IMPURITIES

This slide include detail information about Impurities,Sources of impurities and types of impurities.prepared by Mr. Muli P.N.

1. Pharmaceutical Inorganic Chemistry B. Pharm First Year Mr. Pravin N. Muli Assistant Professor Impurities 1

2. Contents Introduction of Impurities Sources of Impurities Types of Impurities References 2

3. A compound is said to be impure if it is having foreign matter. Hence any material (foreign matter) that affects the purity of the material of interest i.e. active ingredient or drug substance is called impurity. The commonly found impurities in medicinal preparations Activity depressing impurities Impurities due to colouring or flavouring substances, Impurities formed due to changes in humidity. Impurities formed because of decrease in shelf life of drug product Physical and chemical properties. Impurities due to which substances become incompatible Introduction of Impurities 3

4. The type and amount of impurity present in the chemicals or pharmaceutical substances, depends upon several factors. Some of which are Sources of Impurities 4

5. 5 (a) Raw material :The impurities already present in raw material may pass on to the final product via the manufacturing process. Hence, the final product can get contaminated with these impurities. e.g. Zinc sulphate is prepared by reacting either zinc oxide or zinc metal with sulphuric acid ZnO+ H2SO4 → ZnSO4 + H2O Zn+ H2SO4 → ZnSO4 + H2↑ Zinc metal and zinc Oxide contain Al, Cu, Mg, Mn , Ni, As and Fe as impurities and these impurities are likely to be carried in

6. the manufacturing process in appreciable amount to the final product as ZnSO 4 .7H 2 O (b) Method of manufacturing : The process or method of manufacturing may introduce new impurities into the final product arising due to contamination by reagents, catalysts and solvents employed. 1) Reagent employed in manufacturing process: Calcium carbonate contains soluble alkali as impurity which arises from sodium carbonate employed in the process. Calcium carbonate is prepared by interaction of a soluble calcium salt with a soluble carbonate. Therefore, the final product (calcium carbonate) is liable to contain small amount of soluble alkali as impurities which cannot be removed by the washing the process. CaCl 2 + Na2CO 3 → CaCO 3 +2NaCl 6

7. 2) Solvents : Small amount of solvents employed in preparations and purification of reaction intermediates or the final products may also be found in contamination of pharmaceutical substances. e.g. Water is the cheapest solvent and can be a major source of impurity. Various types of water which are available are as follows i ) Tap water: lt contains impurities of calcium ions, magnesium ions, sodium ions, chloride ions, carbonate ions and sulphate sons in trace amounts. The use of tap water on large scale can lead to contamination of final product. (ii) Softened water: It is almost free from divalent ions (calcium and magnesium ions) but contains more sodium and chloride ions as impurity. The final product obtained by using soften water can contain sodium and calcium as a impurity. 7

8. (iii) Demineralised water : Is prepared by means of ion exchange resins and is free from all kind of ions. It may have Pyrogens , bacteria and organic impurities. (iv) Distilled water : it is free from all organic and inorganic impurities and is hence the best as solvent. (C) Reaction vessel : The reaction vessel used in manufacturing process may be metallic such as copper, galvanized iron, glass and silica. Some reagents employed in he manufacturing process may react with the metal of reaction vessel, leading to the traces of metal impurities into the solution and finally contaminating the product. Glass vessels may give traces of alkali to the solvent Strong acid leaches out alkali from borosilicate copper and Zinc react with slightly acidic substances 8

9. ( d) Intermediates: Sometimes an intermediate substance produced during manufacturing process may contaminate the final product e.g. Sodium bromide is prepared by the reaction of sodium hydroxide and bromine in slight excess. 6NaOH+3Br 2 → NaBrO 3 + 5NaBr + 3H 2 O The sodium bromate an intermediate product is reduced to sodium bromide by heating the residue (obtained by evaporating the solution to dryness) with charcoal. NaBrO 3 + 3C → NaBr + 3CO If NaBrO 3 is not completely converted to NaBr , then it is likely to be present as an impurity. 9

10. (e) Atmospheric contamination during manufacturing process: Atmosphere may contain dust and some gases like carbon dioxide, sulphur dioxide, arsenic and hydrogen sulphide. These may contaminate the final product during manufacturing process. Some substances which are susceptible to action by carbon dioxide and water may get contaminated with them during their preparation. e.g. NaOH readily absorbs atmospheric carbon dioxide when exposed to atmosphere. 2NaOH+CO 2 → Na 2 CO 3 + H 2 O (f) Manufacturing hazards: If the manufacture is to control and check impurities from all above mentioned impurities, there exist certain manufacturing hazards which can lead to product contamination. various manufacturing hazards are as follows 10

11. ( i ) Contamination from particulate matter: The particulate contamination arises from wear and tear of equipment. It may also arise from the bulk material used in the formulation or from dirty or improperly maintained equipment. e.g. contamination of eye ointments packed in metal containers of tin and aluminium. (ii) Cross-contamination of the product: It can occur by airborne dust arising from bulk powders, granules and tablets. It is dangerous particularly in case of steroidal and other synthetic hormones and therefore it should be carefully controlled (iii) Contamination by microbes : Many products like liquid separation and cream intended for topical application are liable to be contaminated by microbes during manufacturing. For all products intended for parentral administration and opthalmic preparations, sterility testing is done and it provides an adequate control for microbial contamination in such preparations. 11

12. (g) Errors in manufacturing process: Defects like incompleteness of reaction, imperfect mixing etc. may result in the production of impure compounds. e.g. Zinc oxide, produced by heating metallic Zinc in a current of air. 2Zn+O 2 →2ZnO If zinc metal is not completely converted into ZnO , small amount of zinc metal may be present in the final product as impurity Sometimes in a liquid preparation there is in complete solution of the solute which thought to be detected by normal analytical methods as it can lead to major error. 12

13. (h) Errors in packaging : Similar looking products such as tablets of same size, shape and colour, packed in similar container can result in mislabelling of either or both the products 13

14. ( i ) Instability of Products : Products may be unstable because of following reasons ( i ) Temperature : The rate of chemical decomposition and physical changes of stored products depends upon the temperature. The susceptible substances may have temperature storage requirements assigned to them, in order to protect the against undesirable decomposition. (ii) Chemical Instability: Many pharmaceutically important substances undergo chemical decomposition when storage conditions are inadequate. This chemical decomposition is catalysed by light, traces of acid or alkali, traces of metallic impurities, air oxidation, carbon dioxide and water vapours. The nature of decomposition can easily be predicted from the knowledge of chemical properties of substances. 14

15. (iii) Changes in Physical Properties: Pharmaceuticals may undergo changes in physical properties during storage. There can be changes in crystal size and shape, sedimentation, caking and agglomeration of the suspended particles. These physical changes may result in significant changes in physical appearance, pharmaceutical and therapeutic effect of the product. 15

16. According to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), impurities can be classified broadly into TYPES OF IMPURITIES 16

17. 17 (1) Organic Impurities: Organic impurities can be arise during the manufacturing processes and/or storage of new drug substance. They can be identified or unidentified, volatile or non-volatile and include:

18. 2) Inorganic Impurities: Inorganic impurities can result from the manufacturing process. They are normally known and identified and include 18

19. 3) Residual solvents: Solvents are inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis of new drug substances. Residual Solvents in pharmaceuticals are defined as organic volatile Chemicals that are used or produced in the manufacture of drug substance. 19

20. References Anand & Chatwal , Inorganic Pharmaceutical Chemistry A.I . Vogel, Text Book of Quantitative Inorganic analysis P. Gundu Rao , Inorganic Pharmaceutical Chemistry, 3rd Edition M.L Schroff , Inorganic Pharmaceutical Chemistry 20

21. Thank You 21