GC Head space Analysis, Residual Solvents by GC-HS, ICH Guidelines, ICH Q3C (R6), Pharmaceutical impurities, Impurities in pharmaceuticals, Drug substances, drug products, drug excipient, Residual solvent analysis. Solvents are critical inputs in synthetic processes. An appropriate solvent for synthesis of drug substance may enhance the yield or determine characteristics such as polymorph, purity, solubility and bio-availability. After the desired form of drug substance is achieved, solvents are no longer needed as they do not provide any therapeutic benefit. All residual solvents should, ideally be removed completely to meet product specifications, good manufacturing practices, and other quality-based requirements. However, manufacturing processes cannot remove the solvents completely from drug substances and products and some residue of them are left in pharmaceuticals. The precise amount of a solvent can be measured in direct injection method, based on its concentration and volume of the injection. However, in GC headspace this is not possible since saturated vapors of solvents, accumulated over headspace, are fed into GC system. Responses of respective solvents depend on their relative vapor pressure in diluent which in turn depends on the nature and volume of the diluent. Therefore, weight calculation of impurity or solvent in GC headspace analyses is not straightforward, the topic of this lecture. https://youtu.be/uViLLtaOlnk

1. Residual Solvent Analysis, Part-1
GC-Headspace Calculations of
Residual Solvents
in
Drug Substances & Products
ICH-Q3C(R6)
Arvind Mittal, Ph.D

2. GC-HS Calculations of Solvents
for Drug Substances & Products
 Calculations for direct injection methods are simple.
Sample concentration 1000 ppm (1000 µg/g),
then impurity concentration at 0.10% shall be 1 ppm.
 Calculations for GC-HS are more complex.
 Nominal concentration on ‘as is basis’ and then corrected to absolute
level OR ‘with respect to sample’ (µg/g or ICH level).
 Sample weight taken in head space vial.
 Volume of head space diluent taken in vial.
 Volume of volumetric flasks taken in serial dilution.
 Solvent (Impurity) weight
 Volume of solutions taken from stock solutions to make final nominal
concentration.

3. GC-HS Calculations of Solvents
for
Drug Substances & Products
 Conversion of ppm to Percentage:
Dichloromethane: 600 ppm
600
106
x 100 = 0.06% OR % Impurity x 104 = ppm (µg/gm)
 Standard weight calculation (MDC)
500 mg x 0.06/100 = 0.30 mg MDC
For 2 mL diluent
= 0.30/2 = 0.15 mg/mL MDC
 Example-1 : 500 mg Sample & 2 mL diluent in HS vial

4. 300 mg x 0.06/100 = 0.18 mg MDC
For 3 mL diluent = 0.18/3 = 0.06 mg/mL MDC
 Example-2 : 300 mg Sample & 3 mL diluent in HS vial
GC-HS Calculations of Solvents
for
Drug Substances & Products
 Are these two nominal concentrations same w.r.t. sample?
 Example-1 : 500 mg Sample & 2 mL diluent in HS vial +
0.15 mg/mL nominal concentration
Per gm conc. = 0.15 mg/mL x 2 mL/0.5 gm = 0.6 mg/g Or 600 µg/g = 600 ppm
 Example-2 : 300 mg Sample & 3 mL diluent in HS vial +
0.06 mg/mL nominal concentration
Per gm conc. = 0.06 mg/mL x 3 mL/0.3 gm = 0.6 mg/g Or 600 µg/g = 600 ppm

5. GC-HS Calculations of Solvents
for
Drug Substances & Products
 Example-1 : 500 mg Sample & 2 mL diluent in HS vial +
0.15 mg/mL nominal concentration
Scenario-1
Laboratory glassware
 25 mL volumetric flask: 2 Nos.
 10 mL volumetric flask: 1 No.
 1 mL & 5 mL graduated pipettes
 Stock solution: 0.15 mg/mL x 25 mL x (10mL/1 mL) x (25mL/2.5 mL) = 375 mg MDC
Stock soln
25 mL Int. Stock sol
10 mL
Standard soln
25 mL
1 mL 2.5 mL
375 mg
MDC
0.15 mg/mL
MDC

6. Scenario-2
Laboratory glassware
 25 mL volumetric flask: 1 No.
 50 mL volumetric flask: 1 No.
 10 mL volumetric flask: 1 No.
 1 mL & 5 mL graduated pipettes
 Stock solution: 0.15 mg/mL x 50 mL x (10mL/1 mL) x (25mL/2.5 mL) = 750 mg MDC
Stock soln
50 mL
Standard soln
25 mL
1 mL 2.5 mL
750 mg
MDC
0.15 mg/mL
MDC
GC-HS Calculations of Solvents
for
Drug Substances & Products
Int. Stock sol
10 mL

7. Scenario-3
Laboratory glassware
 25 mL volumetric flask: 2 Nos.
 10 mL volumetric flask: 1 No.
 1 mL & 2 mL Volumetric pipettes
 Stock solution: 0.15 mg/mL x 25 mL x (10mL/1 mL) x (25mL/2.0 mL) = 468.75 ≈
470 mg MDC
Stock soln
25 mL Int. Stock sol
10 mL
Standard soln
25 mL
1 mL 2.0 mL
468.75 mg
MDC
0.15 mg/mL
MDC
GC-HS Calculations of Solvents
for
Drug Substances & Products

8. GC-HS Calculations of Solvents
for
Drug Substances & Products
Scenario-1 375 mg MDC
Scenario-2 750 mg MDC
Scenario-3 468 mg MDC
0.15 mg/mL
500 mg
Sample + 2 mL
in GC-HS vial
What Next? Example 1; Scenario-1
Area of
Sample
Area of
Std
Wt. of
std (mg)
25 mL
1 mL
10 mL
2.5 mL
25 mL
2 mL
Wt. of sample
(mg)
x
x
x
x x
Purity of
solvent
100
x 106 = ppm
7456
13634
368.23
25
1
10
2.5
25
2
504.36
x
x
x
x x
99.8
100
x 106 = 318.77 ppm
Dilution
Factor