IMPURITES AND THEIR TYPES BY VIJAY KUMAR

IMPURITES AND THEIR TYPE S

1. Organic Impurities ⚫ Starting materials ⚫ By-products ⚫Intermediates • Degradation products Reagents, ligands and catalysts Inorganic Impurities Reagents, ligands and catalysts • Heavy metals or other residual metals . Inorganic salts . Other materials (e.g., filter aids, charcoal) Residual Solvents ⚫ Class 1 Solvents To Be Avoided ⚫ Class 2 - Solvents To Be Limited ⚫ Class 3-Solvents with Low Toxic Potential Types of Impurities Solvents To Be Avoided Solvents To Be Limited Solvents with Low Toxic Potential

2. Organic Impurities • Organic impurities mainly arise during the synthesis, purification(manufacturing process )and or storage of the drug substance ⚫ Organic impurities can be classified like.... ✓ Starting materials ✓ Intermediate ✓ Degradation products ✓ Reagents, ligand and catalysts

3. Inorganic impurities derive from the manufacturing process and excipients the, cadmium, chromium, copper, iron, lead, mercury, nickel and sodium. Sometimes they might present in the product during processing or they leached from packing material Generally, excipients contain high levels of heavy metals such as arsenic, bismuth ✓ Heavy metals ✓Inorganic salt ✓Other materails like filter aids, charcoal Inorganic impurities

4. Residual solvents (ICH Q3 C guideline) Residual solvents are potentially undesirable substances. They either modify the properties of certain compounds or may be hazardous to human health . The residual solvents also affect physicochemical properties of the bulk drug substances such as crystallinity of bulk drug, which in turn may affect the dissolution properties, odor and color changes in finished products Residual solvents are those solvents which are used as vehicles for the preparation of solution / suspensions in the synthesis of a new drug substance

5. As per the ICH guidelines, the solvents used in the manufacturing of drug substances classified in to four types • Class 1 solvents: Solvents to be avoided • Class 2 solvents: Solvents to be limited Class 3 solvents: potential Solvents with low toxic Class 4 solvents: Solvents for which No Adequate Toxicological Data was Found

6. a) Class I solvents : Solvents to Be Avoided Solvents in Class 1 should not be employed in the manufacture of drug substances, excipients, and drug products because of their unacceptable toxicity or their deleterious environmental effect. However, if their use is unavoidable in order to produce a drug product with a significant therapeutic advance, then their levels should be restricted as shown in Table 1.

7. Residual solvent Concentration limit (ppm) Benzene 2 (Carcinogenic Carbon tetrachloride 4 (Toxic 1,1 Dichloroethane 8 (Toxic) 1,2 Dichloroethane 5 (Toxic) 1,1,1 trichloro ethane 1500 (Environmental hazard Table 1. b) Class II solvents: Solvents to Be Limited Class II solvents usage should be limited in pharmaceutical products because of their inherent toxicity. Table 2 lists class II solvents with their daily permissible exposure.

8. Solvent PDE (mg/day) Concentration limit (ppm) Acetonitrile 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cumene 1 0.7 70 Cyclohexane 38.8 3880 1,2-Dichloroethene 18.7 1870 Dichloromethane 6.0 600 1,2-Dimethoxyethane 1.0 100 N,N- Dimethylacetamide 10.9 1090 N,N-Dimethylformamide 8.8 880 1,4-Dioxane 3.8 380 2-Ethoxyethanol 1.6 160 Ethylene glycol 6.2 620 Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2- Ethoxyethanol 0.5 50 Methyl butyl ketone 0.5 50 Methylcyclohexane 11.8 1180 Methylisobutylketone2 45 4500 N- Methylpyrrolidone3 5.3 530

9. c) Class III Solvents: Solvents with Low Toxic Potential These are less toxic and possess lower risk to human health than class I or class II • Long-term toxicity or carcinogenicity not reported, which is evident from the available data for the solvents under this category. The use of class III solvents in pharmaceuticals does not have any serious health hazard. Some of the solvents are; Acetic acid, anisole, butanol, 2butanol, isopropyl acetate, methyl acetate, butyl acetate, Ter-butyl methyl ether, pentene, cumene, Dimethyl sulfoxide, ethanol, ethyl acetate, formic acid, formic acid, heptane, isobutyl ketone, tetrahydrofuran, 1-pentanol, 2propanol, methyl isobutyl ketone, propyl acetate, 3methyl- 1-butanol, methyl ethyl ketone.

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