Impurities – Introduction and Sources of Impurities

Impurities – Introduction

Impurities is one of such terms in pharma or any other industries and even in our day to day lives also, very familiar, whose introduction is not needed. It is said that we cannot synthesize/prepare/produce 100% pure substance of any kind. Any substance that exists naturally or prepared/synthesized naturally/artificially or isolated from already existing sources (may or may not be natural) by default is associated with impurities. Any compound is called pure when it has only the substance that is needed i.e., when the compound is having/contains only one type of substance. If the compound contains any substance that is not required even though that unwanted substance is useful or harmless, that compound is called as impure compound.

The term impurity is derived from Latin term impuritas which means uncleanness. Impurity is the substance/thing that is or makes impure or which impairs the purity of something and impurity is also a state of being not pure. In our day–to–day life, we see impurities in almost all the things we use and consume. In pharmaceuticals also, impurities are present and presence of impurities is acceptable up to a certain extinct. However, these limits are given in the standard books like pharmacopoeias. For preparation of pharmaceuticals, their quality and purity testing, impurities, assay and other analytical procedures and limits of results etc. are given in the pharmacopoeias.

In this chapter, we will discuss about the sources and types of impurities in pharmaceutical substances. Starting with the definition of impurities, any unwanted substance regardless it is useful or harmless, is considered as impurity. For example, excipients used in drug formulation are harmless but still, they are not required to cure the symptoms for what the drug is used. Hence, these excipients, although are harmless, are considered as impurities. Adding tea or coffee powder to milk is useful. But still, tea or coffee powder are considered as impurities. Hence, impurities may be useful or harmless. Still, impurities cause side effects and even adverse effects in the recipient. Hence, the impurities as cannot be avoided from being existing in a particular thing that may be used or consumed, they should be in such level that they should not cause severe effects in the recipient. In the following section, we will discuss about the sources of impurities and the types of impurities.

Sources of impurities:

As we have discussed in the earlier section, impurities are unavoidable. No matter how perfect we are maintaining the reaction conditions and how much strict precautions we are taking, some way or the other, impurities will surely enter. There are so many ways for impurities to enter into any formulation or compound like from the starting material used, solvents used, reaction vessels used, reaction procedure followed etc. and all these are called as sources of impurities. The possible sources of impurities in pharmaceutical substances are:

• Raw material used in manufacture process:

Material which is used to prepare/synthesize any final product are known to be the source of impurities. These impurities in starting material/raw material may be carried through the manufacturing process and may be seen in/contaminate the final product.

Example we can consider normal table salt prepared from rock salt. Rock salt have small quantities of calcium sulfate (CaSO₄) and magnesium chloride (MgCl₂). Hence, the normal salt (sodium chloride NaCl) prepared from rock salt will be having the compounds of calcium and magnesium as impurities.

Another example is preparation of copper sulfate from copper turnings and sulfuric acid. Copper turnings are known to have impurities like Iron and Arsenic. If these impurities are present in large quantities, then these impurities may enter into the final product (copper sulfate).

 

Indian pharmacopoeia has mentioned the tolerance limit/level for arsenic, iron and other inorganic compounds as impurities and also prescribed the procedure for limit test for arsenic, iron and also for most inorganic impurities.

• Method of manufacturing:

The method used for manufacturing may be the source of impurities. the way we process the manufacturing, the solvents we use, reagents we use, catalysts we use in the manufacturing process may be the source of impurities.

• Reagents used/employed in manufacturing process:

Reagents used in manufacturing process may be the source of impurities or the reagents themselves may be the impurities in the final product.

Preparation of ammoniated mercury can be considered as an example here. Ammoniated mercury is prepared from the solutions of mercuric chloride (MgCl₂) and ammonium hydroxide (NH₄OH)

In this process, the precipitate of ammoniated mercury contains ammonium hydroxide as an impurity, which has to be removed by washing with cold water. If not washed, then ammoniated mercury will be having ammonium hydroxide as an impurity.

Another example will be the preparation of calcium carbonate from soluble calcium salt [usually calcium hydroxide Ca(OH)₂] and soluble carbonate (usually sodium carbonate (Na₂CO₃).

In this process, the soluble alkali if not washed properly, then can be the impurity in the final product.

• Reagents used to eliminate impurity:

The reagents which are used to remove impurities may be the source of impurities. for example, barium reagent is used to remove sulfate impurities present in potassium bromide. This barium itself may present in the final product as the impurity.

• Solvents used in manufacturing process:

Solvents are used in the manufacturing process or in the purification process also. These solvents may be present as impurities in the final product. For example, water is the cheapest solvent available and is the source of a lot of impurities like calcium ion (Ca²⁺), magnesium ion (Mg²⁺), sodium ion (Na⁺), chloride (Clˉ), carbonate (CO₃^2–), sulfate (SO₄^2–) etc. Hence, if we are not using purified water, it may be the source of these impurities. Also, water is used for purification of the final product. If not dried properly, water itself will be the impurity in the final product. Here we have different types of water and their possible impurities on using.

Table 6.1.: Types of water and possible impurities

S.No.	Type of water	Description
1.	Tap water	Tap water contains all the impurities like Ca2+, Mg2+, Na+, Clˉ, CO32–, SO42– in small amounts
2.	Softened water	When tap water is added soda or sodium carbonate, the divalent ions (Ca2+, Mg2+, CO32–, SO42–) are removed and hence, soft water contains only Na+, Clˉ as impurities.
3.	De-mineralised water	When tap water is passed through ion exchange resin, then the water will be free from ions like Ca2+, Mg2+, Na+, Clˉ, CO32–, SO42–. Hence, the obtained water will not be having any of these ions as impurities but may have some organic impurities.
4.	Distilled water	This water is almost free from impurities. This water is considered as the best to be used. But, distilled water, unlike tap water is costly.

• Chemical process/reactions used in manufacturing process:

Chemical process or reactions used in manufacturing process may be a source of impurities. many chemical reactions like halogenation, nitration, hydrolysis, reduction, oxidation, sulfonation, hydrogenation, etc. are involved in the manufacturing process. These reactions involve many chemicals and also give many side products. These chemicals or the side products may be present as impurities in the final product.

For example, we use water for almost all of the mentioned reactions and water contain many ionic impurities. Hence, these ions may be present as impurities in the final product.

• Atmospheric contamination:

Atmosphere is having so many dust particles (which may contain aluminium oxide, sulfur, silica, etc.) and also some gases like hydrogen sulphide, sulfur dioxide, black smoke etc. These compounds may be present in the final product as impurities.

For example, when sodium hydroxide is exposed to atmosphere, it will react with water vapour and carbondioxide present in atmosphere and form sodium carbonate and water.

Hence, sodium hydroxide cannot be kept in contact to outer environment for longer time during its manufacturing or the manufacture of any pharmaceutical substance.

Indian Pharmacopoeia has prescribed the limit of sodium carbonate in sodium hydroxide as not more than 3%.

• Intermediate products formed:

In most of the cases, the final product will not be attained in a single step. Multiple steps may have to be performed to synthesize the final product. In this process of synthesizing the pharmaceutical product, some intermediate compounds may be formed through which the final product is obtained or which themselves will convert into final product i.e., in some cases, these intermediate compounds will convert into final product where as in other cases, the intermediates are just the additional compounds formed in the reaction. Hence, the intermediate products themselves may be present as impurities in the final product or the intermediate which is not converted completely may be present as impurities in the final product.

For example, consider synthesis of sodium bromide from sodium hydroxide.

In the above reaction, in the first, sodium hydroxide is reacted with bromine and sodium bromate is formed as an intermediate and later, this sodium bromate has been converted into sodium bromide. This intermediate if not converted completely, then it might be present as an impurity in the final product.

Another example is preparation of potassium iodide from potassium hydroxide.

In the above reaction also, potassium iodate (KIO₃) is the intermediate and if it is not converted to final product (KI) completely, may be present as the impurity in the final product. Like this, any intermediate which is not converted completely or the intermediate formed as an extra compound and is not washed out, can be the impurity in the final product.

• Reaction with reaction vessels:

During manufacturing process, some solvents and reagents or sometimes the raw material or even the final product may react with metals of reaction vessel and dissolve these metals. Hence, these dissolved metals may present in the final product as impurities.

Indian Pharmacopoeia has given the tolerance levels/limit of arsenic, iron and other inorganic compounds as impurities and also prescribed procedure for limit test for arsenic, iron and other inorganic impurities.

• Manufacturing Hazards:

Let us think that the manufacturer is managed to control and check impurities from all the above-mentioned sources, still we cannot say that the final product will be free from impurities. even though all the above – mentioned sources are managed, still there might be manufacturing hazards which may cause impurities in the final products. Let us discuss a few such possible manufacturing hazards.

• Contamination from particulate matter:

Particulate matter includes glass particles, dust particles, porcelain, plastic or metallic fragments from sieves, granulating machines, tabletting machines, filling machines, dirt etc. ware and tare of equipment or improperly cleaned equipment may also give some particulate matter. These particulate matters may be present in the end product as impurities.

For example, when we prepare solutions for injections, these solutions must be free from any particulate matter and must be clear. We can see metal particles in eye ointments that are packed in metal tubes.

• Cross contamination:

Cross-contamination is contamination form other substances. This happens when the product or the raw material or reagents or solvents come in contact with the other substances. This may occur due to air – born dust arising due to handling of granules, powders and tablets in bulk. Otherwise, in other condition, when two or more products are manufactured at the same time, then the material of one product may contaminate the material of another product.

• Contamination by microbes:

Most of the liquid and cream preparations which are meant for topical applications are susceptible for microbial contamination during manufacturing. Even parenteral and ophthalmic products also require special care against microbial contamination.

For example, substances like acacia, senna, tragacanth are more susceptible for the microbe Salmonellae.

• Errors in manufacturing/process errors:

Manufacturing process include many processes like solution preparation, addition of solution, mixing time of solutions, etc. incomplete preparation of solutions, not maintaining the prescribed mixing time, error in mixing, filling, tabletting, sterilizing etc. may gives rise to impurities in the final product. Even when the manufacturing tolerance for the quantity of active ingredient in the final product is wide, minor errors/impurities may arise.

• Inadequate storage & packing conditions:

Packing and storage are very important for a pharmaceutical product. Packing helps in transporting the product safely and storage in the right place in right conditions increases durability and safety of the product. Any mistake in these two steps lead to the formation of impurities.

For example, if two products are having same particle size, same colour and shape and packed similarly, then there is a lot of chance to mislabel both the products which may lead to use both the products in wrong procedures.

Another example is storage of alkalies in glass containers. Alkalies stored in glass containers may extract lead from the container as a result, lead can be found in the final product as the impurity.

Even if the storage conditions are inadequate, the following results can be seen.

• Stored products may be contaminated with dust, insect bodies, excreta of insects and animals etc. This condition is called Filth.
• Some products are sensitive to light, air oxidation, traces of acid or alkali, carbon dioxide, traces of metallic ions, water vapour, etc. The compounds which are sensitive to respective material come in contact with that material, will get degraded. Hence, the degraded material will become the impurity. Hence, these material should be protected from these material which may decompose them. This condition of decomposition may be called as chemical instability. For example, light sensitive substances can be stored in amber coloured bottle, which can prevent light from passing into the bottle.
• Changes in physical stage of the pharmaceutical substance may change the efficiency of the substance.
• If the temperature is not stored in proper temperature, chemical and physical changes may occur in the final product.
• Instability of products:

Instability of the product may be the reason of impurities in the final product. Because of instability of the product, the product may form some other

• Chemical instabilities:

During storage of pharmaceutical products, some products may become unstable and may decompose, resulting in the formation of impurities. This majorly happen due to inadequate storage conditions. The pharmaceutical product may undergo decomposition which may be catalysed by the traces of alkali or acid, light, traces of metallic impurities or by oxidation by air and water vapours.

• Physical instabilities:

Even the product may change physically during storage. The change may be seen in the size of crystals, shape of crystals, sedimentation, aggregation, cracking that are seen in suspended particles, etc.

• Reaction with container:

When pharmaceutical substance is stored in a container, the substance may react with the container itself and may be a source of impurities. for example, as we have seen in earlier sources, when an ointment is stored in metallic tube, the ointment may react with the tube and the metallic particles of the tube (container) may be present as impurities in the ointment. Another example can be the plastic containers and closures which have a tendency to give additives such as plasticizers, especially in the presence of non-aqueous solvents which are undesirable.

• Temperature:

The rate of physical changes of the stored product and its chemical decomposition depends upon the temperature. Hence, the substances which are sensitive to temperature or susceptible to thermal degradation have requirements for storage temperature in order to protect them from thermal decomposition.

These requirements are mentioned in Indian Pharmacopoeia.