14
EuropeanPharmacopoeiaTests
The International Conference onHarmonization (ICH) has proposed a set of guide-
lines for residue solvent testing in pharmaceutical formulation and the European
Pharmacopoeia (EP) was the first to revise their regulations.
7,8
However, these
guidelines are challenging, containing over 60 compounds of regulatory interest to
manufacturers of active substances, excipients, andmedicinal products. The EP
methods also allow testing limits based on either a concentration limit in a product,
or calculated from themaximum daily dosage of the product and the permissible
daily exposure limit of the solvent. These technical challenges affect the sampling
method and capillary column needed to ensure precise and accurate results.
The recommended primary capillary column for EP residual solvent testing is the
Rtx
®
-1301. TheRtx
®
-1301 column shows excellent resolutionofmost EPClass 1 and
Class 2 compounds at the regulation limit concentration (
Figure 14
). Restek also
offers Stabilwax
®
columns, the recommended confirmational column for European
Pharmacopoeia residual solvent testing. Formore information on this analysis
request, request cat.# 59107.
min. 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
1 2 3
4
5
6
7
8
9,10
11
12
13,14
15
16
17
18
19
20
21
22,23
24,25
26
27
28
30m x .53mm ID x 3.0mmRtx
®
-1301w/5m phenyl methyl Integra-Guard
™
guard column
(cat.# 16085-126).
Oven temp.:
40°C (hold 20min.) to 240°C@ 10°C/min. (hold 20min.);
Inj./det. temp.:
200°C/250°C;
FID sensitivity:
1.1 x 10
-11
AFS;
Carrier gas:
H
2
@ 35cm/sec.;
Split ratio:
2:1.
Figure 14
The Rtx
®
-1301 column shows
excellent resolution of most
EuropeanPharmacopoeiaClass 1
and 2 compounds at the regulation
limit concentration.
Quantitation Techniques for European
Pharmacopoeia
(External Standard)
This technique uses a separate sample
(standard) that has the compounds of
interest at known concentrations in the
same matrix. This technique is advanta-
geous if various samples are being
analyzed, and all compounds of interest
can be assayed using a single set
external standards.
(Standard Addition)
The standard addition technique uses
known amounts of the compounds of
interest and adds it to the existing sample.
The original concentration of the
compounds of interest are then calculated
using linear regression.
1. methanol
2. 1,1-dichloroethene
3. acetonitrile
4. methylene chloride (dichloromethane)
5. hexane (C6)
6.
cis
-1,2-dichloroethene
7. nitromethane
8. chloroform
9. cyclohexane
10. 1,1,1-trichloroethane
11. carbon tetrachloride
12. benzene
13. 1,2-dimethoxyethane
14. 1,2-dichloroethane
15. trichloroethylene (1,1,2-trichlorethene)
16. methylcyclohexane
17. 1,4-dioxane
18. pyridine
19. toluene
20. 2-hexanone
21. chlorobenzene
22. DMF
23. ethylbenzene
24.
m
-xylene
25.
p
-xylene
26.
o
-xylene
27. N,N-dimethylacetamide
28. 1,2,3,4-tetrahydronaphthalene
Headspace injection of 28Class 1
andClass 2 residual solvents for
pharmaceutical processing. Prepared at
the regulatory limit concentration.
Samples shaken and heated at 80°C
for 15minutes, 1mL headspace injection.
Peak List for Figure 15
Guide
References
These references are not available fromRestek.
1. M.S. Bergren andD.W. Foust, “Comments onUSP
General Chapter, OrganicVolatile Impurities <467>, and
AssociatedMonograph Proposals,”
Pharmacopoeial
Forum
, May/June 1991,Vol. 17, No. 3, pp. 1963-1968.
2. J.A. Krasowski, H. Dinh, T.J. O’Hanlon, R.F. Lindauer,
“Comments onOrganicVolatile Impurities,Method I,
<467>,”
Pharmacopoeial Forum
, May/June 1991, Vol. 17,
No. 3, pp. 1969-1972.
3. Pharmacopoeial Forum,March/April 1991, Vol. 17, No. 2,
p. 1653.
4. Fifth Supplement, USP-NF, OrganicVolatile Impurities
<467>, Nov. 15, 1991, pp. 2706-2708.
5. “OrganicVolatile Impurities <467>,”
Pharmacopoeial
Forum
, May-June 1993,Vol. 19, No. 3, pp. 5335-5337.
6. Pharmacopoeial Forum, September/October 1992, Vol. 18,
No. 5, p. 4028.
7. USP 24/NF 19, <467>OrganicVolatile Impurities, (1877-
1878).
8. “ICHHarmonizedTripartiteGuideline, Impurities: Guideline
for Residual Solvents,”
The Fourth International Conference
onHarmonization
, July 17, 1997.
9. European Pharmacopoeia, Supplement 1999, pp. 14-15, 208.
10. Pharmacopoeial Forum, November - December 1999,Vol. 25,
Number 6, (9223 - 9224).
11. Sixth Supplement, USP-NF, OrganicVolatile Impurities
<467>, May 15, 1997, pp. 3766-3768.
