IMPURITIES IN
PHARMACOPOEIAL SUBSTANCES
Introduction
A substance is said to be impure if it is having foreign
matter. Chemically a compound is impure if it contains undesirable foreign
matter i.e. impurities. Thus chemical purity is freedom from foreign matter. It
is virtually impossible to have absolutely pure chemical compounds and even
analytically pure chemical compounds contain minute trace of impurities. The
chemical purity may be achieved as closely as desired provided sufficient care
is observed at different levels in the manufacturing of a pharmaceutical. The
level of purity of the pharmaceutical substance depends partly on the
cost-effectiveness of the process employed, methods of purification, and
stability of the final product. Setting higher standards of purity for
pharmaceutical substances than that of desirable and pharmacologically safe
level will unduly result in wastage of money, material, labour and time.
Purification of chemical compounds is a very expensive process hence one has to
strike a balance in order to obtain a pharmaceutical substance at reasonable
cost yet sufficiently pure for all pharmaceutical purposes.
The word ‘pure’ is a relative term. Hence, different
pharmacopoeias prescribe “Test for purity” for different substances. For
examples: ‘Purified Water’ of the Indian Pharmacopoeia may be prepared by
distillation or by means of ion- exchange and it may have pyrogens. ‘Sterile
Water for Injection’ on the other hand must be free from pyrogens and must be
sterile. It may have slightly acidic pH or may be very slightly alkaline. Hence,
different limits are prescribed for impurities in waters prepared for different
purposes. Similarly many test like physico chemical properties, limit test,
microbial limits, organic impurities etc.
Types of
impurities in medicinal preparations
Most commonly it may be of the following types:
1. Toxic
effect: The impurities which bring about unpleasant reactions
when present beyond certain limits.
For examples; Lead and arsenic
2. Cumulative toxic
effect: It is the type of toxic effect, where it occurs due to the
accumulation of impurities and produces effect after a certain period. If the
impurities accumulated in large quantities in to a part or organ of the body
then it finally damaged that organ and affects the metabolic process of the
body.
For examples; if copper is present in excess in the body.
3. Therapeutical
effect: The impurities which though otherwise harmless, in large
proportions that the active strength of the substance gets lowered and it will
not provide the required therapeutic effect actively
For Examples: the presence of sodium bromide in the more
expensive potassium bromide is not likely to cause harm to the patient. However
medicinal quality potassium bromide should contain only potassium bromide and
not contain large quantities of sodium bromide.
4. Direct Toxicity:
the impurities which are having a toxic effect and it directly attack the body
and harm the body.
For examples: The impurities which are able to make the
substances incompatible with other substances For example: Boric acid
5. The impurities which are able to decrease the keeping
properties of the substances
For example: a small amount of moisture may cause many
substances to be easily oxidised or to undergo hydrolysis like sodium
hydroxide.
6. The impurities which impart a different colour or odour
to the main substance which are not desirable
For examples: sodium Salicylate is often discoloured due to
phenolic impurities
7. Effect of formulations when the impurities is present it
bring about technical difficulties in the formulations and use of the
substance.
For example: in sodium chloride injection, sodium chloride
is the active ingredient and along with it if contains calcium carbonate is
present then such injection may damage the veins as calcium carbonate
accumulates in the vein and damages the vein.
SOURCES OF
IMPURITIES IN PHARMACEUTICAL CHEMICALS
A substance of pharmaceutical chemicals should not contain
impurities beyond its limit as it may contaminate
Generally medicinal compound should not only be free from
undue amounts of toxic and undesirable substances but should also be of a
reasonably pure quality. Those impurities such as lead and arsenic which have
deleterious effects should not be present in amounts likely to be harmful, Very
low limits are fixed for such type of impurities.
A list of impurities which are likely to 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:
Impurities in Pharmacopeial substances may be due to the
following sources:
·
Raw materials used in manufacture
·
Atmospheric contaminants
·
Chemical processes
Manufacturing process
·
Regents used employed in the process
·
Reagents added to remove other impurities
·
Solvents
·
Equipment used in process of manufacturing
·
Intermediates
Manufacturing hazards
·
Particulate contamination
·
Non Particulate contamination
·
Cross contamination
·
Microbial contamination
·
Process errors
·
Packing error
Storage conditions
·
Inadequate storage condition and their effects
·
Filth
·
Chemical instability
·
Reaction with container materials
·
Physical changes
·
Temperature changes
Deliberate adulteration with spurious or use less materials
a) RAW
MATERIALS USED IN MANUFACTURE
Pharmaceutical chemicals may be isolated from chemical
starting materials prepared by synthesis or from biological source. 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
A good example is the presence of tin, lead, silver, copper,
cobalt and gold in bismuth salts. These metals occur along with bismuth in
bismuth ores.
Rock salt contains small amount of sulphate and calcium
sulphate and magnesium chloride so that the sodium chloride prepared from this
source will almost contain traces of calcium and magnesium compounds.
Likewise the presence of any related or non-related
substance present in the starting material which might conceivably be carried
through the process to contaminate the final product.
Hence raw materials used to prepare pharmaceutical
substances should be of very good and pure quality.
b)
ATMOSHPERIC CONTAMINANTS
Atmospheric contamination may take place through dust,
carbon dioxide sulphur di oxide, hydrogen sulphide…. etc. These may
contaminate the final product during the manufacturing process
Some substances which are susceptible to action by
atmospheric carbon dioxide and water may get contaminated with them during
their preparation
For examples: Sodium hydroxide if left open in atmospheric
condition it absorbs carbon di oxide and becomes liquefied, as it is highly
hygroscopic in nature.
NaOH +
CO2 → Na2CO3 + H2O Sodium hydroxide Sodium carbonate
Calcium hydroxide solutions can absorb carbon dioxide from
the atmosphere to form calcium carbonate.
Ca (OH)2
+ CO2 → CaCO3 + H2O Calcium hydroxide Calcium carbonate
c) CHEMICAL
PROCESSES
For synthesis of drugs, many chemical reactions such as
nitration, halogenations, oxidation, reduction, hydrolysis … etc are
involved. In the chemical reaction, different chemicals are used which may
cause impurities.
For examples; potassium iodide is manufactured from iodine
which is obtained from kelp a sea weed, cyanides tends to get formed when
nitrogenous organic matter is burnt with alkalis.
d)
MANUFACTURING PROCESS:
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 chemical reaction, vessels,
equipment, raw materials and reaction intermediates; every aspect serves as the
source of impurity. These can be explained as follows:
I) Reagents
employed in the process:
Many reagents are used in the process of manufacturing a
product. If the products formed are not washed properly to remove excess
reagent, then these reagents are most likely to be carried as impurities to the
final preparation.
For example:
Lead as an impurity may result from the sulphuric acid used
as reagent, especially if it has been prepared by the lead chamber process.
Soluble alkali may be an impurity in calcium carbonate, if
the calcium carbonate is made by reacting calcium chloride and sodium carbonate
and not properly washed. 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.
CaCl2 + Na2CO3 → CaCO3 ↓
+ 2 NaCl
Soluble Soluble Precipitate Soluble
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
II)
Reagents added to remove other impurities:
In some manufacturing process certain reagents are used to
remove impurities present in the final product. These reagents if not carefully
used are liable to get carried to the end products.
For examples: Potassium bromide is liable to contain traces
of barium which is added in the course of the manufacturing process to remove
excess sulphate.
III)
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 like sodium, calcium, magnesium, carbonate, chloride
and sulphate ions, as different types of water contains different types of
impurities and amount of impurities.
Various types of water which are available are
(i) Tap water: Containing impurities of Ca2+, Mg2+,Na+, Cl-,
CO -2 and SO -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) Demineralised 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, bacteria’s 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.
Water is the solvent easily available and cheap. It is used
in the manufacture of inorganic chemicals. This can give rise to traces of
impurities like sodium, calcium, magnesium, carbonate, chloride and sulphate
ions. These difficulties do not arise in the use of distilled or demineralised
water.
IV)
Equipment used in process of manufacturing:
The equipment or reaction vessels used in the manufacturing
process may be made up of metallic material like copper, iron, galvanised iron,
lead. The material of the equipment may react with the reagents and solvents
used in the process of manufacturing and contribute to impurities in the end
product. But now day’s metallic vessels are replaced by stainless steel or hard
borosilicate glass.
Traces of metallic ions from such vessels may pass into the
solution and contaminate the products. Similarly glass of an unsatisfactory
standard may traces of alkali to the solvent.
Likewise, plastic container used for handling liquid and
semisolid products in the course of manufacture may yield trace metal additives
antioxidants to the product.
V)
Intermediates:
Sometimes, an intermediate substance produced during the
manufacturing process may contaminate the final product
For examples: Sodium bromide is prepared by reaction of
sodium hydroxide and bromine in slight excess.
6 NaOH + 3 Br2
→ NaBrO3 + 5 NaBr + 3 H2O
Then 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 in sodium bromide.
e)
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)
PARTICULATE CONTAMINATION
The presences of unwanted particulate matter can a rise in a
number of ways. These include accidental inclusion of atmospheric pollutants
such as aluminium oxide, silica, sulphur and soot or from glass, porcelain,
metallic and fragments from sieves, granulating, tabletting and filling
machines or even from product containers. The particulate contamination mainly
arises from the wear and tear of the equipment’s. This type of contamination
may also stem either through bulk materials used in the formulation or from
dirty or improperly maintained equipment’s. For examples: metal particles found
in eye ointments packed in metal tubes made up of tin and aluminium.
II) NON
PARTICULATE CONTAMINATION
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 (≥5mg) such as tablets and capsules containing highly
potent medicaments
III) CROSS
CONTAMINATION
This manufacturing hazard has to be considered in the
preparation of solid dosage forms. The handling of powders, granules and
tablets in large bulk frequently creates a considerable amount of air borne
dust, which is not controlled can lead to cross contamination of products.
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.
For examples: If more than one medicinal product is
manufactured in same premises than the product of medicine prepared in one room
may be dispersed by dispersion into another room, where another product is
made. Therefore mixture of one product can contaminate the other product care
should be taken to avoid this.
IV)
MICROBIAL CONTAMINATION
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.
For Examples: Acacia, Senna, Tragacanth must be free
Salmonellae
V) PROCESS
ERRORS:-
Process errors arising from incomplete solution of a solute
in a liquid preparation must be detected readily by the normal analytical control
procedure. The preparation of solutions requires a special precaution such as
filtration to avoid the damage of undissolved solute contaminating part of the
batch. Uneven distribution of suspended matter during the manufacture can
similarly become the source of batch variation or even variation with in a
batch. The process error is very much effective when we will make tablet in
which active ingredient in very less i.e, If we have to make a tablet the
excipient’s like colouring agent, flavouring agent, binding agent should
properly mix with the active ingredient so that all the excipient’s and active
ingredients are properly mixed and are of uniform.
VI) PACKING
ERRORS
Similar looking products, such as tablets of the same size,
shape and colour, packed in similar containers can result in mislabelling of
either or both of the products. Adequate care should be taken to avoid the
handling of such products in the close proximity. Inadequate checks on the
issue of labels, on the filling of labelling machines, on the setting of
printing machines constitute a major packaging hazard. Such mishaps can only be
avoided by taking care in the manufacture.
f) STORAGE
– CONDITIONS
The prepared chemical substances have
to be stored in different types of containers depending upon
the nature of the material , size and the quantity.The material used for
storage purpose may be plastic , polythene , iron vessels, stainless steel ,
aluminium, copper etc. The reactions of these substances with the materials stored
in the storage vessel are found as impurities. The reaction may occur directly
or by the leaching out effect on the storage vessel.
For examples: Alkalies stored in ordinary glass containers
extract lead from it which is found in the final products. Similarly strong
chemicals react with iron containers and extract iron.
Inadequate storage condition and their effects are outlined
as follows:
I) Filth:
The stored products may become contaminated with dust, the
bodies of insect and even animal and insects excretes, unless adequate
precautions are taken.Modern packaging is usually capable of excluding all such
contamination from finished pharmaceutical products, but bulk storage of raw
materials, crude products is far likely to get contaminated. So an appropriate
test for filth is desirable for all materials so stored. Even the
pharmaceutical premises must be clean and no cracks in the walls of the
buildings must be found.
II)
Chemical instability:
The substances when stored under non ideal conditions undergo
chemical decomposition. The nature of the decomposition may be catalysed by
light, traces of acid or alkali, air oxidation, water vapour, carbon di oxide,
and traces of metallic ions can frequently disturb the chemical nature of the
substances. 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 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.
For example; Succinly chloride are prone to hydrolysis when
formulated in aqueous solution
This can be prevented by adapting suitable storage procedure
and condition. Thus light sensitive materials should be stored in darkened
glass vessels.
The medicine which is sensitive to light is stored in an
opaque capsule cell to inhibit photochemical decomposition. For less sensitive
products it is usually sufficient to prescribe storage in a sealed container.
III)
Reaction with container materials:
The possibility of reaction between container and contents
constitutes a hazard which cannot be ignored.
Creams and ointments must not be packed in metal tubes,
unless they have been lacquered internally to inhibit reaction, because creams
and ointments are liable to react with metal surfaces.
The resistance offered by the glass is called hydrolytic
resistance. To release of soluble mineral substances into freshly distilled
water in the container and is determined by titration. Glass containers are
recognised in 3 grades Type I, Type II, Type III.
Type I is neutral glass, with high hydrolytic resistance
arising from the composition of the glass.
Type II also has high hydrolytic resistance but due to the
surface treatment of the glass, It can be distinguished from Type I in a
crushed glass test.
Type III has some limited hydrolytic resistance than that of
glass of Type I and Type II. 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 both Types I and Type II.
Type III glass may be used only for non-aqueous solutions
and injections and injection solids which are stable in this standard of glass.
Plastic containers and closures require careful evaluation
because of the tendency to yield undesirable which increases markedly in the
presence of non- aqueous solvents.
IV)
Physical changes:
Change in physical form of a drug during storage is not
unknown. Changes in crystal size and form agglomeration and even caking
suspended particles, which are not always preventable, may lead to marked
changes in therapeutic efficiency of the product, Thus, particle size and
consequently surface area may be a critical factor in determining the rate of
absorption and hence blood levels of a drug of low solubility.
For examples: Injectable emulsion in which the globule size
has increased in storage may be dangerous as it cause of fat embolism.
V)
Temperature effects:
The rate at which chemical and also physical change occurs
in stored products is conditioned by temperature.
The creams and ointments become solidify due to temperature
effects and also cracking of the medicine take place. Here the therapeutic
effect is not affected due to the temperature effect. So pastes and ointments
must be formulated so as to retain their consistency at higher temperatures
g)
DELIBRATE ADULTERATION WITH SPURIOUS OR USELESS MATERIALS
This is still a common occurrence in some parts of the
country where the drugs and cosmetics act has not yet been properly enforced,
Therefore one has to be careful in purchasing drugs from a reputed manufacturer
For examples: Adulteration of sodium salt for potassium
salt,—etc
Effects of
impurities
Almost pure substances are difficult to prepare and that
some amount of impurity always remains in the material. The impurities present
in the substances may exert the following effects:
1. Impurities having a toxic effect can be dangerous when
present above certain limits.
2. Impurities even present in traces may exert a cumulative
toxic effect after a certain period.
3. Impurities are sometimes harmless, however if they are
present in such large proportions that the active strength of the substance
gets lowered and naturally therapeutic effect gets reduced.
4. Impurities may cause a change in the physical and chemical
properties of the substances, thereby making it mechanically useless.
5. Impurities may bring about technical difficulties in the
formulation and the use of the substances,
6. Impurities may decrease the shelf life of the substances.
7. Impurities may cause an incompatibility with other
substances.