Organic solvents are widely used in the pharmaceutical industry for synthesizing active pharmaceutical ingredients, in formulations, and for cleaning equipment. Residual solvents may remain in final drug products and different analytical techniques like gas chromatography are used to test levels. Solvents are classified into four classes based on toxicity, with class 1 being human carcinogens and class 4 having insufficient toxicity data. Regulatory limits are set for each class to ensure solvent levels do not exceed acceptable toxicological thresholds.

1. SOLVENTS USED
PHARMACEUTICALLY

2. • Organic solvents are very widely used in
the pharmaceutical industry.
Used in the
1) synthesis of active pharmaceutical
ingredient.
2)In formulation
3)Cleaning the equipment..
O.Priyanka, M.Pharmacy,GPRCP,
7/28/2012 Department of Pharmaceutics 2

3. • Steps involved in chemical synthesis of
API
• 1)Reaction
• 2)Separation or extraction
• 3)Purification
• 4)Drying
• Organic solvents are used widely in
synthesis API
O.Priyanka, M.Pharmacy,GPRCP,
7/28/2012 Department of Pharmaceutics 3

4. • Used in formulation of either
1)liquid pharmaceuticals or
2)solid dosage forms
New solvents-SUPER CRITICAL FLUIDS or
IONIC LIQUIDS are developed.
And usually some small amount of solvents
may remain in the final product.They are
called as residual solvents(RS) or organic
volatile impurities.
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP, 4
Department of Pharmaceutics

5. • As residual solvents are not desirable
substances in a final product, different
methods for their removal may be used,
provided they fulfill safety criteria.
• After the drying process, analysis should
be done to check that amount of solvents
used at any step of the production do not
exceed acceptable limits. (taken from ICH
Guideline or from pharmacopoeias).
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP, 5
Department of Pharmaceutics

6. METHODOLOGIES FOR ANALYSIS OF RS
Gas chromatography (GC) is a very useful
technique for analysis of residual solvents.
• HS-GC, GC-MS, HS-GC-MS,SPME-GC,
SDME-GC are excellent tools to determine
OVI.
• When only class 3 impurities are present
loss of weight method is
used.TGA,DTA,DSC may also be used
Various other techniques like
• IR and NMR have been applied to
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP, 6
Department of Pharmaceutics
determine RS.

7. • Special directions published in
pharmacopeias and ICH guidelines
determine maximum allowable amounts of
RS in pharmaceutical products.
• If amounts of RS are below the limits the
analyzed product is cleared for sale.
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP,
Department of Pharmaceutics 7

8. WHY DO WE NEED CERTAIN REGULATIONS
TO LIMIT THE USE OF SOLVENTS.
• 1)Toxicity
• 2)Odor and taste(obviously not good drug
attributes for both manufacturers n
patients)
• Different associations who set limits for RS
• -USP
• -EU(pharma europa)
• -ICH(Q3 C)
7/28/2012
O.Priyanka, M.Pharmacy,GPRCP, 8
Department of Pharmaceutics

9. CLASSIFICATION OF
SOLVENTS
• According to Q3C guideline solvents are
divided into four groups
• CLASS 1 SOLVENTS: human
carcinogens
• Limits:as absolute parts per million in
material under testing.
• Ex:benzene,carbon
tetrachloride,1,1dichloro ethane,1,2
dichloroethane,1,1,1 trichloro ethane.
7/28/2012
O.Priyanka, M.Pharmacy,GPRCP, 9
Department of Pharmaceutics

10. • CLASS 2 SOLVENTS:solvents ought to be
limited.
• -agents of neurotoxicity r teratogenicity
• Ex:Acetonitrile,Chlorobenzene,Chloroform,
Cyclohexane,1,2Dichloroethene,Dichlorom
ethane,1,2Dimethoxyethane,N,NDimethylf
ormamide,1,4-Dioxane,2-Ethoxyethanol,
Ethyleneglycol,Formamide,Hexane,Metha
nol,2-Methoxyethanol,Methylbutyl
ketone,NMethylpyrrolidone,Nitromethane,
Pyridine,Sulfolane,Tetrahydrofuran,Tetrali
n,Toluene,1,1,2-Trichloroethene,Xylene* 10
7/28/2012
O.Priyanka, M.Pharmacy,GPRCP,
Department of Pharmaceutics

11. • Limits: listed in 2 ways
• 1) Option 1:uses the absolute
• parts per million of solvents contained in
the material being tested and is used in
cases where the daily dose is known or
fixed and is expressed by the formula:
• Concentration (ppm) = (1000 × PDE)/dose
(In grams per day)
• 2)Option 2: the sum of amounts of residual
• solvents present in each component of the
drug product per day, should be less than
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP, 11
given by PDE. Department of Pharmaceutics

12. Component Amount in Acetonitrile daily
formulation content exposure
Drug 0.3 g 800 ppm 0.24 mg
substance
Excipient 1 0.9 g 400 ppm 0.36 mg
Excipient 2 3.8 g 800 ppm 3.04 mg
Drug product 5.0 g 720 ppm 3.64 mg
Permitable daily exposure for acetonitrile is
4.1 mg per day
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP, 12
Department of Pharmaceutics

13. • Class 3 solvents: Solvents with low toxic
potential.
• Limits: they have permissions of daily
exposures of 50 mg (0.5%) or less
• Ex:Acetic acid,Heptane,Acetone Isobutyl
acetate,Anisole Isopropyl acetate,1-
Butanol Methyl acetate,2-Butanol 3-
Methyl-1-butanol,Butyl acetate Methylethyl
ketone,tert-Butylmethyl
ether,Methylisobutyl ketone,Cumene 2-
Methyl-1-propanol.
O.Priyanka, M.Pharmacy,GPRCP,
7/28/2012 Department of Pharmaceutics 13

14. • Class 4 solvents: solvents for which no
adequate toxicological data was found.
• Ex:1,1-Diethoxypropane,Methylisopropyl
ketone,1,1-
Dimethoxymethane,Methyltetrahydrofuran,
• 2,2-Dimethoxypropane,Petroleum ether,
Isooctane,Trichloroacetic acid,Isopropyl
ether Trifluoroacetic acid
O.Priyanka, M.Pharmacy,GPRCP,
7/28/2012 Department of Pharmaceutics 14

15. PDE LIMITS:
TABLE 1:CLASS 1 SOLVENTS
SOLVENT CONCENTRATION CONCERN
LIMIT(ppm)
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic and environmental
hazard
1,2 dichloroethane 5 Toxic
1,1 dichloroethene 8 Toxic
1,1,1trichloroethene 1500 Environmental hazard
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP,
Department of Pharmaceutics 15

16. TABLE 2:CLASS 2 SOLVENTS
SOLVENT PDE(mg/day) CONCENTRATION
LIMIT(ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cyclohexane 38.8 3880
1,2 dichloro ethene 18.7 1870
Dichloromethane 6.0 600
1,2 dimethoxy ethene 1.0 100
N,N dimethyl acetamide 10.9 1090
N,N dimethyl formamide 8.8 880
1,4 dioxane 3.8 380
2-ethoxy ethanol 1.6 160
Ethylene glycol 6.2 620
7/28/2012 16
Formamide 2.2 220O.Priyanka, M.Pharmacy,GPRCP,
Department of Pharmaceutics

17. SOLVENT PDE(mg/day) CONCENTRATION
LIMIT(ppm)
Hexane 2.9 290
Methanol 20.0 2000
2-methoxy ethanol 0.5 50
Methyl butyl ketone 0.5 50
Methyl cyclohexane 11.8 1180
N-methyl pyrrolidone 48.4 4840
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetralin 1.0 100
Toulene 8.9 890
1,1,2 trichloroethylene 0.8 80
Xylene 21.7 2170
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP, 17
Department of Pharmaceutics

18. References:
• U.S pharmacopeia<467>organic volatile
impurities
• American chemistry
council(www.american chemistry.com)
• Acta polonia pharmaceutica drug research
vol.67,no.1
• USP 25-NF 20(2002)
• Section 5.4,european pharmacopoeia 4th
edition.
7/28/2012 O.Priyanka, M.Pharmacy,GPRCP, 18
Department of Pharmaceutics

19. THANK YOU
BY
O.PRIYANKA