AnalyticalReferenceMaterials
The ICHguidelineclassifies residual solventsbyclass according to toxicity.Class
1 compounds are carcinogenic and pose a risk to both the consumer and the
environment. The use of these solvents must be avoided or tightly controlled.
Class 2 compounds are nongenotoxic animal carcinogens and their concentra-
tion shouldbe limited.BothClass 1 and2 compounds require chromatograph-
ic determination and are separated into 3 test mixes: Class 1Mixture, Class 2
MixtureA, andClass 2MixtureB.Class 3 compounds have low toxic potential.
Concentration levels of up to 0.5% are acceptable and, therefore, they can be
assayed by nonspecific techniques, such as weight loss on drying. Class 2
MixtureC is not used in the second supplement of USP30/NF25, but contains
solvents that are not readily detectable by headspace analysis. These solvents
shouldbe assayedbyother appropriately validatedprocedures.
ProcedureA - Identification
ProcedureA is the first step in the identificationprocess and is performedon a
G43 column to determine if any residual solvents are present in the sample at
detectable levels. First, Class 1 standard and system suitability solutions and
Class 2MixA standard solutions are assayedunder themethod-specifiedoper-
ating conditions to establish system suitability. All peaks in the Class 1 system
suitability solutionmust have a signal-to-noise rationot less than3, theClass 1
standard solution must have a 1,1,1-trichloroethane response greater than 5,
and the resolutionof acetonitrile anddichloromethanemust be not less than 1
in theClass2MixtureA solution.When system suitabilityhasbeenachieved, the
test solutions are assayed alongwith the Class 1 andClass 2Mixtures A andB
standard solutions. If a peak is determined in the sample thatmatches a reten-
tion time and has a greater response than that of a corresponding reference
material, then Procedure B is performed for verification of the analyte. In the
second supplement of USP 30/NF 25, an exemption is made for 1,1,1-
trichloroethane, where a response greater than 150 times the peak response
denotes an amount above the percent daily exposure limit. Figures 4 through 6
illustrate the analysis of Class 1,Class 2MixtureA, andClass 2MixtureB resid-
ual solvent mixes by Procedure A. The resolution between acetonitrile and
dichloromethanewas easily achievedusing anRtx®-1301 column.
Figure4
USP residual solventClass1 standard solutiononanRtx®-1301
column (G43).
Column:
Rtx
®
-1301, 30m, 0.32mm ID, 1.8µm (cat.# 16092)
Sample:
USP<467>Class 1 standard solution
(cat.# 36279) in 20mL headspace vial
Inj.:
headspace injection (split ratio 1:5), 1mm split
liner, Siltek
®
deactivated (cat.# 20972-214.1)
Inj. temp.:
140°C
Carrier gas: helium, constant flow
Flow rate:
2.16mL/min., 35.3cm/sec.
Oven temp.: 40°C for 20min. to 240°C@
10°C/min. (hold for 20min.)
Det.:
FID@ 240°C
Headspace Conditions
Instrument:
Tekmar HT3
Transfer line temp.:
105°C
Valve oven temp.:
105°C
Sample temp.:
80°C
Sample equil. time:
45min.
Vial pressure:
10psi
Pressurize time:
0.5min.
Loop fill pressure:
5psi
Loop fill time:
2.00min.
Inject time:
1.00min.
GC_PH00909
•
4
•
S/N
1. 1,1-dichloroethene
>3
2. 1,1,1-trichloroethane
>5
3. carbon tetrachloride
>3
4. benzene
>3
5. 1,2-dichloroethane
>3
USP-equivalent standards
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benzene
10mg/mL
carbon tetrachloride
20
1,2-dichloroethane
25
1,1-dichloroethene
40
1,1,1-trichloroethane
50
Quantity discounts not available.
ResidualSolvents -Class1
In dimethyl sulfoxide, 1mL/ampul
cat.# 36279 (ea.)
acetonitrile
2.05mg/mL
chlorobenzene
1.80
cyclohexane
19.40
cis
-1,2-dichloroethene 4.70
trans
-1,2-dichloroethene 4.70
1,4-dioxane
1.90
ethylbenzene
1.84
methanol
15.00
methylcyclohexane
5.90
methylene chloride
3.00
tetrahydrofuran
3.45
toluene
4.45
m
-xylene
6.51
o
-xylene
0.98
p
-xylene
1.52
ResidualSolventsClass2 -MixA
(15 components)
In dimethyl sulfoxide, 1mL/ampul
cat.# 36271 (ea.)
chloroform
60µg/mL
1,2-dimethoxyethane 100
n
-hexane (C6)
290
2-hexanone
50
nitromethane
50
pyridine
200
tetralin
100
trichloroethene
80
Quantity discounts not available.
ResidualSolventsClass2 -MixB
(8 components)
In dimethyl sulfoxide, 1mL/ampul
cat.# 36280 (ea.)
2-ethoxyethanol
800µg/mL
ethylene glycol
3,100
formamide
1,100
N,N-dimethylacetamide 5,450
N,N-dimethylformamide4,400
2-methoxyethanol (methyl
Cellosolve
®
)
250
N-methylpyrrolidone 2,650
sulfolane
800
ResidualSolventsClass2 -MixC
(8 components)
In dimethyl sulfoxide, 1mL/ampul
cat.# 36273 (ea.)
AchievingUSP<467>Compliance
(continued frompage3)
SYSTEMSUITABILITY
CRITERIAMET
