1. Chemical Impurities

2. Impurities are substances inside a confined amount of liquid, gas, or solid,which differ from the chemical composition of the material or compound. Impurities are either naturally occurring or added during synthesis of a chemical or commercial product. During production, impurities may be purposely, accidentally, inevitably, or incidentally added into the substance.

3. The levels of impurities in a material are generally defined in relative terms. Standards have been established by various organizations that attempt to define the permitted levels of various impurities in a manufactured product.

4. Chemical purity of Pharmaceutical Products Modern medicines for human use are required to meet exacting standards which relate to their quality, safety and efficacy. Chemical purity may be described as complete freedom from foreign matter. A state of absolute purity is virtually unattainable, but may be approached as closely as desired.

5. The sources of impurities in pharmaceutical chemicals 1.Raw materials API Excipients 2. The manufacturing process From the environment From the machine and apparatus From the personnel

6. The majority of modern pharmaceutical chemicals are prepared by organic synthesis from starting materials which are, themselves, either synthetic organic chemicals or natural products isolated from biological sources. The process itself may, therefore, introduce impurities into the final product. These may arise from the following: (a) The starting material and its impurities (b) intermediates (c) Reagents, and catalysts used in the process

7. 3. Chemical instability A number of pharmaceutically important substances are known to undergo chemical decomposition when stored under non-ideal conditions. The nature of the decomposition, which is often catalyzed by light, traces of acid or alkali, air oxidation, water vapor, carbon dioxide and traces of metallic ions, can frequently be predicted from a knowledge of the chemical properties of the substance. Elixir and Syrup provides a typical example of oxidative decomposition with loss of potency which can occur under inadequate storage conditions.

8. Reaction with container materials Creams and ointments liable to react with metal surfaces, e.g. Salicylic Acid Ointment, must not be packed in metal tubes unless they have been lacquered internally to inhibit reaction. Atropine Sulphate Injection, which is sterilised by autoclaving, must be packed in glass ampoules which comply with the test for hydrolytic resistance of the European Pharmacopoeia (chemical resistance USP). All glass containers for injectable preparations must comply with the test for hydrolytic resistance. Aqueous injectable solutions must be packed in containers consisting of glass of either Type I or Type II. Type III glass may be used for non-aqueous solutions or oral liquid dosage form which are stable in this standard of glass. Plastic containers and closures require careful evaluation because of the tendency to yield undesirable additives, such as plasticizers.

9. Manufacturing hazards Considerable attention to the design of buildings and manufacturing areas, cleanliness and production procedures is also essential if the highest standards are to be achieved. Particulate contamination The presence of unwanted particulate matter can arise in a number of ways. These include accidental inclusion of atmospheric pollutants, such as aluminium oxide, silica, sulphur. Metallic and plastic fragments from sieves, granulating, tableting and filling machines, or even from product containers. Clarity of solution for injections is particularly important.

10. Cross-contamination The handling of powders, granules and tablets in large bulk frequently creates a considerable amount of air-borne dust, which, if not controlled, can lead to cross- contamination of products. Area segregation, air flow control, vacuum system in the machines and production area and proper design of HVAC (Heating ventilation and air conditioning system) can reduce this incidence. Precautions, such as the use of face-masks and special extraction equipment, used to protect operators from undesirable effects of certain drugs of this type, are also suitable for more general use to limit cross-contamination.

11. Microbial contamination The pharmacopoeial requirement of sterility tests for all products intended for parenteral administration and ophthalmic preparations, provides an adequate level of control for such preparations. They can be prepared by end- sterilisation processes or can be produced under aseptic conditions.

12. Standardisation of pharmaceutical chemicals and formulated products Two types of specification are used to control the quality of pharmaceutical products: (a) Manufacturing product license standards, (b) Pharmacopoeia standards.

13. Identification The purpose of identification tests is to provide means of ensuring that materials have been correctly labelled. Identification is usually achieved by a combination of simple chemical tests and measurement of appropriate physical constants. 1. Infrared (IR) absorption spectroscopy: Because of the high structural specificity, this technique now forms the basis of most identification procedures. 2. Thin-layer chromatography : it can be used for identification. 3. Nuclear Magnetic Resonance (NMR) : In a very few special cases, where complete characterization by such physical tests is either inadequate or inappropriate, this technique can be followed. 4. High pressure liquid chromatography (HPLC) : It is one of the convenient and reliable tools for both identification and quantification.

14. Measurement of physical constants Melting point Melting point sometimes changes if the contaminants are beyond limit. Solubility Density Specific gravity Relative density Refractive index These constants are widely used as standards for liquids, including fixed oils (Arachis Oil; Peanut Oil).

15. Moisture, volatile matter and residual solvents Many substances absorb moisture on storage. Deterioration of this nature is readily limited by a requirement for the loss in weight (loss on drying) when the substance is dried under specified conditions. The temperature must be sufficiently high to produce the required result within a reasonable time, but not so high as to cause decomposition. If the substance is stable the test is usually applied by drying to constant weight at 105° C as with Ethynodiol Diacetate and Sodium Benzoate. Special modifications are adopted for thermolabile substances: in the case of Hyoscine Hydro bromide the sample is first dried at room temperature in vacuum for one hour. and then heated to constant weight at 105°C presumably because it is unstable only in the presence of moisture. Vacuum drying at various suitable temperatures is used for hydrated salts, such as Tubocurarine Chloride.

16. The following example illustrates the calculations involved in utilising the figures for moisture content in conjunction with the assay figures.

17. Heavy metals Contamination by lead and other heavy metals is most effectively controlled by precipitation of their relatively insoluble and characteristically coloured suiphides (Cd, yellow; Hg, black; Pb, brown), which occurs readily when aqueous solutions are treated with hydrogen suiphide or alkali metal sulphides (NaSH). The stability of metal suiphides to acid varies considerably with acid strength. Table shows how the precipitalion of heavy metal sulphides is affected by mineral acid, acetic acid, dilute ammonia and by potassium cyanide which forms stable water-soluble complexes unaffected by the precipitating agent (H 2 S or NaSH) with the majority of heavy metals.

18. Ammonium salts Ammonia is used in the preparation of a number of official substances and these may, therefore, be contaminated by ammonium The standard test as applied to Borax and Alum is based on a of the yellow colour produced by alkaline potassium mercuri-iodide that formed by an Ammonium Standard Solution (1 ppm NH 3 ). substances such as Dried Aluminium Hydroxide which may heavily contaminated are treated quantitatively using the distillation method. Aluminium Aluminium can accumulate and reach toxic levels as a result of treatments with aluminium-containing materials. This is probably Haemodialysis Solutions, and stringent limits are imposed solutions to control impurity at levels not exceeding 15 ppm. methods of analysis are not sufficiently sensitive, and control is adding 8-hydroquinoline and measuring the fluorescence of aluminium complex. Arsenic The test is a modification of the Gutzeit test in which all arsenic is converted into arsine (AsH 3 ) by reduction with zinc and hydrochloric acid. Reaction of the issuing gases with mercuric bromide paper produces a yellow stain, which can be compared with that produced from a known amount of arsenic.

19. Limit test for non metallic impurities include Boron: Compounds of Boron is capable of causing unwanted skin reactions and is toxic to nervous tissue and muscle is rigorously limited in compounds such as salbutamol. It is determined colorimetrically. Free halogens: Some products containing organic iodo compounds are liable to release free iodine. This is controlled in Iophendylate compounds. Control of Organic impurities Physical method Solubiluity pH of solution Thin layer chromatography Gas liquid chromatography Electrophiresis Chemical method: Aldehyde, ketone sugar Free bases in neutral compound Methanol in solvent ether Contamination of organic halogen Contamination by peroxided Alkalods, glycoside and synthetic compound