How do you control impurities in pharmaceuticals?

Pharmacopoeial Methods

Official monographs for pharmaceutical substances provide descriptions and information in addition to prescribing standards for the product and its storage conditions. An official monograph for a pharmaceutical substance generally includes the following: 

1. Title: It is the official name of the substance. Sometimes the common names or synonyms are also mentioned. 

2. Chemical formulae: When the chemical structure of the compound is known, the graphic and molecular formulae and the molecular weight are given following the title.  A chemical formula refers to a chemically pure substance and is not an indication of the purity of the substance. 

3. Chemical names: Sometimes the IUPAC name of the substance is also given. 

4. Category: It indicates the medical or pharmaceutical application of the substance. It is generally the more common application, representing the main pharmacological action of the substance or its active ingredient and the substance may possess other uses or activities also. 

5. Dose: The doses mentioned in the pharmacopoeia are for general guidance and represent the average range of quantities regarded as suitable for adults when administered orally. 

6. Description: It gives information regarding the substance’s general physical and organoleptic properties. It helps in the preliminary evaluation of the integrity of the article and should not be considered an analytical requirement. 

7. Solubility: The solubility of the substance given in the monograph is primarily for information and should not be regarded as standards or test for purity but if a quantitative solubility test is given under ‘STANDARDS’ then the substance should comply with the given requirement. If the exact solubility of the substance is not known, the approximate solubility of the substance is indicated by the descriptive terms. The following table gives the meaning of such descriptive terms for substances at 20 to 30°C.

Descriptive termParts of solvent required for  part of solute 
Very solubleLess than 1 
Freely solubleFrom 1 to 10 
SolubleFrom 10 to 30 
Sparingly solubleFrom 30 to 100 
Slightly solubleFrom 100 to 1000 
Very slightly soluble1000 to 10,000 
Insoluble or practically insoluble10,000 or more

8. Storage: It contains information regarding the storage conditions of pharmaceutical substances so that they can be guarded against possible contamination and deterioration.  The precautions that need to be taken regarding the effect of atmosphere, moisture, heat and light are also indicated where appropriate in the individual monograph. The temperature conditions related to the storage of pharmaceutical substances are specified in some monographs. The following terms are used in the Indian Pharmacopoeia for defining the conditions of temperature. 

(a) Cold: Any temperature not exceeding 8°C and usually between 2°C and 8°C.  A refrigerator is a cold place in which the temperature is maintained thermostatically between 2°C and 8°C. 

(b) Cool: Any temperature between 8°C and 25°C. An article directed to be stored in a cool place, may, alternatively be stored in a refrigerator, unless otherwise specified in the monograph. 

(c) Room temperature: The temperature prevailing in the working area. 

(d) Warm: Any temperature between 30°C and 40°C. 

(e) Excessive heat: Any temperature above 40°C. 

(f) Protection from freezing: The label of the container bears this instruction where, in addition to the risk of breaking the container, freezing results in a loss of strength or potency or destructive alteration of the characteristics of an article. 

(g) Storage under non-specific conditions: When no specific storage conditions are indicated in the monograph, the storage conditions include protection from moisture, freezing and excessive heat. 

9. Standards as determined by the assay: It specifies the quantitative purity of the official compound. If an article does not comply with all the stated requirements it is not of pharmacopoeial quality. These requirements apply only to those articles that are intended for medicinal use and not to articles that may be marketed under the same name for other purposes.

10. Identification test: It includes various chemical tests to verify the identity of the substance. They are not absolute proof of identity. 

11. Test for purity including limits tests: Different limits for impurities are prescribed for different substances. Tests for purity are tests for the presence of impurities in the substance and fix the limits of tolerance for undesirable impurities. 

12. Assay: It describes the official method for the quantitative determination of the active ingredient of the pharmaceutical substance and its preparation. 

Identification Test 

The purpose of the identification test is to ensure the correct labelling of the substances.  Identification tests are specific but they are not sufficient in establishing the absolute proof of identity of the substances. If an article taken from a labelled container does not meet the requirements of a prescribed identification test indicates that the article is either mislabelled or substituted. In some monographs, more than one identification test is given. In such cases, if the article complies with either one or the other identification test, insufficient to verify the identity of the article.

Identification tests are generally based upon the combination of simple chemical tests and measurement of the appropriate physical constants. There is considerable overlap between identification tests and limit tests. Limit tests are designed to ensure that undesirable impurities are within the prescribed limits. Identification tests whether physical or chemical,  provided they are sufficiently specific, can be used as the basis of a quantitative estimation or in the design of specific limit tests. Practically, a single identification test may contribute to the identification as well as standardization of the substance. 

Chemical tests, used for identification are qualitatively confirming to the presence of the substance under investigation. They may be far too general or lack specificity but can be considered sufficiently specific when used in conjugation with the other requirement of the monograph. 

Physical constants such as melting point, boiling point, solubility, weight per ml,  refractive index, optical rotation, viscosity etc. have characteristic values for a given substance. They can be used in identification, checking quality and maintaining standards of purity. 

Test for Purity 

‘Test for purity’ for substances has been prescribed by the pharmacopoeias of various countries to ensure reasonable freedom from undesirable impurities. The so-called ‘Test for purity’ is the test for the presence of impurities in the substance and fixes the limits of tolerance for these undesirable impurities. Purity tests are not framed to guard against all possible impurities rather they provide appropriate limitations of the potential impurities only. 

The guiding factor for fixing a limit of tolerance for the various impurities is the amount of impurity that is likely to be harmful. Arsenic and lead are quite dangerous even in trace amounts therefore very small limits of tolerance have been fixed for their presence in all pharmaceutical substances. Another factor is the practicability of the commercial method of production of the substance meeting the requirements of a particular standard of purity. It would be useless to fix the limits of tolerance which can only be attained at a very high cost.  There are cases in which the limits fixed in the pharmacopoeia were later relaxed because they were found to be too difficult to attain by the available methods of manufacturing. 

The ultimate objective is that the pharmaceutical substances if not completely free from undesirable or toxic impurities should be of reasonable good purity ensuring therapeutic safety. The presence of sodium bromide (NaBr) in the more expensive potassium bromide  (KBr) is not likely to cause any harm to the patient but at the same time, the KBr should be of sufficiently good pharmaceutical quality and purity and not contain an excessive amount of sodium bromide. Some of the tests which may be undertaken to ascertain the purity of a substance  are: 

(a) Clarity of Solution: The degree of clarity or opalescence of solution is measured by direct comparison with a reference solution having standard opalescence. The comparison is against a black background by viewing vertically downward under diffused light. A solution is considered clear if its clarity is the same as that of water or the solvent employed in the preparation of the solution being examined. 

(b) Colour of Solution: In Indian Pharmacopoeia, the colour standards are based on three primary colourimetric solutions: yellow, red and blue prepared from ferric chloride, cobaltous chloride and cupric sulphate respectively. These primary solutions are mixed in various proportions with or without 1% w/v hydrochloric acid to give five reference colour solutions which are yellow (YS), greenish yellow (GYS), brownish yellow (BYS), brown (BS), and red (RS). The colour of the solution is compared with the reference colour solution by viewing vertically downwards through the columns of liquids in diffused light. A solution may be considered colourless if it has the same appearance as water or as the solvent employed in the preparation of the solution being examined. 

(c) Acidity or Alkalinity: Pharmaceutical substances prepared using chemical reactions involving acids and alkalies may possess some degree of acidity or alkalinity resulting from improper purification by inadequate washings after their separation. The limits for acid or alkali impurities are fixed for various pharmaceutical substances and the test for acidity and alkalinity is of great help in determining the extent of such impurities. 

(d) Loss on Ignition: It is the loss of weight in% w/w resulting from a volatile part of any test material that is driven off under specified conditions. It is applied to thermostable substances which contain thermolabile impurities that decompose and lose a volatile product e.g., zinc carbonate decomposes losing carbon dioxide. The substance is heated, cooled and weighed repetitively until a constant weight is attained. The loss on ignition in this case should not be more than 2% w/w.

(e) Loss on Drying: It is the loss of weight in% w/w resulting from water and volatile matter that is lost under specified conditions. The temperature to which the substance is subjected varies considerably according to the nature of the substance.  The temperature applied should not be so high as to cause the decomposition of the substance but at the same time, it should be sufficiently high to produce the desired results within a reasonable time. It is usually applied by drying the substance to a constant weight at 105°C. 

(f) Moisture Content: Sometimes the determination of the moisture content of the substance is a good measure of the purity of the substance especially in the case of crude drugs. 

(g) Ash Values: The determination of ash values in crude drugs, organic compounds and certain inorganic compounds provides valuable information regarding the extent of heavy metals and minerals impurities. 


An assay method should be specific for the substance or chemical species being examined. Nevertheless, non-specific assay methods are quite commonly employed particularly in acid-base titrations. Many inorganic salts are assayed by simply determining the content of one of the ions present e.g., sodium sulphate to assayed by determining its sulphate content by precipitating the sulphate as barium sulphate. Although non-specific an assay method can be considered as sufficiently specific when used in conjugation with other requirements of the monograph. 

Assay Tolerances 

Assay tolerances play an important role in fixing standards for pharmaceutical substances. They include the limits of error of the actual assay process for the active pharmaceutical ingredients, the limits of tolerance of the manufacturing process for the particular dosage form and the sampling errors. The limits of error in the assay process depend upon the method employed. Volumetric and gravimetric methods are very accurate and have quite narrow limits of error whereas spectrophotometric assays are not that accurate and have much wider limits of error.

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