Sources of Impurities in Medicinal Agents

 Chapter 4

 Sources of Impurities in Medicinal Agents

Introduction

• The substances that are used in the pharmaceuticals should be pure enough to be used safely. It is rather difficult to obtain an absolute pure substance. We find substances and chemicals, with varying degrees of purity.

• For example, substances like cane sugar (sucrose), dextrose, common salt and many inorganic salts are found with over 99 % purity while many others only contain traces of impurities.

Sources of Impurities

The type and amount of impurity present in chemicals or pharmaceutical substances depends upon several factors:

• Raw Material Employed i n Manufacture: When substances or chemicals are manufactured, the raw materials from which these are prepared often contain impurities. These impurities get incorporated into the final product. Impurities like arsenic, lead, heavy metal etc. are present in raw materials, and are hence found in substances. It is, therefore, necessary to employ pure chemicals and substances as raw materials for the manufacturing process.

• Method or the Process used in Manufacture: There are a number of drugs and chemicals (especially organic), which are manufactured from different raw materials by adopting different methods or processes. Some impurities get incorporated into the materials during the manufacturing process.

• Chemical Processes and Plant Materials employed the Process: In the synthesis of drugs, many chemical reactions like nitration, halogenations, oxidation, reduction, hydrolysis etc. are involved. In these chemical processes, different solvents, chemicals are used. When chemical reactions are carried out in iron, copper, tin, aluminums vessels, the solvents and chemicals in the vessels react with the metals, thereby forming reaction products.

Effect of Impurities

It can be seen that; almost pure substances are difficult to get and that some amount of impurity is always present in the material. The impurities present in the substances may affect as follows:

1. Impurities which have a toxic effect can be injurious when present above certain limits.

2. Impurities, even when present in traces, may show a cumulative toxic effect after a certain period. Pharmaceutical Analysis 43 Sources of Impurities in Medicinal Agents.

3. Impurities are sometimes harmless but are present in such a large proportion that the active strength of the substance is lowered.

 Permissible Impurities in Pharmaceutical Substances

• Since it is not possible to avoid impurities, it is necessary to have substances that are reasonably pure. The pharmacopeial committee takes the following points into consideration with respect to the problem caused by impurities in substances:

1. For impurities which are of harmful type: lead, arsenic etc., a low permissible limit is prescribed.

2. For impurities that are harmless, the aim is to fix their limits so that their presence does not interfere in the therapeutic usefulness of the drug. Here, again, the limits are prescribed and fixed.

Limit Tests

Introduction

Limit tests are defined as, quantitative or semi - quantitative tests which are performed to identify and control small quantity of impurities which are likely to be present with the substances to be analyzed.

Generally, limit tests are carried out to identify the inorganic impurities present in a pharmaceutical substance. In these tests, the turbidity / opalescence / colour intensity produced by the test sample is compared with turbidity / opalescence / colour intensity produced by the standard.

Limit Test for Chloride

• The limit test for chlorides is based upon the chemical reaction between soluble chloride ions with a silver nitrate reagent in a nitric acid media.

• The insoluble silver chloride renders the test solution turbid (depending upon the amount of silver chloride formed and therefore, on the amount of chloride present in the substance under test.)

• Dissolve the specified quantity of substance. in water or prepare a solution as directed in the pharmacopoeia and transfer to a Nessler's cylinder A. Add 1 ml of dilute nitric acid except when nitric acid is used in the preparation of the solution. Dilute it to 50 ml with water and add 1 ml of silver nitrate solution, stir immediately with a glass rod and set aside for 5 minutes.

Limit Test for Sulphate

• In a limit test for sulphate, the solution of the substance under test is mixed with barium sulphate reagent in a hydrochloric acid medium and the turbidity so produced is compared with the standard in similar manner with a known quantity of sulphate ion (using potassium sulphate). 

• The substance passes the limit test if it produces a turbidity that is less than the standard. A solution of specified quantity of substance is made in water or prepared as directed in the pharmacopoeia in Nessler's cylinder, add 2 ml dilute hydrochloric acid except where hydrochloric acid is used in the preparation of solution.

Limit Test for Iron

• This test is based upon the reaction of iron in an ammoniacal solution, with thioglycolic acid which forms a pink to deep reddish purple colored complex of iron - thioglycolate.

• The colour produced from a specified amount of substance from the test, is compared by viewing.

Method: Prepare a solution by dissolving a specified amount of substance in 40 ml water or take 10 ml of solution as directed in monograph in Nessler's cylinder. Add 2 ml of 20 per cent w / v solution of iron free citric acid and 0.1 ml thioglycolic acid, mix and make alkaline with iron free ammonia solution and dilute it to 50 ml with water. Allow to stand for 5 minutes. For standard, simultaneously dilute 2 ml of standard iron solution with 40 ml of water, add same quantity of reagent as in the sample. Any colour produced by the sample is not more intense than the standard. Earlier, ammonium thiocyanate reagent was used for the limit test of iron. Since thioglycolic acid is more sensitive reagent for iron, it has replaced ammonium thiocyanate in the test.

Limit Test for Heavy Metals

• Metals Besides the limit test for lead, the Indian Pharmacopoeia and USP include limit tests for heavy metals present in many compounds. Lead and other heavy metals are generally found as impurities in pharmaceutical substances. Two separate tests are therefore prescribed by these pharmacopoeias.

Limit Test for Volatile Oils

• In 25 ml glass stoppered test tubes; 10 ml of the oil is mixed with an equal volume of water containing a drop of hydrochloric acid. Hydrogen sulphide is passed through the mixture until it is saturated.

• No darkening in colour should be produced neither in the oil, nor in the water layer, for the sample to pass the test.

Limit Test for Lead

• The limit test for lead as per IP and USP is based upon the reaction between lead and diphenylthiocarbozone (dithizone). Dithizone in chloroform extracts lead from alkaline aqueous solutions as a lead Dithizone complex (red in colour ) . C6H₁ C6H₂ 2S = C NHNH – CHs N = N. C₂H5 + Pb - S = C Fig. 4.2 H N N N = N N = N. NIN H C6H₁ C₂H₂ C = S W

Limit Test for Arsenic

• Arsenic is an undesirable and harmful impurity in medicinal substances, and all pharmacopoeias prescribe a limit test for it. There are many qualitative and quantitative tests for arsenic. The pharmacopoeial method is based on the Gutzeit test.

•  In this test, arsenic is converted into arsine gas, 3) which when passed over a mercuric chloride test paper, produces a yellow stain.