IMPURITIES IN PHARMACEUTICALS SUBSTANCES

IMPURITIES IN PHARMACEUTICALS SUBSTANCES AND LIMIT TEST

IMPURE COMPOUND

·         A compound is said to be impure if it is having foreign matter i.e. Impurities. Pure Chemical Compound

PURE COMPOUND

·         The chemical compound which is having no any foreign matter (impurities) is said to be pure compound.

·         In case of safety and efficacy, the pharmaceutical substances are must be pure.

·         Analytically 100% pure substances are not available and trace of impurities must be present.

·         The purity of substances has been dependent upon several factors like: manufacturer and types of crystallization or purification process.

IMPURITIES

·         Any material (or undesirable particles), that affect the purity of the material called impurities.

·         The pharmaceutical substances may produce toxic effects, on the body and may also lower down the active strength of the pharmaceutical substance.

·         Impurities commonly in chemical substances include small quantities of lead, arsenic, iron, chloride, and sulphate etc.

IMPURITIES COMMONLY FOUND IN MEDICINAL PREPARATIONS

·         Impurities which have toxic effects on body and bring about unpleasant reactions when present beyond certain limits. 

o    E.g. Lead and Arsenic salts.

·         The impurities which are able to make substance incompatible with other substances.

·         The impurities which if present beyond the limit, affect the storage property of the pharmaceuticals.

·         The impurities which are harmless, but if present beyond the limit, it will lower the active strength of the medicinal compound.

o    E.g. Sodium salt in potassium salt. 

·         The impurities which may bring about technical difficulties in the use of the substance.

·         Impurities such as taste, odor, color or appearance which can be easily detected by the senses and make the substance unhygienic and unaesthetic.

o    E.g. Sodium salicylate is discolored due to present of phenolic impurities.

o    Sodium chloride becomes damp because the presence of trace of magnesium salts.

SOURCES OF IMPURITIES IN PHARMACEUTICALS

1.       Raw material used in manufacture

2.       Reagents used in manufacturing process

3.       Method/ process used in manufacture or method of manufacturing

4.       Chemical processes used in the manufacture

5.       Atmospheric contamination during the manufacturing process

6.       Intermediate products in the manufacturing process

7.       Defects in the manufacturing process

8.       Manufacturing hazards

9.       Inadequate Storage conditions

10.    Decomposition of the product during storage

11.    Accidental substitution or deliberate adulteration with spurious or useless materials

1) RAW MATERIALS EMPLOYED IN MANUFACTURE:

·         Impurities known to be associated with these chemicals may be carried through the manufacturing process and contaminate the final product.

·         Example:

o    ROCK SALT: CaSO₄ + MgCl₂ = NaCl

o    Rock salt contains small amount of CaSO₄ and MgCl₂. Thus NaCl prepared from this source will contain trace of Calcium and magnesium compounds.

·         Impurities such as Arsenic, lead and heavy metals are present in raw materials and hence are found in substances.

o    Copper sulphate may be prepared by the action of H₂SO₄ copper turning.

o    Cu + 2H₂SO₄ + 2H₂O + SO₂

o    Copper turning are known to have Iron and Arsenic as impurities. If large quantities of impurities are present in the raw material (eg. Copper turning), they may enter the final product.

o    I.P. prescribes limit of tolerance for Arsenic as impurity to be not more than 8 parts per million in copper sulphate. Similarly it prescribes a limit of Iron as impurity.

2. REAGENTS USED IN THE MANUFACTURING PROCESS:

·         If reagents used in the manufacturing process are not completely removed by WASHING, these may find entry into the final products.

·         Example: Ammoniated mercury may be prepared by adding a solution of mercuric chloride to dilute ammonia solution.

o    HgCl₂ (Soluble) + 2 NH₄OH ((Soluble)) → NH₄HgCl (Ammoniated mercury –ppt.) + NH₄Cl (Soluble) + 2H₂O

·         The precipitate of Ammoniated mercury (Final Product) contains ammonium hydroxide. Thus, this precipitate is washed with cold water to remove ammonium hydroxide.

·         If it is not removed completely by washing with water, the final product may contain in it Ammonium hydroxide as impurity.

3. METHOD OR THE PROCESS USED IN THE MANUFACTURE:

·         Many drugs and chemicals (usually organic) are manufactured from different raw materials, by using different methods or processes.

·         Some impurities are incorporated into the materials during the manufacturing process.

·         The type and amount of impurity present in the drug/ chemical varies. 

·         In certain drugs, a multiple-step-synthesis procedure is used, which produces intermediate compounds.

·         The purification of intermediates is also important; otherwise the impurities present in the intermediate will get incorporated in the final product.

·         Usually side reactions occur during the synthesis.

·         Impurities of the product side reactions also occur in the substances. This may introduce new impurities due to contamination by reagents and solvents at various stages of the process as follows:

o    Reagents employed in the process

o    Reagents added to remove other impurities

o    Solvents

o    Action of solvents and reagents on reaction vessels.

A) REAGENTS EMPLOYED IN THE MANUFACTURING PROCESS:

·         Soluble alkali in Calcium carbonate arises from sodium carbonate used in the process.

·         Calcium carbonate is obtained by interaction of a soluble calcium salt and a soluble carbonate and therefore the product will contain traces of soluble alkali, which the washing process has failed to remove.

B) REAGENTS ADDED TO REMOVE OTHER IMPURITIES:

·         Potassium bromide contains traces of Barium, which is added in the manufacturing process to remove excess of sulphate.

C) SOLVENTS:

·         Tap Water: It has Ca⁺², Mg⁺², Na+, Cl^–, SO₄ ^-2 and CO₃ ^-2 as impurities in small amounts.

·         Softened water: It is obtained by allowing the tap water to pass through the sodium form of Zeolite which removes divalent cations like Ca⁺² and Mg⁺² from tap water in exchange of sodium. So, softened water contains Na⁺, Cl^– ions as impurity.

·         Demineralised: water it is obtained by passing tap water through columns packed with ion exchange resin. The water obtained from this process is free from Ca⁺², Mg⁺², Na⁺, Cl^–, SO₄ ^-2 and CO₃ ^-2 Thus the final product is free from these impurities. The water obtained from this source may still contain organic impurities and so final product contains organic impurities.

·         Distilled water: It is considered the best but it is very costly.

D) ACTION OF SOLVENTS AND REAGENTS ON REACTION VESSELS:

·         During manufacturing process, some of the solvents and reagent may undergo reaction with metals of reaction vessel and may dissolve these metals, which appear as impurities in the final product.

o    Example: Iron is known to contain Arsenic impurity.

o    The inorganic compounds manufactured in Iron vessel will contain Arsenic and Iron as impurities.

o    Thus IP has prescribed limit test for Arsenic and Iron for most inorganic compounds.

4) CHEMICAL PROCESS USED IN THE MANUFACTURE

·         For the synthesis of drugs, many chemical reactions such as Nitration, Halogenation, Oxidation, reduction, hydrolysis are involved.

·         In these chemical processes, different chemicals are used.

·         Tap water is generally used in the various processes and it is often having Cl^–, Mg⁺², Ca⁺² ions, which are generally found in the substance which is being manufactured.

5) ATMOSPHERIC CONTAMINATION DURING THE MANUFACTURING PROCESS

·         In the industrial areas, the atmosphere is contaminated with dust particles and some gases like Hydrogen sulphide, Sulphur dioxide, and black smoke.

·         During the manufacture or purification of the pharmaceutical products, these impurities enter the final products.

·         There are many pharmaceutical products which when manufactured are contaminated with atmospheric CO₂ and water vapour. E.g NaOH absorbs atmospheric CO₂.

·         Example:

o    2NaOH + CO₂ → Na₂CO₃ + H₂O

o    Due to this reaction, NaOH should not be kept open for a longer time during its manufacturing.

o    Therefore, I.P. has prescribed that NaOH should not contain more than 3% Na₂CO₃.

6) DEFECTS IN THE MANUFACTURING PROCESS

·         In many manufacturing processes, there are defects like imperfect mixing, incompleteness, non-adherence to proper temperature, pressure, pH or reaction conditions, which may give chemical compounds with impurities in them.

·         Example:

o    Zinc oxide may be prepared by heating metallic zinc to bright redness in a current of air. The vapours of Zinc burn to form Zinc oxide which is collected as a fine white powder.

o    But if there is less heat or air or both, zinc metal is not completely converted to zinc oxide.

o    Thus the final product, Zinc oxide may still contain metallic zinc as impurity.

o    So, IP has prescribed a test for Zinc metal in zinc oxide.

7) INTERMEDIATE PRODUCTS IN THE MANUFACTURING PROCESS

·         There are some intermediates which are produced during the manufacturing process. Sometimes these intermediates may be carried through to the final product as impurity.

·         Example:

o    Potassium iodide is prepared by reacting Iodine with Potassium hydroxide.

o    6KOH + 3I₂ → 5KI + KIO₃ + 3H₂O

·         The resulting solution is first evaporated and then heated with charcoal.

o    KIO₃ + 3C → KI + 3CO

·         In this presence, if the intermediate product (KIO₃) is not completely converted into KI, then it may be carried through to the final product as an impurity.

8) MANUFACTURING HAZARDS

a)       Particulate contamination

b)       Process error

c)       Cross contamination

d)       Microbial contamination

e)       Packing error.

A) PARTICULATE CONTAMINATION

·         The presence of unwanted particulate matter can arise due to dirt, dust, glass, porcelain or plastic fragments from sieves, granulating or tableting machines or from product containers.

·         Ware and tare of equipment or improperly cleaned equipment may also cause particulate contamination.

·         Clarity of solutions for injection is particularly important.

·         E.g Metal particles which have been found in eye ointments packed in metal tubes.

B) PROCESS ERROR

·         Gross errors arising from incomplete solution of a solute in a liquid preparation must be detected readily by the normal analytical control procedures.

C) CROSS CONTAMINATION

·         The handling of powders, granules, and tablets in large bulk creates air-borne dust, which leads to cross contamination of the product.

·         So, face masks and special extraction equipment are used to protect operators from harmful effects of drugs.

·         E.g penicillin preparation requires special handling during its manufacture. 

D) MICROBIAL CONTAMINATION

·         Parenteral preparations and ophthalmic preparations require special care against microbial contamination.

·         Many liquid preparations and creams are liable to bacterial and fungal contamination. So care should be taken.

·         Eg. Acacia, senna, tragacanth—They should be controlled for Salmonellae.

E) PACKING ERRORS:

·         Products of similar appearance such as tablets of same size, shape, colour packed in similar containers can constitute a potential source of danger.

·         Improper labeling or destruction of stock of unused labels also constitutes a major packaging hazard. 

9) STORAGE CONDITION

·         The chemical substances when prepared have to be stored in different types of containers depending upon its nature, batch size, quantity etc.

·         Many types of materials are used for storage purpose like plastic, polyethylene, Iron vessel, stainless steel, aluminum etc.

·         Leaching out effect: Alkalies stored in ordinary glass containers; extract lead from it, which in found as impurity in the final product.

INADEQUATE STORAGE AND THEIR EFFECTS ARE AS FOLLOWS:

a)       Filth (Dirt): Stored products may become contaminated with dust, bodies of insects, animal and insect excreta.

b)       Chemical instability: decomposition because of light, traces of acid or alkali, air oxidation, water vapour, CO₂ and traces of metallic ions. e.g. light sensitive materials should be stored in amber colored bottles.

c)       Reactions with container materials: e.g. salicylic acid ointment must not be stored in metal tubes.

d)       Physical changes: The occurance of changes in the physical form of drug like change in crystal size can lead to change in efficiency of product.

e)       Temperature effect: Chemical and physical changes occur if materials are not stored at proper temperature.

10) DECOMPOSITION OF PRODUCT DURING STORAGE

·         Some substances decompose on storing due to presence of air, light and oxygen. So, the final product is contaminated.

·         Deliquescent substances absorb water from the atmosphere and get liquefied.

·         Decomposition products appear as impurities in the substances.

11) ACCIDENTAL SUBSTITUTION OR DELIBERATE ADULTERATION WITH SPURIOUS OR USELESS MATERIALS:

·         It is possible to avoid accidental substitution by storing the toxic substances together separately or in a locked cupboard.

·         Many pharmaceutical chemicals are adulterated with cheaper substances.

·         E.g The expensive potassium may be adulterated with sodium bromide.