Source and effect of impurities in Pharmacopoeial Substances

Pharmacopoeial substance impurities affect pharmaceutical products' safety, efficacy, and quality. Pharmacopoeia sets a limit and guidelines regarding impurities in pharmacopoeial substances. Thus it is essential to understand sources of impurities in pharmacopoeial substances and their effects.

Sources of impurities in pharmacopoeial substances (Pharmaceutical Chemicals).

• 1. Raw materials: Raw materials are used to synthesize pharmacopoeial substances in laboratories/industries. If raw materials have impurities, they will enter into the final product.

Example 1. Copper Sulphate.

Sulphuric acid reacts with copper to form copper sulfate.

Cu + 2H2SO4 = CuSO4 + 2H2O + SO2

Copper contains arsenic and iron impurities, Which may enter into the final product copper sulfate. Indian pharmacopeia prescribes a limit for arsenic impurities not more than 8 parts per million (PPM).

Example 2. Zinc Sulphate (ZnSO4)

Sulphuric acid reacts with the zinc metal or zinc oxide to form zinc sulfate.

Zn + H2SO4 = ZnSO4 + H2O

ZnO + H2SO4 = ZnSO4 + H2O

Zinc metal or zinc oxide commonly contains some impurities like aluminum, iron, arsenic, copper, magnesium, etc. These impurities may be present in the zinc sulfate.

• 2. Reagents used: Reagents are used in the manufacturing of several pharmacopoeial substances. Unconsumed reagents are washed out from the product. But traces of these unconsumed reagents may present in the pharmacopoeial substances even after complete washing.

Example 1: Ammoniated mercury (NH2HgCl).

Addition of ammonium chloride solution into dilute ammonium hydroxide solution forms Ammoniated mercury (NH2HgCl) precipitate.

HgCl2 + NH4OH = NH2HgCl + NH4Cl + 2H2O.

Ammoniated mercury (NH2HgCl) precipitate is washed with cold water to remove ammonium hydroxide. But final product may contain ammonium hydroxide as impurities.

Example 2: Calcium carbonate (CaCO3)

Mixing of sodium carbonate solution with calcium chloride solution forms calcium carbonate precipitate.

CaCl2 + Na2CO3 = CaCO3 + 2NaCl

Calcium carbonate precipitate is washed with cold water to remove unconsumed sodium carbonate and sodium chloride. These impurities may present in the calcium carbonate upon improper washing.

• 3. Intermediate products: The manufacturing process may develop intermediate products during chemical reactions. These intermediate products may enter the final product as impurities.

Example 1: Potassium iodide (KI)

The interaction of potassium hydroxide and iodine produces potassium iodide and potassium iodate.

6KOH + 3I2 = 5KI + KIO3 + 3H2O.

The product is dried and then heated with charcoal to form dried powder potassium iodide.

KIO3 + 3C = KI + 3CO

The final product potassium iodide may contain potassium iodate as an impurity

• 4. Synthetic processes: Many pharmacopoeial substances are synthesized in laboratory/industry. Impurities enter pharmacopoeial substances during this synthesis due to improper mixing, incomplete reaction, improper temperature, improper pH, by-products, or any side reactions.

Example 1: Calcium chloride

Mixing calcium carbonate and hot dilute hydrochloric acid with stirring produces calcium chloride. The product is filtered. In this reaction slight excess of calcium carbonate is added to consume all hydrochloric acid. Calcium carbonate is insoluble and is removed by filtration. Hydrochloric acid may be present in the final product if reactants are not mixed properly. Filtrate is concentrated to form calcium chloride crystals.

CaCO3 (soluble) + 2HCl (insoluble) = CaCl (soluble) + H20 + CO2 (gas)

Example 2: Zinc oxide

Heating of metallic zinc in air current up to its redness develops zinc vapour. Zinc vapor burns to form zinc oxide white powder.

3Zn + O2 = 2ZnO.

Some zinc metal may remain upon improper heating or low temperature. The final product zinc oxide may contain zinc as impurity.

• 5. Solvents: Water is commonly used as a solvent in the manufacturing of pharmacopoeial substances. This water may be tap water, softened water, demineralized water, or distilled water.

Tap water/potable water: Tap water contains several minerals. These minerals may enter into the final product as impurities.

Softened water: Softened water is prepared by removing minerals from the tap water. But softened water has also some soluble minerals. These minerals may enter the final product as impurities.

Demineralized water (DM Water): Demineralised water is by passing tap water through ion exchange resins. Demineralized water is free from all dissolved minerals. It is not used as drinking water but it is a better solvent in the manufacturing of pharmacopoeial substances. It does not contain soluble inorganic chemicals but it may contain organic chemicals.

Distilled water: Distilled water is prepared by distillation of tap water/potable water. It is free from all soluble organic and inorganic impurities. It is the best solvent for the pharmaceutical industry but it is costly.

• 6. Manufacturing equipment: Chemicals from the wall of manufacturing equipment and containers enter into the final product during the manufacturing process as impurities. If manufacturing equipment and containers are not properly cleaned, impurities enter into the final product. Residues from previous batches also enter into the final product of the next batch.

Example: Metallic containers made of copper, iron, aluminum, etc are used in the manufacturing of pharmacopoeial substances. Traces of these elements may enter the final product during the manufacturing process. Nowadays stainless steel containers or borosil glass containers are used to avoid impurities entry during the manufacturing process.

• 7. Atmospheric contamination: The industrial area atmosphere and air inside the industry contains several hazardous chemicals and gases. These impurities may enter the final product during the manufacturing or purification stages.

Example: Sodium hydroxide

Sodium hydroxide quickly absorbs carbon dioxide from the air to form sodium carbonate.

2NaOH + CO2 = NA2CO3 + H2O.

Exposure of sodium hydroxide to atmospheric air during their manufacturing and storage develops sodium carbonate impurities in the sodium hydroxide.

• 8. Storage and handling: Poor storage conditions, the exposure to air, light, or moisture cause deterioration of pharmacopoeial substances. This develops impurities in the pharmacopoeial substances.

Example 1: Iodine

Iodine is stored in a glass container with a glass cap/stopper or in an iodine-resistant container because iodine reacts with some metals, rubber, and cork.

Example 2: Potassium iodide

Potassium iodide is deliquescent in nature. (Deliquescent is a substance that absorbs moisture from the air to form a liquid solution. Examples: Sodium hydroxide, Potassium hydroxide, Calcium chloride, Zinc chloride, Magnesium chloride, etc).

Example 3: Ferrous sulphate

Ferrous salt oxidizes in air slowly to form ferric salt. This develops a brown color. Ferrous salt should be stored in an airtight container to protect from exposure to air. Improper storage develops ferric sulfate impurity in ferrous sulfate.

• 9. Packaging materials: High-quality packaging materials are used for pharmacopoeial substances. Impurities from packaging materials enter pharmacopoeial substances during their transportation and storage if the quality of packaging materials is not up to mark.

• 10. Adulterants: Manufacturers or suppliers may add some cheap substitutes in the pharmacopoeial substances intentionally.

Examples: Sodium bromide in potassium bromide. Sodium bromide is cheaper than potassium bromide.

Effect of Impurities in Pharmacopoeial Substances

• 1. Safety: Impurities in pharmacopoeial substances are not safe for patients. They may cause toxic or allergic reactions. It is very important to identify impurities in pharmacopoeial substances to assess their health hazards.

• 2. Efficacy: Impurities in pharmacopoeial substances change the physical and chemical properties of API. They affect the stability, bioavailability, and therapeutic effect of the drugs. This affects the efficacy of the pharmacopoeial substances.

• 3. Incompatibility: Impurities may develop incompatibility.

• 4. Dosage forms: Impurities develop technical difficulties in the formulation of dosage forms.

• 5. Shelf life of drugs: Each drug has its certain shelf life. Impurities in pharmacopoeial substances accelerate their degradation. This reduces the shelf life of the drug and its overall stability.

• 6. Variability: Impurities in pharmacopoeial substances cause variation in the quality and effectiveness of formulation from batch to batch. This will be challenging to ensure the same therapeutic outcome from each batch.

• 7. Quality control: Impurities reduce the quality and purity of the pharmacopoeial substances. They lead to attract non compliance from the government regulatory bodies.

There are several analytical methods to identify and measure precent impurities present in the pharmacopoeial substances. Such as spectroscopy, HPLC (High Performance Liquid Chromatography), etc.