Sources and types of impurities
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This document discusses pharmaceutical impurities, which are unwanted chemicals that remain with active pharmaceutical ingredients or develop during formulation or aging. Impurities can come from raw materials, intermediates, reagents, catalysts, solvents, reaction vessels, improper storage, cross contamination, manufacturing errors, packaging errors, microbial contamination, chemical instability, storage containers, or atmospheric contamination. The presence of impurities can affect the efficacy, safety, and purity of pharmaceutical products. Common impurities include metals, microbes, residual solvents, and degradation products. Strict controls are needed in manufacturing to minimize impurities.
Sources and types of impurities
- 1. BY VANA JAGAN MOHAN RAO M.S.Pharm, MED.CHEM NIPER-KOLKATA Asst.Professor, MIPER-KURNOOL Email: jaganvana6@gmail.com
- 2. What is Impurity? • Impurity is defined as the presence of one substance in another substance in lower concentration. • A Pharmaceutical Impurity is the unwanted chemical that remain with the APIs (active pharmaceutical ingredients) or develop during formulation or upon aging of both API and formulation. • These impurities may influence the efficacy and safety of Pharmaceutical product.
- 3. Any material that affects the purity of Pharmaceutical drugs (or) products • Presence of impurities may slow produce toxic effects on the body and may also lower down the active strength of Pharmaceutical substance. • These impurities includes small quantities of Lead, Arsenic, Chloride, Sulphate, Iron, etc. UNWANTED UNDESIRABLE EXCESS HARMFUL
- 4. • Impurity can be Organic, Inorganic, Microbial, Residual solvents, Dust, Moisture, etc. • In a pharmaceutical substance, the nature of impurity can be predicted by the source from which it has been obtained. • There are 2 types of impurities in medicines: a) Impurities associated in with APIs b) Impurities that form are created during formulation and with aging or that are related to the formulated forms.
- 5. Impurities commonly found in medicinal preparations Impurities which have toxic effects on body and bring about unpleasant reactions when present beyond certain limits. e.g Lead and Arsenic salts. The impurities which are able to make substance incompatible with other substances. The impurities which if present beyond the limit, affect the storage property of the pharmaceuticals. The impurities which are harmless, but if present beyond the limit, it will lower the active strength of the medicinal compound. E.g Sodium salt in potassium salt. The impurities which may bring about technical difficulties in the use of the substance. Impurities such as taste, odour, colour or appearance which can be easily detected by the senses and make the substance unhygienic and unaesthetic. E.g. Sodium chloride becomes damp because of the presence of traces of magnesium salts. Also phenolic impurities present in sodium salicylate alters its odour.
- 6. Impurities imparted in pharmaceutical products through: • Raw materials • Intermediates • Reagents • Catalysts & Solvents • Reaction vessels • Improper storage • Cross contamination • Manufacturing Errors • Packing errors • Microbial contamination • Chemical instability • Storage containers • Atmospheric contamination • Deliberate adulteration, etc.
- 7. RAW MATERIALS EMPLOYED IN MANUFACTURING Rock salt- CaSO4 + MgCl2 + NaCl Calcium sulphate Magnesium Chloride Sodium Chloride • Rock salt contains small amounts of Calcium sulphate and Magnesium chloride. Thus Sodium chloride prepared from this source will contain traces of Calcium and Magnesium compounds. Copper sulphate may be prepared by the action of sulphuric acid on copper turnings: • Cu+ 2 H2SO4 CuSO4 + 2 H2O + SO2 Copper turnings are known to have Iron and Arsenic as impurities.
- 8. INTERMEDIATES FORMED DURING MANUFACTURING • Sometimes the Intermediates that are formed during the manufacturing may be carried through to the final product as the impurity. Example: • Potassium iodide is prepared by reacting Iodine with Potassium hydroxide. 6KOH+ 3I2-------------------- 5KI + KIO3 + 3H2O • The resulting solution is first evaporated and then heated with charcoal. KIO3 + 3C ---------------------KI + 3CO In this process if the intermediate product (KIO3) is not completely converted into KI, then it may be carried through to the final product as an impurity.
- 9. REAGENTS USED IN MANUFACTURING • In manufacturing all the reagents will not be removed by the washing process. So, some reagents may enter into the final products. Example: • Ammoniated mercury may be prepared by adding a solution of Mercuric chloride to dilute ammonia solution. • The precipitate of Ammoniated mercury (Final Product)contains ammonium hydroxide. • Thus, this precipitate is washed with cold water to remove ammonium hydroxide. • If it is not removed completely by washing with water, the final product may contain in it. • Ammonium hydroxide as impurity. HgCl2+ 2NH4OH-------------NH2HgCl + NH4Cl + 2 H2O Soluble soluble Ammoniated mercury (ppt) (soluble)
- 10. CATALYSTS • If the used catalysts are not seperated from the solution after the reaction it may be observed in the final product. Ex:- Enzymes
- 11. SOLVENTS USED IN MANUFACTURING • Generally water is used as solvent. It may containers impurities. Tap Water It has Ca+2, Mg+2, Na+, Cl-, SO -2 and CO -2 as 4 3 impurities in small amounts Softened water It is obtained by allowing the tap water to pass through the sodium form of Zeolite which removes divalent cations like Ca+2 and Mg+2 from tap water in exchange of sodium. So, softened water contains Na+, Cl- ions as impurity. De-mineralised water It is obtained by passing tap water through columns packed with ion exchange resin.The water obtained from this process is free from Ca+2, Mg+2, Na+, Cl-, SO -2 and CO -2 4 3 Thus the final product is free from these impurities. The water obtained from this source may still contain organic impurities and so final product contains organic impurities. Distilled water It is considered the best but it is very costly. Esha Shah
- 12. REACTION VESSELS USED IN MANUFACTURING • During manufacturing process, some of the solvents and reagent may undergo reaction with metals of reaction vessel and may dissolve these metals, which appear as impurities in the final product. Example: Iron is known to contain Arsenic impurity. The inorganic compounds manufactured in Iron vessel will contain Arsenic and Iron as impurities. Thus IP has prescribed limit test for Arsenic and Iron for most inorganic compounds.
- 13. IMPROPER STORAGE The chemical substances when prepared have to be stored in different types of containers depending upon: Nature of the material Batch size Quantity Many types of materials are used for storage purpose like plastic, polythene, iron vessels, stainless steel and aluminium. Leaching out effect: Alkalies stored in ordinary glass containers extract lead from it, which in found as impurity in the final product. Strong chemicals react with iron containers and extract Iron an impurity in final product.
- 14. • Inadequate storage and their effects are as follows: a) Filth: Stored products may become contaminated with dust, bodies of insects, animal and insect excreta. b) Chemical instability: decomposition because of light, traces of acid or alkali, air oxidation, water vapour, CO2 and traces of metallic ions. • e.g. light sensitive materials should be stored in amber colored bottles. c) Reactions with container materials: e.g. salicylic acid ointment must not be stored in metal tubes. d) Physical changes: The occurrence of changes in the physical form of drug like change in crystal size can lead to change in efficiency of product. e) Temperature effect: Chemical and physical changes occur if materials are not stored at proper temperature.
- 15. CROSS CONTAMINATION The handling of powders, granules, and tablets in large bulk creates air-borne dust, which leads to cross contamination of the product. So, face masks and special extraction equipment are used to protect operators from harmful effects of drugs. E.g penicillin preparation requires special handling during its manufacture.
- 16. MANUFACTURING ERRORS • In many manufacturing processes, there are defects like imperfect mixing, incompleteness, non-adherence to proper temperature, pressure, pH or reaction conditions, which may give chemical compounds with impurities in them. Example: • Zinc oxide may be prepared by heating metallic zinc to bright redness in a current of air. The vapours of Zinc burn to form Zinc oxide which is collected as a fine white powder. • But if there is less heat or air or both, zinc metal is not completely converted to zinc oxide. • Thus the final product, Zinc oxide may still contain metallic zinc as impurity. • So, IP has prescribed a test for Zinc metal in zinc oxide.
- 17. PACKAGING ERRORS • Products of similar appearance such as tablets of same size, shape, colour packed in similar containers can constitute a potential source of danger. • Improper labelling or destruction of stock of unused labels also constitutes a major packaging hazard.
- 18. MICROBIAL CONTAMINATION • Parenteral preparations and ophthalmic preparations require special care against microbial contamination. • Many liquid preparations and creams are liable to bacterial and fungal contamination. So care should be taken. • E.g., Acacia, senna, tragacanth---They should be controlled for Salmonellae.
- 19. CHEMICAL INSTABILITY For the synthesis of drugs, many chemical reactions such as Nitration, Halogenation, Oxidation, reduction, hydrolysis are involved. In these chemical processes, different chemicals are used. Those may observed as impurities. Tap water is generally used in the various processes and it is often having Cl-,Mg+2, Ca+2 ions, which are generally found in the substance which is being manufactured.
- 20. STORAGE CONTAINERS • If the storage containers are metals those are highly reactive in nature with so many chemical substances. • It may lead to form some impurities after manufacturing while storage.
- 21. ATMOSPHERIC CONTAMINATION In the industrial areas, the atmosphere is contaminated with dust particles and some gases like Hydrogen sulphide, Sulphur dioxide, and black smoke. During the manufacture or purification of the pharmaceutical products, these impurities enter the final products. There are many pharmaceutical products which when manufactured are contaminated with atmospheric CO2 and water vapour. E.g. NaOH absorbs atmospheric CO2. 2NaOH + CO2 -------------------------------- Na2CO3 + H2O Due to this reaction, NaOH should not be kept open for a longer time during its manufacture. Therefore, IP has prescribed that Sodium hydroxide should not contain more than 3% of sodium carbonate.
- 22. DELIBERATE ADULTERATION It is possible to avoid accidental substitution by storing the toxic substances together separately or in a locked cupboard. Many pharmaceutical chemicals are adulterated with cheaper substances. E.g. The expensive potassium may be adulterated with sodium bromide.