Pharmaceutical Impurities

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1 4 MEDICINAL CHEMISTRY CHAPTER 1 Pharmaceutical Impurities 1. INTRODUCTION In a broader perspective, the chemical entities (or compounds) commonly met with in commerce (used in pharmaceutical formulations, dosage forms, or drug products) do vary both extensively and intensively in terms of purity; and hence, overall quality of the substance available. Importantly, the actual proportion of total impurities is invariably found to be very small (sometimes in traces only). Example: Following are two classical examples of commonly used compounds being incorporated in dosage forms, such as: l Refined Sugar It is indeed a mass-produced compound of reasonably high purity that essentially contains more than 99.9% of sucrose; whereas, the total impurities including the moisture content should be as low as 0.06%; and l Vacuum Salt (NaCl) It is usually prepared on a large scale by the critical purification of rock salt usually comprises more than 99.9% of sodium chloride (NaCl). In fact, impurity relates any component that is present in the intermediate or active pharmaceutical ingredient (API), which is not the desired entity, that could be either product connected or process connected. The impurity profile refers to a detailed description of the identified and unidentified impurities present in a usual batch of active pharmaceutical ingredient (API) that is normally produced by a particular controlled production process, which predominantly includes: l identity or some qualitative analytical description, l range of each impurity observed, and l type of each identified impurity. Thus, for each and every API there must be an impurity profile describing the identified and unidentified impurities present in a typical production batch size. Sources of Impurities: The impurities usually present in either chemical substances or active pharmaceutical ingredients (APIs) may be actually traced to several different sources. Following are some of the known and established sources of impurities, such as: 1. Raw Materials Impurities, in general, are most commonly derived from the raw materials from which the chemical substance or API is being prepared actually. 4

2 PHARMACEUTICAL IMPURITIES 5 Example: The presence of silver (Ag), copper (Cu), and lead (Pb) in the bismuth salts, or from the materials used in the laid down process of manufacture. 2. Traces of Metallic Impurities These are quite often being introduced by virtue of the unavoidable crucial solvent action upon the metal of construction of the plant in which the desired chemical substance or API is being manufactured commercially. Such diversed and varied substances could be any of these materials: l Glass l Silica l Earthenware l Rubber l Wood l Silver l Lead l Copper l Brass l Cast Iron l Galvanized Iron l Tinned Iron l Steel l Aluminium and a variety of alloys are being used in the construction of chemical plant; and, therefore, probably most of these do provide a viable and apparent source of contamination.* 3. Decomposed Product(s) There are quite a few such substances that undergo decomposition specifically in the presence of air and light thereby resulting into the formation of undesirable impurities, such as: Ether and Chloroform. CHAPTER 1 NOTE: Vegetable drugs, for instance: Opium, Volatile oils, Fats, and Waxes plus other substances may be suitably adulterated in such a manner that can only be detected by certain specially developed techniques. Remarks In short, it would be most appropriate indeed to critically ascertain a justified appreciation of various impurities likely to be found in a pharmaceutical substance. Therefore, it would be an absolute necessity to involve an indepth knowledge of the following cardinal aspects, such as: l processes used in the manufacture, l composition of raw materials employed, l characteristic features of the substances itself,** and l possibility of adulteration with cheaper materials as substitutes. In conclusion, it would certainly be a futile attempt to enlist each of these critical aspects: l possible impurity in each manufactured pharmaceutical substance, and l to trace back the original source of every impurity that has been actually found, keeping in view the fact that both methods of manufacture and purification are being altered constantly. NOTE: Importantly, almost all tests of impurities pertaining to the various pharmaceutical substances are duly mentioned in a number of Pharmacopocias, such as: USP, BP; Eur. P., IP, Jap. P., etc. 2. LIMIT TESTS FOR HEAVY METALS Heavy metals are high molecular weight metal, ions, such as: Lead, Iron, Arsenic, and Mercury. The pharmacopoeia prescribes the limit for heavy metals as indicated in the individual monographs specifically in terms of ppm i.e., the parts of lead, iron, or arsenic, per million parts (by weight) of the substance under examination (or scrutiny). * Evers and Haddock: Quart Jr. of Pharm, 5 : 458, ** That is, specifically its behaviour under normal and abnormal conditions of storage.

3 6 MEDICINAL CHEMISTRY Principles for Fixing the Limits for Impurities In fixing the so-called limits for impurities, certain cardinal principles have been duly postulated and subsequently followed. Following are some of the vital and important criteria for fixing the limits for impurities: l The very first aspect being how much of the impurity is either: v supposed to be harmful, or v cause undesirable results in dispensing. Interestingly, it is not quite necessary and mandatory that either intended for use as a solvent must be of such a high standard of purity as that employed as an anaesthetic; and that the presence of a trace of iron in copper sulphate [CuSO 4 ] fails to render its presence so apparent or objectionable as the same quantum would be in sodium salicylate. l The second aspect relates to the very small limits duly fixed for most substances intended for internal usage. There are certain impurities viz., Arsenic and Lead, which being really so common as well as so dangerous that their limits have got to be fixed very low. NOTE: Interestingly, the other limits may be reasonably generous in comparison. l The third aspect refers to another important criteria with respect to the practicability of manufacturing commercial substances having a specific standard of purity. NOTE: It is, however, pertivent to state here that it would be rather useless to fix such limits that are absolutely unattainable in actual practice, or can only be attained at an exhorbitant and probitive cost (i.e., cost-ineffective product).* l The Overriding Principle The overriding principle states explicitly the following exceptionally uncompromised dictums, namely: v medicinal substances or active pharmaceutical ingredients (APIs) should be completely free from such substances as: Ø dangerous impurities, and Ø objectionable impurities. v medicinal substances or APIs should be of reasonably good commercial grade (or quality). Example: This essentially includes: Official Compounds of Potassium It needs to comply with a stipulated test for sodium. Besides, the presence of NaBr (sodium bromide) in more expensive KBr is not supposed to harm the patient; however, it is extremely important to expect KBr of medicinal quality only to be KBr; and not contaminated with a relatively large quatum of NaBr. Importance of Official Tests In true sense, the designated Official Tests are not intended to guard against every possible impurity, and a substance is not be regarded as of the so-called Pharmacopocial Standard if it is loaded with such impurities that rational considerations would never tolerate (in any case), even if their absence is not provided for the 'Official Tests' (BP, 1963). Perhaps based upon this valid reason, any critical examination of a pharmaceutically active substance with a view to estimating its ultimate purity profile must include such vital aspects as: * However, there are several well-documented evidences of the fact that the standards of purity initially fixed in the Pharmacopoeia were relaxed subsequently, since they were found to be very difficult to accomplish in actual manufacturing practice.

4 PHARMACEUTICAL IMPURITIES 7 l meticulous, l systematic, and l qualitative analysis LIMIT TEST FOR LEAD The limit for the presence of heavy metals is duly indicated as under Sections 2.1, 2.2, and 2.3 respectively in terms of ppm i.e., the parts of lead (Pb) per million parts (by weight) of the pharmaceutical active ingredient (PAI). Indian Pharmacopoeia (2007)* describes four different methods to determine the limit for the presence of heavy metals, namely: Method A: Standard Solution Into a 50 ml Nessler Cylinder pipette 1.0 ml of the lead standard solution (containing 20 ppm Pb) and dilute with water (DW) to 25 ml. Adjust with either dilute acetic acid (CH 3 COOH) or dilute ammonia solution (NH 4 OH) to a ph ranging between 3.0 and 4.0; dilute with water (DW) to nearly 35 ml and mix. Test Solution Into a 50 ml Nessler Cylinder place 25 ml of the solution prepared for the test (as directed in the specific/individual monograph or dissolve the specified quantum of the substance under examination in sufficient water to produce 25 ml). Adjust with dilute acetic acid or dilute ammonia solution to a ph ranging between 3.0 and 4.0, dilute with water to about 35 ml and mix. Procedure To each of the two Nessler Cylinders containing the standard solution and test solution respectively, add 10 ml of the freshly prepared hydrogen sulphide (H 2 S) solution, mix thoroughly, dilute to 50 ml with water (DW), allow to stand for 5 minutes and view vertically downwards against a white background; the colour produced with the test solution is not more intense than that produced with the standard solution. Method B: Standard Solution: Proceed as directed under Method A above. Test Solution Weigh in an appropriate crucible the amount of the substance specified in the individual monograph (IP/BP/USP), add sufficient sulphuric acid to wet the given sample (analyte), ignite carefully at a low temperature until charred completely. Add to the resulting charred mass 2mL of nitric acid and 5 drops of sulphuric acid and heat cautiously until white fumes are no longer evolved, ignite, preferably in a Muffle Furnace, at 500 to 600, until the carbon gets burnt off completely. Cool and add 4 ml of HCl, cover, digest on a water-bath for 15 minutes, uncover, and slowly evaporate to dryness on a water-bath. Moisten the residue with 1 drop of HCl, add 10 ml of hot water (DW) and digest carefully for 2 minutes. Add ammonia solution dropwise until the solution gets just alkaline to litmus paper, dilute to 25 ml with water (DW) and adjust with dilute acetic acid (CH 3 COOH) to a ph between 3.0 and 4.0. Filter, if deemed necessary, rinse the crucible and the filter with 10 ml of water (DW), combine the filtrate and washings in a 50 ml Nessler Cylinder, dilute with water to about 35 ml and mix. Procedure Proceed as directed under Method A above. Method C: Standard Solution Into a 50 ml Nessler Cylinder pipette 1.0 ml of lead standard solution (20 ppm Pb), add 5 ml of dilute sodium hydroxide solution (NaOH), dilute with water (DW) to 50 ml and mix. CHAPTER 1 * Indian Pharmacopoeia. Vol-1, The Indian Pharmacopoeia Commission, Ghaziabad (India), 2007.

5 8 MEDICINAL CHEMISTRY Test Solution Into a 50 ml Nessler Cylinder containing the standard solution and the test solution respectively, add 5 drops of sodium sulphate solution [Na 2 SO 4 ], mix, allow to stand for 5 minutes, and view vertically downwards over a white surface (porcelain tile/white paper), the colour thus produced with the test solution does not appear more intense than that produced with the standard solution. Method D: Standard Solution Into a small Nessler Cylinder pipette 10.0 ml of either: l Lead Standard Solution (1 ppm Pb), or l Lead Standard Solution (2 ppm Pb). Test Solution Prepared the test solution as directed in the individual monograph and pipette 12 ml into a small Nessler Cylinder. Procedure To the Nessler Cylinder containing the standard solution of Pb add 2.0 ml of the test solution and mix thoroughly. To each of the cylinders and 2 ml of acetate buffer ph 3.5, mix, add 1.2 ml of the thioacetamide reagent,* allow to stand for 2 minutes and view vertically downwards against a white surface; the colour produced with test solution is not more intense than that produced with the standard solution LEAD In general, the limit for lead is duly indicated in the individual monograph in terms of ppm i.e., the parts of lead (Pb), per million parts (by weight) of the substance (analyte) under examination. Extraction of lead by Solution of Dithizone The following method describes the method based upon the extraction of lead by solutions of dithizone: l All reagents employed in the test must have as low a content of lead as practicable. l All reagent solutions should be stored only in the containers of borosilicate glass. Besides, each glassware must be rinsed thoroughly with warm dilute nitric acid (6M) followed by water. Method The various steps involved are as stated under: 1. Transfer the exact volume of the prepared sample (as directed in the monograph viz., IP, BP, USP) to a separator. 2. Unless otherwise directed in the monograph, add 6 ml of ammonium citrate solution Sp.** 3. Add 2 drops of phenol red solution and make the solution just alkaline (red in colour) by the addition of strong ammonia solution. 4. Cool the resulting solution (if so required) and add 2 ml of potassium cyanide solution Sp. (Caution). * Thioacetamide Reagent: Add 1 ml of a mixture of 15 ml of 1 M NaOH, 5 ml of water and 20 ml of glycerin (85%) to 0.2 ml of thioacetamide solution, heat in a water-bath for 20 seconds cool and use quickly. ** Ammonium Citrate Solution Sp. (IP, 2007): Dissolve 40 g of citric acid in 90 ml of water, add 2 drops of phenol red solution, and then add slowly strong ammonia solution until the solution acquires a reddish colour. Remove any lead present by extracting the solution with successive quantities, each of 30 ml of dithizone solution until the dithizone solution retains its orange-green colour.

6 PHARMACEUTICAL IMPURITIES 9 5. Immediately extract the solution with several successive quantities each of dithizone extraction solution, draining off each extract into another separating funnel, until the dithizone extraction solution retains the green colour. 6. Shake the combined dithizone solution for 30 seconds with 30 ml of a 1% (v/v) solution of HNO 3 and discard the chloroform layer. 7. Add to the acid solution exactly 5 ml of dithizone standaid solution and shake for 30 seconds; the colour of the chloroform layer is not more intense than that obtained by treating in the same manner a volume of lead standard solution (1 ppm Pb) equivalent to the amount of lead permitted in the substance under examination (or analyte ), instead of the solution under examination IRON The various sequential steps involved in the limit test of iron are as given below: 1. Dissolve the specified quality of the substance under examination in water or prepare a solution as directed in the monograph (IP, BP, USP), and transfer to a Nessler Cylinder. 2. Add 2 ml of a 20% (w/v) solution of iron-free citric acid and 0.1 ml of thioglycollic acid, mix, make alkaline with iron-free ammonia solution, dilute to 50 ml with water and allow to stand for 5 minutes. 3. Any colour thus produced is not more intense than that duly obtained by treating exactly in the same manner 2.0 ml of iron standard solution (20 ppm Fe) instead of the solution under examination (i.e., the analyte sample ) LIMIT TEST FOR ARSENIC Preamble The limit for arsenic is invariably indicated in the respective individual monographs (IP, BP, USP) in terms of ppm (i.e., the parts of arsenic, As, per million parts (by weight) of the substance under examination. CHAPTER 1 NOTE: It is, however, pertinent to state here that all reagents for the limit test for arsenic must have as low a content of arsenic as possible. Apparatus Figure 1.1 depicts the diagrammatic representation of the apparatus used officially for the so-called- Limit Test of Arsenic, wherein all the dimensions are stated in millimeter (mm) only. * As per Indian Pharmacopoeia, Vol. 1, 2007 [All dimensions are in mm.] Fig. 1.1: The Apparatus for Limit Test for Arsenic*

7 10 MEDICINAL CHEMISTRY Description of the Apparatus It essentially includes: 1. The apparatus (Fig. 1.1) comprises a 100 ml conical flask or bottle duly closed with a ground glass stopper via which passes a glass tube (20 cm 5 mm). 2. The lower segment of the glass tube is drawn: v to an internal diameter of 1.0 mm; and v 15 mm from its tip is a lateral orifice 2 to 3 mm in diameter. 3. Importantly, when the tube is in position in the ground glass stopper, the lateral orifice must be at least 3 mm below the surface of the stopper. 4. The upper and of the tube has a perfectly flat surface at right angles to the axis of the tube; whereas, a second glass tube having the same internal diameter (1.0 mm) and 30 mm long, with a flat similar surface, is placed in contact with the first and is duly held in position by two spiral springs (see Fig. 1.1). 5. Into the lower tube insert 50 to 60 mg of lead acetate cotton, packed loosely, or a small plug of cotton and a rolled piece of lead acetate paper weighing between 50 to 60 mg. 6. Just between the flat surfaces of the tubes place a disc or a small square of mercuric chloride paper large enough to cover the orifice of the tube (15 mm 15 mm). Method The various steps involved in this method are: 1. Into the conical flask introduce carefully the test solution prepared as directed in the individual monograph (IP, BP, USP), and add 5 ml of 1 M potassium iodide (KI) and 10 g of zinc AST. 2. Assemble the apparatus immediately and immerse the conical flask in a water bath preset at a temperature so that a uniform evolution of gas* is duly maintained. 3. After 40 minutes any stain produced on the mercuric chloride paper is not more intense than that obtained by treating in the same manner 1.0 ml of arsenic standard solution (10 ppm As) diluted to 50 ml with water. NOTE: In usual practice, some operators also make use of printed colour charts for comparison purposes a procedure which was suggested by Harvey.** 3. LIMIT TEST FOR CHLORIDE AND SULPHATE Limit Test for Chloride: A solution of the analyte (or substance) is duly acidified with nitric acid diluted to a definite volume and finally treated with silver nitrate solution. Thus, the opalescence produced, due to the critical formation of silver chloride (AgCl), is favourably compared with that produced by the addition of silver nitrate solution to a saturated solution containing a definite quantity of hydrochloric acid (HCl). Procedure***: Dissolve the specified quantity of the substance (or analyte sample) under examination in water, or prepare a solution as directed in the individual monograph (IP, BP, USP), and * That is, arsine (AsH 3 ). ** Harvey : Chemist and Druggist, 66 : 168, *** Indian Pharmacopoeia, Vol. 1, The Indian Pharmacopoeia Commission, Ghaziabad (India), 2007.

8 PHARMACEUTICAL IMPURITIES 11 then transfer to a Nessler Cylinder. Add to it 10 ml of dilute nitric acid except when nitric acid is used in the very preparation of the solution, dilute to 50 ml with water and add 1 ml of 0.1 M silver nitrate. Stir immediately with a glass rod and allow to stand for 5 minutes (protected from light). When viewed transversely against a black background any opalescence produced is not more intense than that obtained by treating a mixture of 10.0 ml of chloride standard solution (containing 25 ppm Cl ) and 5 ml of water in the same manner as described above. Limit Test for Sulphate: In this particular instance, a solution of the substance (analyte) is duly acidified with hydrochloric acid (HCl) diluted to volume and treated with barium sulphate [BaSO 4 ] reagent (i.e., a solution of barium chloride, BaCl 2, containing ethanol and a small quantum of potassium sulphate, (K 2 SO 4 ), and the turbidity thus produced (due to the critical formation of barium sulphate, (BaSO 4 ) is duly compared with that produced by addition of the reagent to a standard solution containing a definite (known) quantum of sulphuric acid [H 2 SO 4 ]. CHAPTER 1 NOTE: Importantly, the potassium sulphate enhances the so-called sensitivity of the test by attributing ionic concentrations in the reagent that just exceed the solubility product of barium sulphate [BaSO 4 ]. Besides, the very presence of ethanol helps crucially to check and prevent the phenomenon of super saturation.* Finally, the comparisons of the opalescence produced by the sulphates are made in the Nessler Cylinder of standard dimensions. It is desired that the liquids must be stirred thoroughly and set aside at least for five minutes before making the comparison (between the test sample and standard ), since the complete opalescence (or turbidity) is not developed immediately.** REVIEW QUESTIONS 1. What do you understand by the term Pharmaceutical Impurities? Explain with suitable examples. 2. Write short notes on the following: (a) Limit Tests for Heavy Metals (b) Apparatus for Limit Test for Arsenic 3. Discuss briefly the Limit Test for Chloride and Sulphate. FURTHER READING REFERENCES Soine TO and Wilson CO : Roger s Inorganic Pharmaceutical Chemistry, 8th edn., Lea and Febiger, Philadelphia (USA), Atherden LM : Beuttey and Driver's Textbook of Pharmaceutical Chemistry, 8th edn., Oxford University Press, London (UK), Indian Pharmacopoeia, Vol. 1 : The Indian Pharmacopoeia Commission, Ghaziabad (India), * Atherden LM : Bentley and Driver s Textbook of Pharmaceutical Chemistry, 8th edn., Oxford University Press, London (UK), ** USP makes use of a solution of barium chloride [BaCl 2 ] instead of barium sulphate [BaSO 4 ].

9 12 MEDICINAL CHEMISTRY

10 SECTION-II Chapter 2: Monographs

SPECIFICATIONS & TEST PROCEDURES ASPIRIN USP. Molecular Weight : Reference : USP 39

SPECIFICATIONS & TEST PROCEDURES ASPIRIN USP. Molecular Weight : Reference : USP 39 Page 1 of 18 Molecular Formula : C 9 H 8 O 4 CAS Registry No. : [50 78 2] Molecular Weight : 180.16 Reference : USP 39 Other Names : Benzoic acid, 2 - (acetyloxy) - Salicylic acid acetate, Acetyl salicylic