IMPURITIES IN PHARMACEUTICALS
Chemical compounds manufactured on commercial scale contain different types of impurities, although the proportion of total impurities may be very small. These impurities include the raw materials, dust particles, moisture, etc.
The impurities commonly present in pharmaceutical preparations are of the following types:
(i) Toxic impurities, e.g. lead and asrenic salts.
(ii) Activity depressing impurities, e.g. presence of water in hard soap.
(iii) Impurities due to which the substance becomes incompatible with other substances.
(iv) Impurities causing technical difficulties in the use of the substance; e.g. presence of potassium iodate (KIO3) in potassium iodide (KI) or presence of carbonate in solutions of ammonia.
(v) Impurities due to colouring or flavouring substances, e.g. sodium salicylate is discoloured due to phenolic compounds; sodium chloride becomes damp due to the presence of magnesium salts.
(vi) Impurities due to humidity, e.g. presence of traces of moisture may cause many substances to lose their free flowing qualities or they may be easily oxidizable.
(vii) Impurities which change the physical and chemical properties of the substances and making them unfit for Medicinal Use.
(viii) Impurities decreasing the shelf-life of a compound.
The pharmaceutical preparations should be free from toxic and other impurities. Pharmacopoeias prescribe limits for harmful compounds present in the substances.
In some cases, the impurities may add to the therapeutical value of substances, e.g. presence of traces of copper adds medicinal value of iron preparations which helps in the formation of haemoglobin due to its catalytic action.
SOURCES OF IMPURITIES
Following are the important sources of impurities in pharmaceutical preparations:
1. Raw Materials
Raw materials are usually present in final products as impurities from which the substances are prepared. For example, all sodium compounds may contain traces of chloride which are usually prepared from sodium chloride. In bismuth salts silver copper and lead are present and these materials are used in the process of manufacture of bismuth.
Zinc metal contains arsenic, aluminium, copper, iron. magnesium, manganese and nickel as impurities. If these metals are present in trace amounts in the raw materials, e.g. zinc metal, then these impurities are added during production process in appreciable amounts to the final product like aine sulphate. Copper may contain iron and arsenic as impurities which may be derived to the final products, e.g. copper sulphate
2. Process used in the Manufacture
When a solvent reacts with the metallic container in which the reaction is carried out, traces of metallic impurities are added to the compound. The equipment used in the manufacturing process of drugs is constructed from glass, silica, earthenware, wood. rubber. silver, copper, lead, Iron, steel, alumintum, nickel. tin and different alloys. Most of these metallic substances react with some organic compounds and mineral acids and contaminate the final products. The water and steam pipe may contain lead which is added in the drug. Sulphuric acid is manufactured by lead chamber process and when this acid is used, lead may be added as an impurity.
Tap water is used in different processes. It generally containe chloride, calcium and magnestum which may be added to the final products. Some specific impurities may be due to a particular process used in the manufacturing of some chemical compounds example, potassium lodide is manufactured from lodine which is obtained from a sea weed 'kelf. When nitrogenous for organic matter is burnt with alkalies, cyanides are formed. Therefore, the pharmacopoeia prescribes a limit test for cyanide a potassium lodide.
If reagents used for the production of drugs are not removed completely by washing. they may be present in the final products as impurities. For example, ammoniated mercury is synthesized by reacting mercuric chloride (HgCL,) with ammonia solution. If the precipitated ammoniated mercury is not washed properly to remove ammonium hydroxide, the end-product may contain ammonium hydroxide as impurity. Similarly, calcium carbonate should be washed to remove excess of sodium carbonate and sodium chloride.
Sometimes intermediate products may be added to the final products For example, potassium is synthesized by treating potassium hydroxide with lodine. The resulting mixture is evaporated to dryness and the residue heated with charcoal to yield potassium iodide and carbon monoxide. Sometimes the intermediate products, potassium Sodate, is not completely converted into potassium lodide and may be present in the final product as impurity.
6KOH + 31₂ KIO, + 3C KI + CO
5KI + KIO, + + 2H₂O
Improper concentration of reactants and incomplete reactions may produce compounds containing impurities. For example, if calcium carbonate is not completely reacted with hydrochloric acid during preparation of calcium chloride due to imperfect combination, then any unreacted substance will be in the final product. Similarly, zinc metal is not completely converted into the zinc oxide when it is burnt in the presence of oxygen. Therefore, a small amount of zinc metal may be present in the final product.
Atmospheric impurities, e.g. dust particles containing aluminium oxide, silica glass, porcelain and plastic particles. sulphur dioxide, hydrogen sulphide and black smoke may be added as impurities to the product during manufacturing process. Sodium hydroxide readily absorbs carbon dioxide from the atmosphere producing sodium carbonate.
2NaOH + CO₂ Na, CO + H₂O
3. Impurities Due to Storage Conditions
Storage conditions affect the stability of every drug. If a drag not stored properly. Its deterioration takes place due to which Impurities in the drug are added and all types of properties changed. These changes may affect the therapeutic values of medicament or increase its toxicity. Environmental condition such as temperature, atmospheric gases, moisture contents, light and microorganisms are the worst enemy of drugs. Certal chemical reactions always take place inside the drug molec whether it is in tablet, powder, syrup or liquid form Che reactions tend to take place more rapidly in liquid system tha in the dry state. Therefore, solutions are less stable than suspensions which in turn are less stable than solid donage forms. Most of the drugs have a tendency to deteriorate.
The most common decomposition reactions in medical products are oxidation and phytochemical reactions proceeded by absorption of light by the molecules. Atmospheric oxygen ca initiate oxidation of a medicament even present in low concentration. Such reactions are catalyzed by traces of metala and ultraviolet radiation from light sources. Chloroform, ether volatile oils, fats, vitamin A, vitamin C, vitamin D, and many other organic drugs are deteriorated by the action of oxygen. The photo-oxidation of tablet coatings is particularly important the pharmaceutical industries.
Ferrous sulphate is converted into insoluble ferric oxide by air and moisture. Surgical solution of chlorinated soda rapidly deteriorates when exposed to light and heat. Solution of potassium hydroxide absorbs atmospheric carbon dioxide and exerts a solvent action on lead containing glass. Therefore, it should be preserved in lead-free air-tight bottles of green glass. Ether and chloroform decompose in the presence of air and light.
lodine reacts with rubber corks and some metals. There It should be preserved in glass bottles fitted with glass stoppers. Iodine may contain metals or rubber as impurities with which reacts, Potassium iodide is liquified in the presence of moist al for long time. Similarly, potassium and sodium hydroxides and calcium chloride absorb moisture from the atmosphere.
All chemicals should be stored in well-closed container made of metal or dark glass and extremes of temperatures an avoided, as inorganic are not much effected by ordinary temperatures. Sunlight does not influence many inorganic compounds.
Hydrolysis of drugs with water vapour is an important in the pharmaceutical industry. Aspirin, diazepam. digoxin, laevodopa, chloral hydrate, etc. are hydrolyzed forming action different undesirable products. Penicillins are very sensitive to moisture contents.
4. Impurities due to Crystal Packing
In solids the reactions are very sensitive to crystal packing. In drugs such as oxyphenarisine, cephalosphorin and tetracycline the crystallization effect is very important. Polymorphic transformations can also affect the properties of creams. If the wrong polymorph is used, a phase transformation can occur. resulting in crystal growth of the new phase. The creams then become gritty and cosmetically unacceptable. A large number of compounds crystallize with solvent of crystallization. Crystals of many drugs effervesce and rapidly dehydrate at room temperature. The loss of solvent of crystallization can change the dissolution rate, bioavailability and stability of crystals of pharmaceuticals
There is now a growing concern and emphasis regarding the chiral purity of drugs. For any new drug which exists in racemic form, the manufacturer needs to establish the stereogeometry of the molecule and optical purity apart from pharmacological and toxicological data for each isomer as well as the racemate. The development of a single enantiomeric product is required today as it normally has toxicity. greater effectiveness at lower doses and at times may be more cost effective. However, if racemates are to be marketed, sufficient justification needs to be provided.
In case a bulk drug exhibits polymorphism, then it is essential to identify and establish the difference in the behaviour of different polymorphic forms, which otherwise may drastically effect physical appearance and bioavailability pattern of a dosage form. Similarly, for a generic drug, it should be therapeutically equivalent in terms of potency, stability, safety and bioavailability to that of the innovator's product.
5. Accidental Substitution or Deliberate Adulteration
Accidental substitution can be prevented by storing toxic substances separately. Deliberate adulteration by cheaper. spurious, inferior, defective or harmful substances is a common practice in case of scarcity or when the price of a drug is high.Sometimes foreign matters are added which are cheap comparison with the drug.
All the tests of impurities of drugs are mentioned in pharmacopoeia. For chiorktes, sulphates, Iron, arsenic and lead, general quantitative and limit tests are given with necessary variations. For other impurities special quantitative are prescribed. In determining limits for impurities, certain principles are adopted. The harmful quantity of the impurity is to be known. Arsenic and lead are very common and dangerous and very small limits have to be fixed for their presence in all the compounds intended for internal use. Potassium bromide my be adulterated with cheaper Sodium bromide. Potassium salts are more expensive than their respective sodium salts.
Medicinal substances should be free from dangerous and undesirable impurities. There may be some impurities for which official tests are given.
