PHARMACEUTICAL IMPURITIES IN PHARMACOPOEIAL SUBSTANCES
Pharmaceutical Impurities
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 pharmaceutical impurities in medicinal preparations
Most commonly it may be of the following types:
- Toxic effect:The impurities which bring about unpleasant reactions when present beyond certain limits.
For examples; Lead and arsenic
- 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.
- 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.
- 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
- 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.
- 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
- 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 PHARMACEUTICAL IMPURITIES IN 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.
VII) 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
VI) 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 pharmaceutical 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:
- pharmaceutical impurities having a toxic effect can be dangerous when present above certain limits.
- pharmaceutical impurities even present in traces may exert a cumulative toxic effect after a certain period.
- pharmaceutical 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.
- pharmaceutical impurities may cause a change in the physical and chemical properties of the substances, thereby making it mechanically useless.
- pharmaceutical impurities may bring about technical difficulties in the formulation and the use of the substances,
- pharmaceutical impurities may decrease the shelf life of the substances.
- pharmaceutical impurities may cause an incompatibility with other substances.
Pharmaceutical impurities Frequently Asked Questions (FAQs)
- What are pharmaceutical impurities? Pharmaceutical impurities are unwanted substances that coexist with the active pharmaceutical ingredient in a drug formulation.
- Why is pharmaceutical impurities management important in the pharma industry? Impurity management is crucial to ensure the safety, efficacy, and quality of pharmaceutical products.
- What are the common types of pharmaceutical impurities? Common types include organic impurities, inorganic impurities, residual solvents, and degradation products.
- How are pharmaceutical impurities detected and quantified? Impurities are detected and quantified using advanced analytical techniques like HPLC, MS, and NMR.
- What is the role of stability testing in pharmaceutical impurities management? Stability testing helps assess the impact of storage conditions on impurity formation in pharmaceutical products.
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