This document discusses limitations of Lewis acid-base reactions, properties of buffer solutions, buffer capacity, the Henderson-Hasselbalch equation, and applications of buffers in pharmacy. It also covers general principles for adjusting solutions to isotonicity and its importance, types of impurities found in pharmaceutical substances, sources of impurities, effects of impurities, and limit tests for chloride, sulfate, iron, heavy metals, lead, and arsenic. Limit tests are used to identify and control small quantities of impurities that may be present in substances.

1. Unit-1
ACIDS, BASES AND
BUFFERS

2. Limitations of Lewis
• As lewis acid base reactions involve electrons,
they are expected to be very fast reactions.
However there are many lewis acid-base
reactions which are slow

3. Properties of Buffer solutions
1.pH remain constant
2.pH does not change on dilution
3.pH doesn’t change even after addition of
small quantities of acids or bases
4.Constant pH: Useful in number of
chemical reactions
5.pH does not change on keeping for long
time
Buffer Solutions: Solutions that are able to resist the
changes in pH values

4. Buffer capacity- Amount of acid/ Base
that must be added to the buffer to
produce a unit change of pH

5. Significance of Henderson-Hasselbalch
equation
• pH of buffer solution can be calculated
• Dissociation constant of an acid (pKa) can be
calculated
• Dissociation constant of an base (pKb) can be
calculated

6. Applications of buffers in pharmacy
1.Solubility- Solubility of compounds can
be frequently controlled by providing a
medium of suitable pH.
Eg. Inorganic salts (Phosphates)- soluble in
acidic media and precipitate in basic media
2. Color- Color of many dyes are pH
dependant
Eg. Red color of cherry maintained at
acidic pH

7. Applications of buffers in pharmacy
(NR)
3. Stability of certain compounds
Eg. Penicillin-unstable in alkaline pH
4. Some compounds structurally unstable
at certain pH ranges
Eg. Nitrites become brown in acidic media
due to formation of nitrogen oxide
5. Patient comfort- Injectables/ internal or
external preparations are irritating if pH is
different from normal

8. Applications of buffers in pharmacy
6. Medicinal compounds activity-
Optimum pH is maintained
Eg. Buffering methenamine with sodium
dihydrogen phosphate
7. Analytical lab- buffers of known pH
used as standard

9. General Principles for adjusting
isotonicity and its importance
• Solutions for i/v injection: Approximate
isotonicity is always desirable
• Solutions for s/c injection: Isotonicity is
needed but it is not essential since they are
injected into fatty tissues and not in blood
stream
• Solutions for i/m injection: The aqueous
solutions should be slightly hypertonic to
promote rapid absorption

10. • Solutions for intra-cutaneous injection: The
parenteral preparations which are meant for
diagnostic pupose should be isotonic in order to
avoid false reaction
• Solutions for intrathecal injection: these must be
isotonic, because volume of C.S.F (cerebrospinal
fluid) is only 60 to 80 mL. Hence, a small volume
of paratonic solution will disturb the osmotic
pressure and may cause vomiting and other side-
effects.

11. • Solutions used for nasal drops: Isotonicity is
needed, since paratonic solution may cause
irritation
• Solutions used as eye drops and eye lotions:
Eye lotion should be isotonic with lachrymal
secretion, since a large volume is brought in
contact with the eye. Eye drops may not be
isotonic because only a small volume is used
quickly get diluted by the lachrymal secretion.

12. Isotonicity –concept and importance
• Osmosis- Diffusion of solvent through a semi-
permeable membrane from less concentrated
solution to higher concentrated solution.
• Osmotic Pressure- The pressure needed to stop
the osmotic flow [It stops the flow of solvent
molecules from a dilute solution to a
concentrated solution]
• Tonicity- Measure of the osmotic pressure of two
solutions separated by a semi-permeable
membrane

13. Isotonicity –concept and importance
• Isotonic solutions- A solution having the same
solute concentration as in a cell/ Body fluid
[A solution containing 0.9% NaCl is isotonic with
blood plasma and is regarded as standard]
• Iso-osmotic solutions-Two solutions having
the same osmotic pressure
• Paratonic solutions- Solutions which are not
having the same osmotic pressure

14. Hypertonic
isotonic
Hypotonic
NaCl 2%
NaCl 0.9%
NaCl 0.2%
solute ‹ solute
Inside outside
solute =solute
Inside outside
solute › solute
Inside outside
shrinkage
equilibrium
swelling

15. Calculations for adjustment to
isotonicity
1. Based on Freezing point-
% w/v of adjusting substance needed= (0.52-a)/b
a= F.P of unadjusted solution
b= F.P of 1% w/v solution of adjusting substance
2. Based on molecular concentration
% w/v of adjusting substance needed= (0.03M/N
M= Gram molecular weight of the substance
N= No. of ions into which the substance is ionized

16. Examples
Q1. Find the concentration of sodium chloride
required to make a 1 percent solution of boric
acid, iso-osmotic with blood plasma.
Given- The F.P of 1% w/v solution of boric acid
is 0.288 °C. The F.P of 1% w/v solution of Nacl
is 0.576 °C.

17. Q2. Find the concentration of Nacl
required to produce a solution iso-
osmatic with blood plasma.

18. Q3. Find the proportion of dextrose
needed to form a solution iso-osmotic
with blood plasma.

19. Q4. Find out the proportion of
procaine hydrochloride which will yield
a solution iso-osmotic with blood
plasma
F.P of procaine hydrochloride is 0.122

20. Impurities in
Pharmaceutical
substances

21. Types of impurities found in medicinal
preparations
Impurity: A compound is said to be impure if it is having foreign
matter i.e impurities
1. The impurities which are having a toxic effect when present
beyond certain limits (eg lead and arsenic salts)
2. The impurities which otherwise are harmless but lowers the
therapeutic activity of pure substance.
3. The impurities which are able to lessen the keeping properties
of the substance
4. The impurities which are able to make the substance
incompatible with other substances
5. The impurities which can be easily detected by the senses like
taste, odor, color or appearance (eg. Sodium salicylate is
usually discolored due to phenolic impurities)

22. Effects of impurities
1. Impurities can be injurious when present above certain limits
2. Impurities even present in traces may exert a cumulative
toxic effect after a certain period
3. If impurities are present in large proportions , they lowers
the therapeutic activity of the substance
4. Impurities may change the physical and chemical properties
of the substance
5. Impurities may bring about technical difficulties in the
formulation
6. Impurities may cause incompatibility with other substances
7. Impurities may decrease the shelf life of the substance
8. Impurities may change color, odor, taste etc.

23. Sources of impurities
1.Raw materials employed in
manufacturing
For eg. Cu turnings are known to
have iron and arsenic as impurities

24. 2. Reagents used in the manufacturing
process
For eg The solid precipitate is washed
with water to remove excess of
sodium carbonate and soluble
chlorides as impurities

25. 3. Method or the process used in
manufacture
a)Reagents employed in the process- Soluble alkali
in calcium carbonate arises from sodium
carbonate
b. Solvents- Tap water is having Ca2+ ,Mg2+ ,Na+
,Cl- ,SO42- , CO32- as impurities in very small
amount

26. 4. Chemical processes used in the
manufacture
Tap water is used in various processes and has
chloride, calcium and magnesium which may find
access to the substance being manufactured
5. Atmospheric contamination during
the manufacturing process
For eg. Sodium hydroxide absorbs
atmospheric carbon dioxide

27. 6. Intermediate products in the manufacturing
process- if the intermediate product KIO3 is not
completely converted to KI, then it may be
carried through to the final product as an
impurity

28. 7. Defects in the manufacturing
process
If there is lesser heat or air or both, zinc metal
is not completely converted into zinc oxide thus
the final product ZnO may still contain metallic
zinc as impurity

29. 8. Manufacturing hazards
• Particulate contamination
• Process errors
• Cross-contamination
• Microbial contamination
• Packing errors

30. 9. Storage conditions
• Filth
• Chemical instability
• Reaction with container
materials
• Physical changes
• Temperature effects

31. 10. Decomposition of the product
during storage
Many organic substances get
spoiled due to decomposition
on exposure to the atmosphere
eg amines, phenols

32. 11. Accidental substitution or delibrate
adulteration with spurious or useless
materials
KBr may be adulterated with
cheaper sodium bromide

33. LIMIT TESTS
Limit tests are quantitative or semi-
quantitative tests designed to identify and
control small quantities of impurity which
are likely to present in the substance

34. Limit test for Chloride
Basic reaction:
Soluble
Chlorides
Silver
nitrate
HNO3
• Silver
chloride
• Turbidity

35. Sample pass the limit test if turbidity
of sample is less than the standard
turbidity
TEST SOLUTION STANDARD SOLUTION
Specified substance (1g) + H20 (10mL) 0.05845 % w/v Solution of NaCl (1mL)
Add HNO3 (1mL) Add HNO3 (1mL)
Upto 50 mL (With H2O) Upto 50 mL (With H2O)
Add AgNO3 (1mL) Add AgNO3 (1mL)
Stirr and Kept aside for 5min, compare
opalescence with standard
Kept aside for 5min, compare
opalescence with sample

36. Limit test for Sulphate
Basic reaction:
Dil
HCL
Soluble
sulphates
Barium
chloride
• BaCL2 is replaced by BaSO4 reagent in IP (Modified
limit test for Sulphate)
• BaSO4 reagent- BaCl2 + Sulphate free alcohol+ Solution
of potassium sulphate
• Sulphate free alcohol- Prevents super saturation and
produce more uniform opalescence
• Potassium Sulphate- Increase sensitivity of the test

37. Sample pass the limit test if turbidity
of sample is less than the standard
turbidity
TEST SOLUTION STANDARD SOLUTION
Specified substance (1g) 0.1089 % w/v Solution of K2SO4 (1mL)
Add HCL(2mL) Add HCL(2mL)
Upto 45 mL (With H2O) Upto 45 mL (With H2O)
Add BaSO4 reagent (5mL) Add BaSO4 reagent (5mL)
Stirr and Kept aside for 5min, compare
opalescence with standard
Stirr and Kept aside for 5min, compare
opalescence with sample

38. Limit test for IRON
Citric acid In the
ammonical alkaline
medium
Basic reaction
• Purple color Chelate
because of Fe
• Colorless in acidic or
neutralization solutions

39. Principle
Iron in ammonical
solution
+ Citric acid
(20%)
• Doesn’t allow
precipitation of
iron by ammonia
by forming a
complex with it
• Eliminate
interference of
other metal
cations
+ Thioglycollic acid
• Colorless,
unpleasant odor
• More sensitive
Pale pink to deep
reddish purple
color is formed
due to ferrous
compounds

40. Sample pass the limit test if color of sample is
less dark than the color of standard
TEST SOLUTION STANDARD SOLUTION
Specified substance (1g) [NaCl] Standard solution of Iron/ Ferric
ammonium sulphate i.e. 2mL [NH4Fe
(SO4)2.12H2O], 0.173 g + HCL (1.5mL),
Volume makeup upto 1000 mL using H2O
Add water (40 mL) Add water (40mL)
+ 20% w/v Iron free citric acid (2mL) + 20% w/v Iron free citric acid (2mL)
Add Thioglycollic acid (2drops) Add Thioglycollic acid (2drops)
• Made alkaline with Iron free ammonia
• Volume makeup upto 50 ml using
water
• Allow to stand and compare with
standard
• Made alkaline with Iron free ammonia
• Volume makeup upto 50 ml using
water
• Allow to stand and compare with
sample

41. Limit test for heavy metals
[lead, mercury, bismuth, arsenic,
antimony, tin, cadmium, silver, copper,
molybdenum]

44. Sample pass the limit test if color of
sample is less intense than the color of
standard
TEST SOLUTION STANDARD SOLUTION
25 mL of solution prepared for the test as
directed in the individual monograph or
dissolve the specified quantity of the
substance under examination in a
mixture of 20mL of water
20 ppm lead standard solution (1mL)
Add dil NaoH (5mL) Add dil NaoH (5mL)
Volume makeup Upto 50mL (H2O) Volume makeup Upto 50mL (H2O)
Sodium sulphide solution (5drops) Sodium sulphide solution (5drops)
Allow to stand for 5min and view
downwards over a white surface
Allow to stand for 5min and view
downwards over a white surface

45. Limit test for Lead
Expressed as parts of lead per million parts of the substance under examination

46. The color of the chloroform layer should not be more intense than standard solution

47. TEST SOLUTION STANDARD SOLUTION
Transfer sample solution into separator/
separating funnel
1 ppm lead standard solution
Add Ammonium citrate solution Sp. (6mL) * For
Iron salts (10mL)
Add Ammonium citrate solution Sp. (6mL) * For
Iron salts (10mL)
Hydroxylamine Hydrochloride solution Sp.
(2mL)
Hydroxylamine Hydrochloride solution Sp.
(2mL)
• Phenol red solution (2drops)
• Make solution alkaline and red in color
(Strong ammonia solution)
• Potassium cyanide solution Sp. (2mL)
• Extract the above solution with dithizone
solution (5 ml for each time)until the
dithizone extraction solution retain it
become green
• 1% v/v Nitric acid (30mL)
• Discard the chloroform layer
• Shake the combine dithiazone solution for
30 seconds
• Dithizone solution (5mL) and shake for 30
seconds
• Phenol red solution (2drops)
• Make solution alkaline and red in color
(Strong ammonia solution)
• Potassium cyanide solution Sp. (2mL)
• Extract the above solution with dithizone
solution (5 ml for each time)until the
dithizone extraction solution retain it
become green
• 1% v/v Nitric acid (30mL)
• Discard the chloroform layer
• Shake the combine dithiazone solution for
30 seconds
• Dithizone solution (5mL) and shake for 30
seconds

49. Limit test for Arsenic
• Indicated in terms of ppm i.e parts of
arsenic as per million parts (by weight )
of the substance
• Apparatus:
• Conical flask closed with stopper through
which passes a lower glass tube ( insert
50-60mg of lead acetate cotton)
• A second glass tube is placed in contact
with the first and is held in position by
clips
• Between the flat surfaces of the tubes
place a disc of mercuric chloride

50. TEST SOLUTION STANDARD SOLUTION
Test solution 10 ppm Arsenic standard solution
diluted to 50ml water (1mL)
Add 1M KI (5mL) + Zinc AsT (10g) Add 1M KI (5mL) + Zinc AsT (10g)
Assemble the apparatus, immerse the
flask in water bath at a temperatures
such that a uniform evolution of a gas is
maintained
Assemble the apparatus, immerse the
flask in water bath at a temperatures
such that a uniform evolution of a gas is
maintained
After 40min any stain on the mercuric
chloride paper should not be more
intense than the standard solution
After 40min any stain on the mercuric
chloride paper should not be more
intense than the standard solution