Sources of Impurities.

Impurities are unwanted substances (foreign substances) that are present in chemical substances and drugs, which may harm their quality, safety, and effectiveness. They may come from different sources like during their preparation,storing , or handling . In inorganic pharmaceuticals these impurities are often as heavy metals, extra ions, or intermediate products.

The different sources of impurities are as-

1. Raw Materials

Impurities can come from the starting materials, like minerals or chemicals, which may have traces of other elements if not pure.

Example: In making sodium chloride (NaCl) from rock salt, calcium sulfate (CaSO₄) or magnesium chloride (MgCl₂) can present as impurities.

Copper sulfate (CuSO₄·5H₂O) from copper metal with iron or arsenic present as traces amount

Cu + 2H₂SO₄ → CuSO₄ + SO₂ + 2H₂O (Iron or arsenic from copper metal mixes in; IP limits arsenic to ≤8 ppm).

Zinc sulfate (ZnSO₄) from zinc with metals like lead or cadmium.

Zn + H₂SO₄ → ZnSO₄ + H₂ (Heavy metals from impure zinc cause toxicity).

2. Reagents and Solvents

The Reagents or solvents used may come as impurities if they are not pure or if they are remain.present due to incomplete reaction or improper purification process.

Example: In ammoniated mercury (NH₂HgCl), extra ammonium hydroxide (NH₄OH) can present if not washed properly.

HgCl₂ + 2NH₄OH → NH₂HgCl + NH₄Cl + 2H₂O (NH₄OH remain as impurity).

Water used in processes adds ions like Ca²⁺ or Mg²⁺ from tap water, or Na⁺ from softened water.

Solvents like methanol may be come as impurity during crystallization.

If such type of impurities come to final products,which e may cause side effects or decrease the drug stability.

3. Manufacturing Process and Methods used for final products

During manufacturing process of the drug, side reactions, incomplete steps, or intermediate formed may lead as impurities. This includes multi-step processes like oxidation or reduction.

Example: In potassium iodide (KI), potassium iodate (KIO₃) remains if reduction is not complete.

6KOH + 3I₂ → 5KI + KIO₃ + 3H₂O, then KIO₃ + 3C → KI + 3CO (if KIO₃ is not completely reduced come as impurity).

Sodium bromide (NaBr) with sodium bromate (NaBrO₃).

6NaOH + 3Br₂ → NaBrO₃ + 5NaBr + 3H₂O, then NaBrO₃ + 3C → NaBr + 3CO (if incomplete reduction NaBrO₃ will present).

In aspirin preparation, acetic acid remain present.

C₇H₆O₃ (salicylic acid) + C₄H₆O₃ (acetic anhydride) → C₉H₈O₄ (aspirin) + CH₃COOH (acetic acid) (Impure if not completely removed).

In paracetamol, 4-aminophenol intermediate present as impurity.

C₆H₅NO₂ (nitrobenzene) + H₂ → C₆H₇NO (4-aminophenol) → C₈H₉NO₂ (paracetamol) + C₆H₇NO (4-aminophenol) (incomplete reaction intermediate come as impurity).

Cross-contamination from other drugs in the same industry, factory; isomers from poor control (e.g., in ibuprofen); reaction by-products or unstable intermediates may come as various way in the product.

4. Reaction Vessels and Equipment

Equipment like metal pots or glass can release impurities, especially in acidic conditions.

Example: From Iron vessels or container impurities as arsenic or iron, From glass vessel impurities as alkali come.

Fe + 2H⁺ → Fe²⁺ + H₂ (Corrosion releases Fe²⁺ ions as impurity).

Metal particles from machine wear and equipment used in different formulation of product, which can speed up oxidation.

These impurities leads to toxic metals present into the final product and  change the drug stabilities and properties.

5. Residual Catalysts

Generally Catalysts  are used to speed up the  reactions,which also  can come traces as impurity .For example hydrogenation by using palladium,platinum and Nickel  catalyst.Also   reductions of nitro group  to amino groups (e.g., in paracetamol synthesis above).

6. Atmospheric and Environmental Contamination

Air, dust, microbes, or gases may be added as impurities during manufacturing or improper storage.

Sodium hydroxide (NaOH) absobs CO₂ gases to form sodium carbonate.

2NaOH + CO₂ → Na₂CO₃ + H₂O (IP limits Na₂CO₃ to ≤3%).

Calcium hydroxide (Ca(OH)₂) forms calcium carbonate.

Ca(OH)₂ + CO₂ → CaCO₃ + H₂O.

Dust, microbes in sterile drugs; airborne particles; water quality issues; endotoxins in injections. Which may cause infections or allergies.

7. Storage and Decomposition

Due to careless storage and improper knowledge condition (heat, light, moisture) causes degradation and chemical instability of product or reactions with containers.

Example: Penicillin breaks down in moisture.

C₁₆H₁₈N₂O₄S (penicillin) + H₂O → C₁₆H₂₀N₂O₅S (penicilloic acid) (Loses potency).

Hydrolysis in esters.

R-COOR’ + H₂O → R-COOH + R’OH (due to traces of acids and bases it Speeds up)

Salicylic acid reacts with metal tubes, so its ointment canot be packed in metal tube.

Ferrous sulphate slowly changed into ferric oxide by air and moisture, it should be kept in air tight closed container.

Oxidation, photolysis, or thermal breakdown causes due to temperature changes in during storage and transport of various substances.

8. Packaging Materials

Packaging can leak chemicals into the drug.

Plasticizers like phthalates in liquids; leaching from plastics.

Plastic container for injection should be translucent for visual observation of the contents

Plastic containers and closure require careful evaluation otherwise it adds toxic substances on the product over a time.

9. Handling, Transportation, and Distribution

Due to certain manual process,Human handling  or movement can add impurities.

Example: Biological contaminants from hands; physical damage exposing to dirt; temperature swings causing degradation.

10. Natural Sources and Intentional Adulteration

From nature or deliberate addition or adulteration leads certin impurities in the drug substances

Example: Trace metals or proteins in plant/animal materials; adding cheap stuff like melamine in products.

11. Other Sources

Liquid preparations and cream generally prone to microorganism during manufacture

Particulate matter enter during processing.

Human errors in cleaning, leading to old batch residues.

Summary Table of Sources with Examples

Dr.Dash Srimanta

Hi…! Currently, I am working as an  Professor at Department of Pharmaceutical Chemistry(H.O.D),The Pharmaceutical College, Barpali, Odisha. I have more than 19 years of teaching & research experience in the field of Chemistry & Pharmaceutical sciences.