ADV06-15_1-412

Figure 2

USP Residual Solvent Class 2 Mixture A standard solution

on an Rtx®-624 (G43) column.

Organic volatile impurities (OVIs), commonly

referred to as residual solvents, are trace level

chemical residues in drug substances and drug

products that are byproducts of manufacturing, or

that form during packaging and storage. The United

States Pharmacopeia recently revised the general

chapter on residual solvent analysis, USP 467, to

mirror the International Conference on Harmon-

ization (ICH) guidelines. This revision, effective

July 1, 2007, replaces previous methods that were

not consistent with the ICH guidelines.

The revised procedure consists of a static headspace

extraction coupled with a gas chromatographic

separation and flame ionization detection (GC/FID),

and is divided into two sections based on sample

solubility – water soluble and water insoluble arti-

cles. Altogether, the test method consists of three

separate procedures – A, B and C–that are designed

to identify, confirm and quantify residual solvents

in pharmaceuticals.

Procedure A is the first step in the identification

process and is performed to screen samples for

residual solvents. A series of residual solvent

mixes, consisting of Class 1 and Class 2 mixes A and

B, are analyzed along with the system suitability

and test solutions on an Rtx®-624 column – equiv-

alent to an Rtx®-1301 (G43) column (Figures 1-3).

If a peak in the sample matches a retention time,

and exceeds the response of the corresponding

standard, the analyst proceeds to Procedure B for

verification of the analyte.

Once a residual solvent is identified, Procedure B is

performed to confirm analyte identity. We recom-

mend a Stabilwax® (G16) capillary column as a

confirmation column because it yields an alternate

selectivity compared to an Rtx®-624 column or an

Rtx®-1301 (G43) column. (See our OVI retention

time index at

www.restek.com/ovi

). The same ref-

erence mixes are analyzed with an acetonitrile/

trichloroethylene system suitability solution. If a

residual solvent is verified, Procedure C is used to

quantify the analyte by comparison to a specific,

individual standard for the analyte identified. For

water-insoluble articles, the procedure is the same,

except dimethylformamide and 1,3-dimethyl-2-

imidazolidinone are used as the diluent and Class

2 Mix C (higher boiling point solvents mix) is ana-

lyzed as a reference solution.

Figure 1

USP Residual Solvent Class 1 standard solution on an

Rtx®-624 (G43) column.

•

2007 vol. 2

Pharmaceutical

Revised USP 467 Residual Solvent Method

Satisfy New Method Requirements with Restek Columns and Standards

By Rick Lake, Pharmaceutical Innovations Chemist

• Overview of the new USP 30/NF 25 procedure.

• New reference standards - stock mixes, custom preparations.

• Optimize your testing within the constraints of the method.

Column:

Rtx

-624 30m, 0.32 ID, 1.8μm (cat. # 10970)

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:

2.16 mL/min., 35.3 cm/sec.

Oven temp.:

40°C for 20 min., to 240°C @

10°C/min., hold for 20 min.

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:

45 min.

Vial Pressure:

10psi

Pressurize Time:

0.5 min.

Loop Fill Pressure:

5psi

Loop Fill Time:

2.00 min.

Inject Time:

1.00 min.

1. 1,1-dichloroethene

2. 1,1,1-trichloroethane

3. carbon tetrachloride

4. benzene

5. 1,2-dichloroethane

GC_PH00909

Time (min)

14.8 15.0 15.2 15.4 15.6 15.8 16.0

Time (min)

4.0

4.2

4.4

4.6

Time (min)

1. methanol

2. acetonitrile

3. dichloromethane

trans

-1,2-dichloroethene

cis

-1,2-dichloroethene

6. tetrahydrofuran

7. cyclohexane

8. methylcyclohexane

9. 1,4-dioxane

10. toluene

11. chlorobenzene

12. ethyl benzene

13.

-xylene /

-xylene

14.

-xylene

GC_PH00910

GC_PH00910A

GC_PH00910B

1112

1,4-dioxane

dichloromethane

For conditions see Figure 1

Sample: USP 467 Class 2 Mixture A Standard Solution (cat.# 36271) in 20mL headspace vial

Sample:

USP 467 Class 1

Standard Solution

(cat.# 36279) in 20mL

headspace vial

resolution = 1.35

acetonitrile