1st Sem B.Pharm Pharmaceutical Inorganic Chemistry

1. Impurities in Pharmaceuticals
Mrs. Gopi Patel
Assistant Professor
Indukaka Ipcowala College of Pharmacy
New V.V. Nagar

2. Impurity
As per IP
Any component or drug substance for
pharmaceutical use or a drug product
not a chemical entity
Pure: free from foreign matter
Impure: having foreign matter
@GOPI PATEL

3. Affect of Impurities……
• Even small amount may influence on
efficacy and safety of the pharmaceuti
cal product
• Alter physical and chemical properties
• Decrease shelf life
• May lead technical problem in the app
lication of the substance
@GOPI PATEL

4. Step…….
Identify impurities
Select method to remove impurities
Confirm for purity
@GOPI PATEL

5. Origin……
API/Excipients
Equipment
Utilities
Atmosphere
Container and closure
Impurities in FP
@GOPI PATEL

6. Type of impurities
Identified Potential Unidentified
In process
@GOPI PATEL

7. Commonly found impurities…..
1. Affect on aesthetic properties
Ex. Taste, odour, colour – easily notice
Ex. Benzoic acid, salicylic acid, Aspirin
phenolic impurity- odour
@GOPI PATEL

8. 2. Toxic impurities:
Metallic impurities- toxic even in trace
amount
Ex. Arsenic, Lead, Mercury….etc..
@GOPI PATEL

9. 3. Harmless impurities
Beyond certain tolerance limit
They affect the efficacy and potency
Ex.
- Sodium impurities – harmful in the
patient with restricted diet
- Glucose level
@GOPI PATEL

10. 4. Due to improper storage
condition
• Modification on storage condition
Ex. NaCl – Moisture
tends to liquid
@GOPI PATEL

11. 5. Create incompatibility
• Unable to live together
• API + Excipients
• Impurity present in any one ingredient
create incompatibility
@GOPI PATEL

12. 6. Create technical and technical
difficulty
• Difficulty in mfg. process
• Ex. Mixing, granulation….
• light cut off
@GOPI PATEL

13. Sources of Impurities
1. Raw materials
2. Methods of preparation- process
 Reagent
 Solvent
 Equipment
 Intermediate
 Atm. Condition
 Specific method
@GOPI PATEL

14. 3. Mfg. Hazards
 Contamination with particulate
 Contamination with non particulate
 Cross contamination
 Microbial contamination
 Error in mfg. process
 Error in packaging
@GOPI PATEL

15. 4. Instability
 Chemical instability
 Physical instability
 Reaction with container
 Temperature
 Adulteration
@GOPI PATEL

16. 1. Raw Materials
Sources
Natural Synthetic Semi-synthetic
• Mineral
• Plant
• Animal
- Need to purify
Need to purify
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17. • Ex.
BaSO4 Naturally found
Metallic impurity- lead, arsenic
Purification is difficult
To overcome this problem, mfg. – synthetically
BaCl2 + Na2SO4 BaSO4 + 2NaCl
@GOPI PATEL

18. 2. Process
a. Reagent
API
Active Pharmaceutical
Ingredients
Excipients
1. Organic – Recrystallization, distillation
2. Inorganic – Simple washing, Recrystallization
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19. Ex.: Mfg. of Calcium carbonate
CaCl2 + Na2CO3 CaCO3 + 2NaCl
Removed by simple
Washing with hot water
@GOPI PATEL

20. b. Solvent
Organic compound In organic compound
Common solvent: water
Non – aqueous formulation – sufficient amount
of water leads to drug degradation
• Residual solvent affect on stability
• Water – sources of impurities – type of water
@GOPI PATEL

21. 1. Tap water: Ca+2, Mg+2, Na+, Cl-
Trace amount of impurities present after
sufficient washing
Impurities will remain in product
2. Soft water: free from divalent cation
Only present Na+ , Cl- as an impurities
Softening process – ion exchange resin,
sboiling hard water
@GOPI PATEL

22. 3. DM water ( Demineralised water)
By ion exchange resin but having
pyrogen, bacteria
Better solvent than tap and soft water
4. Distilled water:
Free from organic, inorganic,
5. Water for injection:
free from microorganism
@GOPI PATEL

23. c. Reaction vessels
 Metallic impurities
 Chance of corrosion
Metal + corrosion --- passing impurities
in final product
• SS – std.: grade 304, 316
• Glass – alkali
• Iron- arsenic impurities
• Galvanized – Zinc impurities
@GOPI PATEL

24. d. Intermediate
A + B D + I P
Ex.
6 KOH + 3I2 5 KI + KIO3 + 3H2O
KIO3 + 3 C KI + 3CO
Impurities
Used to remove KI
@GOPI PATEL

25. e. Atmosphere contamination
Dust, gases – contaminate the final product
2 NaOH + CO2 Na2CO3 + H2O
Ca(OH)2 + CO2 CaCO3 + H2O
@GOPI PATEL

26. f. Specific method
• Heating at particular temp
• Cooling
• Autoclave
• Stirring etc.
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27. • Ex.:
In acid – base titration – use CO2 free
water
How to prepared CO2 free water ?
Ans.: Warm the water
Why ?
H2O + CO2 H2CO3
Carbonic acid- error in end point detection
@GOPI PATEL

28. 3. Manufacturing Hazard
1. Contamination from particulate matter
• Unwanted particulate matter
• accidental inclusion of atm. polluants
• Metallic fragment from sieve, tableting,
granulation
• Wear and tear of equipment
(metal detector used for checking metal
by sensor)
@GOPI PATEL

29. 2. Non – particulate matter
Gaseous atm. pollutants
Ex.: SO2, CO2, H2S
Proper care should be taken during mfg.
process
@GOPI PATEL

30. 3. Cross contamination
• One product to another product
• Batch change
• Area separate
Schedule M:
Good Manufacturing Practice
- to avoid cross contamination
@GOPI PATEL

31. 4. Microbial contamination:
Sterility test- mostly for ophthalmic
and parenteral preparation
@GOPI PATEL

32. 5. Error in mfg. process
During process:
mixing, shifting, weighing, measuring etc.
2 Zn + O2 2 ZnO
• Heating at high
• Inadequate heating – metallic impurities
Zinc remain as it is in Zinc oxide
• Test for Zinc in Zinc oxide
@GOPI PATEL

33. 6. Packaging:
• Container and closures
• Similar looking tablets
• Packaging, labelling…
• Light sensitive pharmaceuticals have
to pack in light protective packaging.
@GOPI PATEL

34. 4. Instability
a. Chemical instability:
• Inadequate solubility
• Impurities arise during storage
• Light
• Metallic imp.
• Oxidation
• Water vapour
Ex.:
• Chlordiazepoxide (sedative)-:
photolytic degradation
• Aniline - oxidation
@GOPI PATEL

35. b. Physical properties:
• Colour, odour, taste….
• Crystal form change
• Sedimentation
• Caking
@GOPI PATEL

36. c. reaction with container closures
Container + material
Ex.: Salicylic acid oint.:
Not used metal tube
Used only lamy tube
Atropine sulphate:
packed in glass ampoules
@GOPI PATEL

37. d. Temperature:
• Chemical decomposition
• Physical change
Must follow instruction – labelling
@GOPI PATEL

38. e. Adulteration:
• Similar looking substance
• Get substituted in place of genuine
drug
Ex.:
• Honey – sugar
• Black pepper – dry papaya seed
• Ghee – Veg ghee
@GOPI PATEL

39. SUMMARY
Impurity – as per IP
Affect of impurity
Step involved
Type of impurities
Sources of impurities
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40. Test for Purity
• To ensure reasonable freedom for the
undesirable impurities
• Fix the limit of tolerance
• Some impurities are harmful in trace
amount
• Objectives: to reasonable good purity,
ensure therapeutic safety
@GOPI PATEL

41. 1. Clarity
• Appearance of solution
• Clarity or opalescence of solution
• Measure by direct comparison with
ref. solution
• B/W board
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42. 2. Colour
3 primary colour
• Yellow- ferric chloride solution
• Red- Cobaltous solution
• Blue – Cupric sulphate solution
Other solution prepared by various
proportion with or without 1% v/v HCl
@GOPI PATEL

43. 3. Acidity and Alkalinity
Litmus paper
pH paper
pH instruments
@GOPI PATEL

44. Indicator method
Range of acidity pH indicator Colour
Alkaline ＞8 Thymol blue Blue
Slightly alkaline 8-10 Phenolphthalein pink
Strongly alkaline ＞10 Phenolphthalein Red
Neutral 7 (6-8) Methyl red Yellow
Acidic 5-6 Methyl red Red
Faintly acidic 4-6 Bromo cresol green Blue
Strongly acidic Congo red Green/ blue
@GOPI PATEL

45. 4. Loss on ignition
• Samples are ignited under specified
condition
• Crucible – platinum, porcelain
• Only apply to thermostable comp
• Empty wt.+ Sample --- after ignition
reweight
@GOPI PATEL

46. Ex.
1. Calamine: 2 g, temp: 900 °C
Limit: NMT 2 %
2. Zinc oxide: 2 g, 500 °C
Limit: NMT 1 %
@GOPI PATEL

47. 5. Loss on drying (LOD)
• Use Oven to Remove
• Water content
• Volatile materials
• Temperature according to nature of
substance
Ex.
Aspirin
1 g 100 °C
@GOPI PATEL

48. 6. Moisture content
• Karl fisher method – titration
• Only for water content
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49. Others
• Solubility
• M.P. and B.P.
• Optical rotation – carbohydrate
• Wt./ml – liquid sample
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