Unit I Sources of Impurities in Medicinal Agents

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Sources of Impurities in Medicinal Agents:

IMPURITY
• A compound is said to be impure if it is having foreign matter.Pure chemical compound refer to
that compound which is having no foreign matter i.e., impurities.
• Purification of chemicals is an expensive process, substances should not be purified more than
required as it brings about waste of time, material and money.
• Sugarcane, dextrose, inorganic salts 99% purity while many other only are having traces of
impurity.
• Pure Relative term Pharmacopoeia of India and BP has been prescribed test for purity.
Impurities commonly found in Medicinal preparations:
1. Activity depressing impurities.
2. Due to colouring or flavouring substances, e.g., Sodium Salicylate.
3. Humidity.
4. Decrease shelf life.
5. Physical and chemical properties.
6. Impurities due to which substances become incompatible.

SOURCES OF IMPURITIES

1. Raw Materials Employed in the Manufacturing of the Pharmaceutical Substance:

Pharmaceutical substances are either isolated from natural sources or synthesized from chemical
starting materials. The natural sources include mineral sources, plants, animals and microbes. It is
essential to verify the identity of the source material and to establish its quality otherwise impurities
associated with the raw materials may be carried through the manufacturing process to contaminate
the final product. In nature minerals rarely occurs in a reasonably pure from. Almost always
mixtures of closely related substances occur together e.g., aluminum ores are usually accompanied
by alkali and alkaline earth compounds, barium and magnesium impurities are found in calcium
minerals, zinc accompanies magnesium or iron compounds, lead and heavy metals are found as
impurities in many sulphide ores, among the acid radicals or anions, bromides and iodides are often
found as impurities in chlorides, bismuth salts contains silver copper and lead as impurities.
Rock salt used for the preparation of sodium chloride is contaminated with small amounts of
calcium and magnesium chlorides, so that sodium chloride prepared from rock salt will definitely
contain traces of calcium and magnesium compounds impurities.
2. Method of Manufacture: The process or method of manufacture may introduce new impurities
into the final product arising due to contamination by reagents, catalysts and solvents employed at
various stages of the manufacturing process. The new impurities may also arise from the reaction
vessels and reaction intermediates.
3. Reagents employed in the manufacturing process: Calcium carbonate contains ‘soluble alkali’
as impurity which arises from the sodium carbonate (Na2CO3) employed in the process. Calcium
carbonate is prepared by the interaction of a soluble calcium salt with a soluble carbonate.
Therefore, the final product (CaCO3) is liable to contain small amount of ‘soluble alkali’ as
impurities which were not removed by the washing process.
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4. Regents used to eliminate other impurities: Barium is used in the preparation of potassium
bromide to remove sulphate which in turn arise form the bromine used in the process. It is likely
that potassium bromide will now be contaminated by traces of barium.
5. Solvents: Most of the pharmaceutical substances are prepared in solvated crystalline form. Small
amounts of solvents employed in preparation, and purification of reaction intermediates or the final
product may also result in the contamination of the pharmaceutical substances. Water is the
cheapest solvent available and is used quite frequently in the preparation of inorganic
pharmaceuticals. Water can be the major source of impurities as different types of water containing
different types and amount of impurities are available. Various types of water which are available
are
(i) Tap water: Containing impurities of Ca2+, Mg2+, Na+, Cl– , CO3–2 and SO4–2 in trace amounts.
The use of tap water on large scale will lead to the contamination of the final product with these
impurities because the impurities will remain in the product even after washings.
(ii) Softened water: It is almost free from divalent cations (Ca2+, Mg2+ ) but contains more of Na+
and Cl– ions as impurities because of the usual chemical water softening process. Therefore, the
final products obtained using softened water as solvent will not have Ca2+ and Mg2+ impurities but
still contain Na+ and Cl– impurities.
(iii) Demineralized water: It is prepared by means of ion-exchange and is free from Na+, Ca2+,
Mg2+, Cl– , SO4 –2 and CO–2 etc. It may have pyrogens, bacterias and organic impurities. So, it is a
better solvent than tap water or softened water but the economic factors discourage its use on large
scale.
(iv) Distilled water: It is free from all organic and inorganic impurities and is therefore the best as a
solvent but it is quite expensive. As it is free from all impurities, it does not pass on any impurities
to the final products.
6. Reaction vessels: The reaction vessels employed in the manufacturing process may be metallic
such as copper, iron, cast iron, galvanized iron, silver, aluminium, nickel, zinc and lead. Glass and
silica are also used in the construction of the chemical plants but these days many of these are
replaced by stainless steel and variety of other alloys. Some solvents and reagents employed in the
process may react with the metals of reaction vessels, leading to their corrosion and passing traces
of metal impurities into the solution, contaminating the final product. Similarly, glass vessels may
give traces of alkali to the solvent. Lead (Pb) may be found as impurity in commercial sulphuric
acid which has been manufactured by lead chamber process. Also, substances prepared by same
electrolytic process, may contain electrode material as an undesirable impurity e.g., antimony,
bismuth etc.
7. Intermediates: Sometimes, an intermediate substance produced during the manufacturing
process may contaminate the final product e.g., Sodium bromide is prepared by reaction of sodium
hydroxide and bromine in slight excess.
6NaOH + 3Br2 → NaBrO3 + 5NaBr + 3H2O
The sodium bromate an intermediate product is reduced to sodium bromide by heating the residue
(obtained by evapourating the solution to dryness) with charcoal.
NaBrO3 + 3C → NaBr + 3CO
Sodium bromate Sodium bromide
If sodium bromate is not completely converted to the sodium bromide then it is likely to be present
as an impurity
8. Atmospheric contamination during the manufacturing process:Atmosphere may contain dust
aluminum oxide, sulphur, silica, soot etc.) and some gases like carbon dioxide, sulphur dioxide,
arsine and hydrogen sulphide. These may contaminate the final product during the manufacturing
process. Some substances which are susceptible to action by atmospheric carbon dioxide and water
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may get contaminated with them during their preparation e.g., sodium hydroxide readily absorbs
atmospheric carbon dioxide when exposed to atmosphere.
2NaOH + CO2 → Na2CO3 + H2O
Calcium hydroxide solutions can absorb carbon dioxide from the atmosphere to form calcium
carbonate.
Ca(OH)2 + CO2 → CaCO3 + H2O
9. Manufacturing hazards: If the manufacturer is able to control and check impurities from the all
above mentioned sources there exists certain manufacturing hazards which can lead to product
contamination. The various manufacturing hazards can lead to:
(i) Contamination from the particulate matter: The unwanted particulate matter can arise by a
number of ways, such as accidental inclusion of dirt or glass, porcelain, plastic or metallic
fragments from sieves, granulating, tabletting and filling machines and the product container. The
particulate contamination mainly arises from the wear and tear of the equipments. It may also arise
from the bulk materials used in the formulation or from dirty or improperly maintained equipments
e.g., metal particles found in eye ointments packed in metal tubes made up of tin and aluminium.
(ii) Cross-contamination of the product: This manufacturing hazard has to be considered in the
preparation of solid dosage forms. Cross-contamination of product can occur by air-born dust
arising out of handling of powders, granules and tablets in bulk. Cross-contamination is dangerous
particularly in case of steroidal and other synthetic hormones and therefore, it should be carefully
controlled. Precautions, such as use of face mask and special extraction equipment can minimize
these undesirable contaminations.
(iii) Contamination by microbes: Many products, like liquid preparations and creams intended for
topical applications are liable to contamination by microbes from the atmosphere during
manufacturing. For all products intended for parenteral administration and ophthalmic preparations,
sterility testing is done and it provides an adequate control for microbial contaminations in such
preparations. Microbial contamination can be controlled by adding suitable antimicrobial and
antifungal agents.
(iv) Errors in the manufacturing process: Sometimes in a liquid preparation, there is incomplete
solution of the solute. This ought to be detected by the normal analytical methods as it can lead to
major error. A proper check on the efficiency of mixing, filling, tabletting, sterilization etc. should
be exercised in order to obtain a product of maximum purity and desired quality. Special
precautions are required to be observed to avoid mixing and filling errors in the preparation of low
dosage forms (e ú 5 mg) such as tablets and capsules containing highly potent medicaments.
(v) Errors in the packaging: Similar looking products, such as tablets of the same size, shape and
colour, packed in similar containers can result in mislabeling of either or both of the products.
Adequate care should be taken to avoid the handling of such products in the close proximity.
10. Instability of the Product :
(A) Chemical instability: Impurities can also arise during storage because of chemical instability
of the pharmaceutical substance. Many pharmaceutically important substances undergo chemical
decomposition when storage conditions are inadequate. This chemical decomposition is often
catalyzed by light, traces of acid or alkali, traces of metallic impurities, air oxidation, carbon
dioxide and water vapours. The nature of the decomposition can easily be predicted from the
knowledge of chemical properties of the substance. All such decompositions can be minimized or
avoided by using proper storage procedures and conditions. The photosensitive substances should
be protected from light by storing them in darkened glass or metal containers thereby inhibiting
photochemical decomposition. Materials susceptible to oxidation by air or attack by moisture
should be stored in sealed containers and if necessary the air from the containers can be displaced
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by an inert gas such as Nitrogen. Oxidation can also be prevented by adding suitable antioxidants
which are capable of undergoing oxidation at the expense of the substances.
(B) Changes in physical properties: Pharmaceuticals may undergo changes in physical properties
during storage. There can be changes in crystal size and shape, sedimentation, agglomeration and
caking of the suspended particles. These physical changes are not always avoidable and may result
in significant changes in the physical appearance, pharmaceutical and therapeutic effects of the
product. Particle size and consequently surface area is a critical factor in determining the
bioavailability of the low solubility drug such as griseofulvin. Physical changes such as
sedimentation and claying in case of multidose suspension may constitute a safety hazard leading to
the possibility of under dosage and later to overdosage of the drugs. Similarly increase in the
globule size of the injectable emulsions on storage may lead to fat embolism.
(C) Reaction with container material: The possibility of reaction between the container material
and the contents cannot be ruled out as it constituents a safety hazard. Preparations susceptible to
reaction with metal surfaces e.g., salicylic acid ointment must not be packed in metal tubes.
Solutions of substances which are alkali-sensitive e.g., atropine sulphate injection must be packed in
glass ampoules which comply with the test of hydrolytic resistance therefore such preparations must
not be packed in containers made from soda glass. Plastic containers and closures must be carefully
evaluated because of their tendency to give undesirable additives, such as plasticizers, particularly
in the presence of non-aqueous solvents. Plastic containers intended for injectables should be
sufficiently translucent to allow visual inspection of the contents and if they are having higher than
500 ml capacity, they must also comply with the test limiting animal toxicity in the cat, ether-
soluble extractive and metal additives with special reference to barium and heavy metals like lead,
tin and cadmium. Rubber closures are more susceptible to absorb medicaments, antioxidants and
bactericides from solution, unless they are appropriately pretreated by immersion in solutions of the
concerned compounds.
(D) Temperature: The rate of chemical decomposition and physical changes of stored products
depends upon the temperature. The susceptible substances may have temperature storage
requirements assigned to them in order to protect them against undesirable decomposition.