INPURITIES IN RESIDUAL SOLVENT

1. Topic :Impurities in residual
solvents
Presented by,
R.Venkatesan.
M.Pharm 1st semester
Dept. pharmaceutical analysis
Karnataka college of pharmacy
Bangalore
02-May-2023
Presented to,
Dr.C.Sreedhar,
Professor and HOD
Dept. pharmaceutical analysis
Karnataka college of pharmacy
Bangalore
ADVANCED PHARMACEUTICAL ANALYSIS

2. CONTENT
1. Introduction
2. Classification
3. Limit of residual solvent
4. Analytical procedure
5. Conclusion
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3. Residual solvents are defined as organic volatile impurities that may remain in active
substances, excipient, or medicinal products after processing. During the manufacturing
processes.
Appropriate selection of the solvent for the synthesis of drug substance may enhance the
yield, or determine characteristics such as crystal form, purity, and solubility.
Residual solvents do not have any therapeutic effect.
Therefore efforts should be made to remove them to the extent possible to meet the
specifications prescribed. Depending upon the safety data and their risk to the human
health.
Introduction
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4. Classification
Residual solvent should be classified as
1. Class 1
2. Class 2
3. Class 3
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Residual solvent classified
according to their risk assesments to
human health
Class 1 solvent
Solvent to be avoided
Class 2 solvents
Solvent to be limited
Class 3 solvents
Solvents with low toxic
potential
1

6. Class 1- solvent to be avoided
These solvents are known to cause unacceptable toxicities and should be avoided in
the manufacture of active pharmaceutical substances, excipients and medicinal
products. However if their use is unavoidable, the restricted limits shown in table 1
should be applied.
SOLVENT CONCENTRATION LIMIT
(PPM)
Benzene 2
Carbon tetrachloride 4
1,2- Dichloroethane 5
1,1-Dichloroehtane 8
1,1,1-Trichloroethane 1500
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7. Class 2-solvent to be limited
These solvents are associated with less severe toxicity but should be limited in
pharmaceutical products for the protection of consumers from potential adverse
effects. Restricted limits shown in table 2 are applicable if any solvent of this class
is used
SOLVENT CONCENTRATION (ppm)
Chloroform 60
Acetonitrile 410
Cyclohexane 3880
Dichloromethane 600
Formamide 220
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8. Class 3 – Solvent with low toxic
These solvents are less toxic and of lower risk to human health.
Nevertheless, they need to be limited by good manufacturing practices
or other quality based requirements. The concentration limits of 5000
ppm would be acceptable for the solvents listed in table.
CONCENTRATION
Acetic acid
Acetone
Anisole
Ethanol
cumene
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9. Analytical techniques for the
determination of residual solvents
Loss on drying (LOD)
Karl fischer titration
Near- IR Spectroscopy
NMR – spectroscopy
Gas chromatography – direct injection, head space injection, SPME –
Solid phase microextraction, SDME – Single drop microextraction
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10. 1.Loss on drying
The loss on drying technique is largely used in pharmaceutical laboratories to
determine the total amount of volatiles, i.e., water and residual solvents vaporized under the
experimental conditions. The test is quite simple and depends only on a properly calibrated
analytical balance and an oven usually programmed at 105 ºC.
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11. 2. Karl-Fischer Titration
The Karl Fischer (KF) reaction is based on the quantitative
reaction of water with iodine (I2) in presence of an alcohol, a base, and
sulfur dioxide (SO2), with potentiometric determination of the endpoint.
The Karl Fischer method is used to determine the total water content.
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12. Karl Fischer titration is a classic titration method in chemical analysis
that uses coulometric or volumetric titration to determine trace amounts
of water in a sample. It was invented in 1935 by the German chemist
Karl Fischer.Today, the titration is done with an automated Karl Fischer
titrator.
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13. 3. Near-IR Spectroscopy
The infrared spectroscopy (IR) has a high potential for identification (classification) and
quantification, especially when combined to chemometric methods. It is non-destructive, requires
minimum sample preparation and can be used to determine water and residual solvents. The near
infrared spectroscopy (800-2500 nm or 12821-4000 cm-1) was reported to be the best method to
differentiate between different water species. According to Cao et.al. NIR spectra at 1860-2020 nm
(OH stretching and OH bending) could be deconvoluted into individual spectra corresponding to
hydrate and surface water of mannitol.
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14. TYPES OF
VIBRATION
FREQUENCY (CM-1)
Alkanes (strectch) 3000 - 2850
CH3 (bend) 1450 – 1375
CH2 (bend) 1465
Alkenes ( stretch) 3100 – 3000
Aromatic (stretch) 300-650
Alkyne ( stretch) 900-650
Aldehyde 2900 - 2800
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Example:

15. 3.Gas Chromatography
GC methods have been developed to monitor residual solvents in pharmaceutical products routinely.
The most popular techniques of sample introduction into the gas chromatograph include direct injection, static
or dynamic headspace, solid-phase microextraction and single drop microextraction. In gas Chromatography
various solvent peaks appeared at different tr (Retention times) in the graph. Based on the area of the peaks,
concentration of the solvents in sample is calculated.
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16. Katarzyna Grodowska, et.al. (2010)
developed an analytical method for Residual solvents determination in pharmaceutical products. A
30m X 0.32mm column coated with a 5m X 0.53mm guard column deactivated with phenylmethyl siloxane
phase with FID detector. Helium was used as a carrier gas, the detector temperature was kept at 250ºC. This test
was performed for confirmation that benzene, methylene chloride, trichloroethylene, 1,4-dioxane and
chloroform are below maximum acceptable limits 10.
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17. CONCLUSION
 Solvents are being used in almost every step of the elaboration of a drug product. Their residues could
be determine for the processability and stability of the pharmaceutical products and the safety of
patients.
 The testing and control of Residual solvents has been thoroughly assessed and is based on robust and
sensitive techniques.
 After studying the different techniques of residual solvent determination it was found that Gas
chromatography offers greater sensitivity, accuracy and robustness over all the other analytical
techniques.
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18. THANK YOU
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