IMPURITIES
Ø Chemically a
compound is impure if it contains undesirable foreign matter i.e. impurities.
Thus chemical purity is freedom from foreign matter.
Ø Impurities are foreign substances, which are
introduced by contamination, adulteration or any other process during the
synthesis or preparation of pharmaceutical substances.
Ø Impurities may be Foreign Substances (Extraneous
Contaminants), Inorganic impurities (can result from the manufacturing
process), Process Contaminants (reagents, catalysts, heavy metals, chloride, or
sulfate may be introduced during manufacturing or handling procedures), Related
Substances (structurally related to a drug substance), Residual Solvents,
Specified Degradation Products, Toxic Impurities(significant undesirable
biological activity).
Sources
of Impurities in
pharmacopoeial substances
A
list of impurities which may be present in a given pharmaceutical substance can
be easily compiled from the knowledge of the raw materials employed, the
manufacturing process and stability of the final product. Impurities may also
arise from physical contamination and improper storage conditions.
The
various sources of impurities in pharmaceutical substances are as follows:
1.
Raw materials employed in the manufacturing of the pharmaceutical substance:
Ø Pharmaceutical
substances are either isolated from natural sources or synthesized from
chemical starting materials.
Ø The natural sources include mineral sources,
plants, animals and microbes. It is essential to verify the source material and
to establish its quality otherwise impurities with the raw materials may be
carried through the manufacturing process to contaminate the final product.
Ø For e.g., aluminum is usually accompanied by
alkali and alkaline earth compounds, barium and magnesium impurities are found
in calcium minerals, lead and heavy metals are found as impurities in many
sulphide.
Ø 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:
Ø The Process or
method of manufacture may introduce new impurities into the final product due
to contamination by reagents, catalysts and solvents.employed at various stages
of the manufacturing process.
Ø The new
impurities may also arise from the reaction vessels and reaction intermediates.
(A)Reagents employed in the manufacturing
process:
Ø
Calcium
carbonate is prepared by the interaction of a soluble calcium salt with a
soluble sodium carbonate. Therefore, the final product (CaCO3)
contains small amount of soluble alkali as impurities which were not removed by
the washing process.
CaCl2 +
Na2CO3 → CaCO3 ↓ + 2 NaCl
Soluble Soluble Precipitate Soluble
Ø Anions like Cl- and SO4-2 are
common impurities in many substances because of the use of hydrochloric acid
and sulphuric acid respectively in processing.
(B)
Regents used to eliminate other impurities:
Ø Barium is used
in the preparation of potassium bromide to remove sulphate which arise form the
bromine used in the process. It is likely that potassium bromide will now be
contaminated by traces of barium.
(C)
Solvents:
Ø Most of the
pharmaceutical substances are prepared in solvated crystalline form.
Ø 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.
Ø Water is the
cheapest solvent available and is used quite frequently in the preparation of
inorganic pharmaceuticals.
Ø Water can be the
major source of impurities as different types of water containing different
types and amount of impurities are available.
(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.
(D) Reaction vessels:
Ø 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.
Ø Glass and silica
are also used in the construction of the chemical plants but now many of these
are replaced by stainless steel and variety of other alloys.
Ø 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.
Ø For Ex - Lead (Pb) may be found as impurity in
commercial sulphuric acid which has been manufactured by lead chamber process.
Also, substances prepared by electrolytic process, may contain electrode
material as an impurity e.g. antimony, bismuth etc.
(E)
Intermediates:
Ø Sometimes, an
intermediate substance produced during the manufacturing process may
contaminate the final product
Ø For Ex - Sodium bromide is prepared by
reaction of sodium hydroxide and bromine in slight excess.
6 NaOH + 3 Br2 →
NaBrO3 +
5 NaBr + 3 H2O
The
sodium bromate an intermediate product is reduced to sodium bromide by heating
the residue (obtained by evaporating the solution to dryness) with charcoal.
NaBrO3 +
3 C → NaBr
+ 3 CO
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.
(F)
Atmospheric contamination during the manufacturing process:
Ø Atmosphere may
contain dust (aluminium oxide, sulphur, silica, etc.) and some gases like carbon
dioxide, sulphur dioxide, arsine and hydrogen sulphide. These may contaminate
the final product during the manufacturing process.
Ø Some substances
with atmospheric carbon dioxide and water may get contaminated during their
preparation
Ø e.g. sodium hydroxide
readily absorbs atmospheric carbon dioxide when exposed to atmosphere.
2
NaOH + CO2
→ Na2CO3 + H2O
Calcium hydroxide solutions can
absorb carbon dioxide from the atmosphere to form calcium carbonate.
Ca (OH)2 + CO2 → CaCO3 + H2O
(G)
Manufacturing hazards:
Ø 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) Particulate contamination
Ø 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.
Ø It may also arise from the bulk materials used
in the formulation or from dirty or improperly maintained equipments
Ø e.g. metal particles found in eye ointments
packed in metal tubes made up of tin and aluminum.
(ii)
Cross-contamination of the product:
Ø 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.
Ø Cross-contamination
is dangerous particularly in case of steroidal and other synthetic hormones and
therefore, it should be carefully controlled.
Ø Precautions,
such as use of face mask and special extraction equipment can minimize these
undesirable contaminations.
(iii)
Contamination by microbes:
Ø Many products,
like liquid preparations and creams intended for topical applications are
contamination by microbes from the atmosphere during manufacturing.
Ø 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.
Ø Microbial
contamination can be controlled by adding suitable antimicrobial and antifungal
agents.
iv)
Errors in the manufacturing process:
Ø Sometimes in a
liquid preparation, there is incomplete solution of the solute. This is to be
detected by the normal analytical methods as it can lead to major error.
Ø 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.
Ø Special
precautions are required to be observed to avoid mixing and filling errors in
the preparation of low dosage forms (≥5mg) such as tablets and capsules
containing highly potent medicaments.
(v)
Errors in the packaging:
Ø 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.
Ø Adequate care
should be taken to avoid the handling of such products in the close proximity.
3.
Instability of the product:
(A)
Chemical instability:
Ø Impurities can
also arise during storage because of chemical instability of the pharmaceutical
substance.
Ø Many
pharmaceutically important substances undergo chemical decomposition when
storage conditions are inadequate.
Ø This chemical
decomposition is often catalyzed by light, traces of acid or alkali, traces of
metallic impurities, air oxidation, carbon dioxide and water vapours.
Ø The nature of
the decomposition can easily be predicted from the knowledge of chemical properties
of the substance.
Ø All such
decompositions can be minimized or avoided by using proper storage procedures
and conditions.
Ø The
photosensitive substances should be protected from light by storing them in
darkened glass or metal containers thereby inhibiting photochemical
decomposition.
Ø Materials susceptible to oxidation by air or
attack by moisture should be stored in sealed containers and also be prevented
by adding suitable antioxidants. Materials susceptible to oxidation by air or
attack by moisture should be stored in sealed containers and also be prevented
by adding suitable antioxidants.
(B)
Changes in physical properties:
Ø Pharmaceuticals
may undergo changes in physical properties during storage. There can be changes
in crystal size and shape, sedimentation and caking of the suspended particles.
Ø These physical
changes are not always avoidable and may result in significant changes in the
physical appearance, pharmaceutical and therapeutic effects of the product.
Ø Particle size and consequently surface area is
a critical factor in determining the bioavailability of the low solubility drug
such as griseofulvin.
Ø 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 over dosage of the drugs.
(C)
Reaction with container material:
Ø The possibility
of reaction between the container material and the contents can not be ruled
out as it constituents a safety hazard.
Ø Preparations
susceptible to reaction with metal surfaces e.g. salicylic acid ointment must
not be packed in metal tubes.
Ø 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.
Ø 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.
Ø 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:
Ø The rate of
chemical decomposition and physical changes of stored products depends upon the
temperature.
Ø The susceptible
substances may have temperature storage requirements assigned to them in order
to protect them against undesirable decomposition.
