aqueous injection
Method IV
G43 (6% cyanopropylphenyl/94% dimethylpolysiloxane)
30m, 0.53mm ID, 3.0µm, (Rtx
®
-G43 column, cat.# 16085)
Sample Introduction:
static headspace
MethodV
G43with 5m phenylmethyl guard column
(6% cyanopropylphenyl/94%dimethylpolysiloxane)
30m, 0.53mm ID, 3.0µm (Rtx
®
-G43 column, cat.# 16085-126)
Sample Introduction:
direct aqueous injection
MethodVI
Choice of 9 columns, depending onmonograph
Sample Introduction:
direct aqueous injection
Method for CoatedTablets
0.2% polyethylene glycol,MW 1500 (G39) on graphitized carbon (S7)
(0.2%Carbowax
®
1500 on 80/100CarboBlack
™
C packed column, cat.# 80122)
Sample Introduction:
static headspace
