Table of Contents
Introduction
The substances that are used in pharmaceuticals should be pure enough to be used safely. It is rather difficult to obtain an absolutely 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. The purity of substances depends upon several factors/methods of manufacture and types of crystallization or purification process. In the pharmaceutical field, one deal with a large number of drugs, chemicals and other substances which are used in formulations. All such materials need to be pure. However, it is almost impossible to get an absolutely pure material, as impurities get incorporated into them either during manufacture, purification or storage.
Sources of Impurities
The type and amount of impurity present in chemicals or pharmaceutical substances depends upon several factors:
Raw Material Employed in 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. The type and amount of impurity present in the drugs or chemicals varies. Furthermore, for certain drugs, a multiple-step synthesis procedure is used, which produces intermediate compounds. The purification of the intermediates is also essential; otherwise, impurities present in the intermediates will get into the final compound. Often, side reactions take place during the synthesis. Impurities of the side reaction product are also found in the substances.
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, and chemicals are used. When chemical reactions are carried out in iron, copper, tin, and aluminium vessels, the solvents and chemicals in the vessels react with the metals, thereby forming reaction products. These reaction products derived from the plant material occur as impurities in the final product. Thus, impurities of iron, lead, heavy metals, copper etc., in substances are due to the above-mentioned reasons.
Storage Condition:
The chemicals and substances when prepared are stored in different types of containers, depending upon the nature of the material, batch size and quantity. Various types of materials are used for storage purposes. These could be plastic, polythene, iron vessels, stainless steel, aluminium, copper etc. The reaction of these substances with the material of the storage vessel takes place and the products formed, occur as impurities in the stored material. The reaction may take place directly or by the leaching effect on the storage vessel. Alkalis stored in ordinary glass containers, extract lead from it, which occurs in the final product. Similarly, strong chemicals react with iron containers and extract iron.
Decomposition:
Some substances decompose and the decomposition is greater in the presence of light, air or oxygen. The result of decomposition causes contamination of the final product. Many substances lose water of crystallization when kept open, while deliquescent substances absorb water from the atmosphere, and get liquefied. Crude vegetable drugs are especially susceptible to decomposition. A number of organic substances get spoiled, because of decomposition on exposure to the atmosphere, e.g. amines, phenols, potent drugs etc. The decomposition products thus appear as impurities in the substances.
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:
- Impurities which have a toxic effect can be injurious when present above certain limits.
- Impurities, even when present in traces, may show a cumulative toxic effect after a certain period.
- Impurities are sometimes harmless but are present in such a large proportion that the active strength of the substance is lowered. The therapeutic effect of the drug is decreased.
- Impurities may bring about a change in the physical and chemical properties of the substance, thus making it medically unfit.
- Impurities may cause technical difficulties in the formulation and use of the substances.
- Impurities may bring about incompatibility with other substances.
- Impurities may lower the shelf life of the substance.
- Impurities, though harmless in nature, may bring about changes in odor, color, taste, etc. thus making the use of the substance unhygienic.
Permissible Impurities in Pharmaceutical Substances
Since it is not possible to avoid impurities, it is necessary to have substances that are reasonably pure. The pharmacopoeial committee takes the following points into consideration with respect to the problem caused by impurities in substances.
- For impurities that are of harmful type: such as lead, arsenic, etc., a low permissible limit is prescribed. This is based on, how much of these can be tolerated. Which itself is based on how much of the impurity is harmful.
- For impurities that are harmless, the aim is to fix their limits so that their presence does not interfere with the therapeutic use of the drug. Here, again, the limits are prescribed and fixed. This is done depending on the nature of the impurity, the type of substance, the use of the substance, etc.
- Another consideration is the practicability of obtaining substances without impurities at reasonable costs. It may be possible to prepare substances through a series of steps of purification without any impurities, but this could escalate the cost. Considering this aspect, the limits of various impurities are fixed.
- Deliberate adulteration by using materials having similar qualities also accounts for the presence of impurities in the substance, e.g. adulteration of sodium salt with potassium salt, calcium salts with magnesium salts, etc. Such adulteration which brings impurities into substances, need not exhibit less therapeutic activity but it is reasonable to expect unadulterated material from an ethical point of view. Pharmacopoeias guard against this type of impurity by employing tests for identification.
Test for Purity:
Pharmacopoeias of various countries prescribe ‘tests for purity, for substances which are to be used for medical purposes. The so-called ‘tests for purity’ means detecting impurities in the substances and pharmacopoeias fix the limits of tolerance for these impurities. The governing factor for these tests is to determine how much impurity is likely to be harmful or to bring about technical and other difficulties when the substance is used. Pharmacopoeias do not aim at ensuring freedom from every possible impurity in a substance, but to test for a few major impurities, which are likely to interfere with their use. Certain tests which are carried out on the substances are:
1. Colour, Odour and Taste:
The description of taste, odour, colour etc. is given in the pharmacopoeias. Though they have limited value, they are useful in determining whether the substance is reasonably pure, hygienic etc.
2. Physico-chemical Constants:
Solubility of the substance in various solvents, determination of melting and boiling points for organic substances, optical rotation for optically active substances and refractive index for liquids, are some values which tell us about the purity of the substance. Determination of the acid value, iodine value, saponification value, acetyl value, and ester value for vegetable oils are generally constants and a variation in their value signifies the presence of impurities. The extent of the variation in these values usually depends upon the nature and extent of impurities present in the substances. However, a very low concentration of impurities may fail to alter these constants, and thus remain undetected unless tested specifically, by special tests.
3. Acidity, Alkalinity and pH:
Substances that are prepared from chemical reactions involving acids and alkalis often contain considerable amounts of the acid or alkali, as an impurity. Thus, the tests for acidity or alkalinity are a great help to estimate the extent of the impurity. Furthermore, solutions of certain substances have a definite pH at a given concentration. The presence of impurity will bring about a change in the pH and thus it can be detected.
4. Anions and Cations:
A large number of synthetic inorganic and organic drugs are prepared using strong acids like hydrochloric, sulphuric, nitric etc. The presence of chloride and sulphate ions is thus a common impurity. Test for these ions (anions) is thus generally carried out. Similarly, tests for sodium and ammonium (cations) are often carried out to detect impurities in inorganic compounds (test for sodium in potassium salt and vice versa, calcium in magnesium salts etc.). Tests for heavy metals, like lead, iron, copper and mercury are also carried out as these are very common impurities in substances.
5. Insoluble Residue:
Pure substance gives a clear solution in a given solvent. When insoluble impurities are present in a substance, the solution appears cloudy or shows opalescence. The measurement of turbidity or opalescence helps to determine the amount of insoluble impurity present in the substance. If the insoluble residue is high, this can be determined by filtering and weighing the insoluble residue.
6. Ash, Water Insoluble Ash:
Determination of ash in crude vegetable drugs, organic compounds, and some inorganic compounds, gives a good indication of the extent of impurities of heavy metals or minerals in nature. This determination is, therefore, commonly employed for a number of substances. In certain cases, water-insoluble ash is also determined to find water-soluble heavy metals or mineral types of impurity.
It is thus clear that, depending upon the type of material or substance, pharmacopoeias prescribe tests for purity of particular nature, e.g. salicylic acid in acetylsalicylic acid, phenetidine in phenacetin, acetaldehyde in glycerine, p-aminophenol in paracetamol etc. In general, it could be said that impurities of chloride, sulphate iron, heavy metals, lead and arsenic, are common in drugs and chemicals. Pharmacopoeias of various countries, therefore, prescribe, and limit tests to be carried out for these, by a particular method.
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