Physical and Therapeutical Incompatibilities

1. BY:
VENUGOPAL N

2. 2
2
Incompatibility
Definition
Incompatibility refers to interactions between two or more
substances which lead to changes in chemical, physical,
therapeutic properties of the pharmaceutical dosage form.

3. 3
3
Types of Incompatibility
Therapeutic Incompatibility
Physical Incompatibility
Chemical Incompatibility
1
2
3

4. 4
4
Therapeutic
Incompatibility
Definition:
It is the modification of the therapeutic effect of one drug by the
prior or simultaneous administration of another.
Based on:
 Pharmacokinetic properties
 Pharmacodynamic properties

5. 5
5

7. 7
7
Mechanisms
Pharmacokinetics
Involve the effect of a drug on another from the point of view
that includes absorption, distribution, metabolism and
excretion.
Absorption Distribution
Metabolism Excretion

8. 8
8

10. 10
10
Physical
Incompatibility
Definition:
Interaction between two or more substances which lead to
change in color, odor, taste, viscosity and morphology.
It is also called pharmaceutical incompatibilities.
It is a result of insolubility & immiscibility, precipitation,
liquefaction, adsorption & complexation of solid materials.

11. 11
11
Physical incompatibilities can be corrected by one or more
methods viz.
• Order of mixing
• Alteration of solvents
• Changes in the form of ingredients
• Alteration of volume
• Accurate choice of emulsifying & suspending agent.

12. 12
12
Chemical
Incompatibility
Definition:
Reaction between two or more substances which lead to change in
chemical properties of pharmaceutical dosage form.

13. 13
13
Types Of Chemical Changes
• Oxidation
• Hydrolysis
• Polymerization
• Isomerization
• De-carboxylation
• Absorption of Carbon-di-oxide
• Combination
• Formation of insoluble complexes.

14. 14
14
THERAPEUTIC
INCOMPATIBILITIES

15. 15
15
Pharmacokinetic
Interactions
1. Altered GIT absorption
2. Displaced protein binding
3. Altered metabolism
(Enzyme inhibition, induction and metabolism)
4. Altered renal excretion

16. 16
16
ADME

17. 17
17
Pharmacodynamic
Interactions
It include,
1. Additive effect
2. Synergistic effect
3. Potentiation effect
4. Antagonistic effect

18. 18
18
Additive effect
Occurs when two or more drugs having the same effect are combined and
the result is the sum of the individual effects relative to the doses used.
This additive effect may be beneficial or harmful to the patients.
Example: Codeine with acetaminophen work together to produce better
pain control.
• An additive effect may be intentional or may unintentionally cause harm.
Example: Alcohol and aspirin can both cause GI bleeding; taken together
they greatly increase the risk.
1+1=2

19. 19
19
Synergistic effect
Occurs when two or more drugs, with or without the same overt
effect, are used together to yield a combined effect that has an
outcome greater than the sum of the single-drugs active
components alone.
Example: A beneficial synergistic effect occurs when two different
types of antibiotics that work in very different ways are combined,
such as penicillin G and an aminoglycoside antibiotic.
1+1=3

20. 20
20
Potentiation effect
Describes a particular type of synergistic effect-a drug interaction
in which only one of two drugs exerts the action that is made
greater by the presence of the second drug.
In other words, a drug that has a mild effect enhances the effect of
a second drug.
Example: Hydroxyzine increases the effect of morphine.
1+0=2

21. 21
21
Antagonistic effect
Reactions have the opposite effect of synergism and result in a
combined effect that is less than either active component alone.
Antagonistic interactions can also occur at receptor sites.
Example: Protamine reverses the action of heparin.
1+1=0/0.5

22. 22
22
Therapeutic incompatibility is due to:
A) Medication errors
B) Drug interactions

23. 23
23
A) Medication Errors
Medication errors done by doctors, pharmacists, nurses &
patients.
Medication errors can be categorized as –
1. Prescription errors
2. Dispensing errors
3. Selection errors
4. Bagging errors
5. Administration errors

24. 24
24
1. Prescription Error
The prescription should be neatly & correctly written by the
medical practitioner, otherwise it is major hassle for the
pharmacists.
- Spelling mistakes.
- Illegible handwriting.
Types of Prescription errors:
a) SALA Medicines(Sound Alike Look Alike):
Tab. Dulcolax a laxative tablet & Tab . Duoclox an antibacterial
tablet.

25. 25
25
b) Type of dosage form:
Same drug can be available in tablet, capsule or liquid oral
dosage forms for adults, drops for pediatric patients. Selection
of dosage form is based on ability of patients to take that
medicines.
c) Quantity to be dispensed:
Pharmacists should check the dose & see that the quantity of
medicine is sufficient to complete a course.

26. 26
26
d) Strength of Medicines:
Some medicines, especially those whose dosing is critical , are
available in different strengths.
Eg. Haloperidol , antipsychotic drug available in the form of
tablets of various strength viz. 0.25, 2mg, 5mg,10mg, 20 mg.
e) Dose & Direction:
Pharmacists should check the dose, dosage regimen & direction
to use.

27. 27
27
2. Dispensing Errors
a) Poor handwriting
b) Long prescription
c) Incomplete patient information
d) Deviation in attention of pharmacist
e) Misunderstanding of verbal orders.

28. 28
28
3. Selection of medicine
•While removing medicines from shelves pharmacist should be
alert.
•He should remove the correct medicine.
•SALA medicines should not be kept adjacent to one another.

29. 29
29
4. Bagging Errors:
• After billing, dosage forms should be packed in appropriate
bags or covers & handed over to the right person.

30. 30
30
5. Errors in administration
i) Breaking the coated or sustained release tablets.
ii) Suspension administration without shaking.
iii) Taking medicament at wrong time before or after meal.
iv) Skipping dose
v) Wrong time (before or after meals)
vi) Adult medicine to children

31. 31
31
B) Drug interactions
1. Contra-indicated drugs
2. Synergistic and antagonistic action
3. Intentional drug interaction
4. Unintentional drug interaction

32. 32
32
1. Contra – indicated drugs
There are certain drugs which may be contraindicated in a
particular disease or a particular patient who is allergic to it.
Example:
a)The penicillin & sulpha drugs are contraindicated to the patients
who are allergic to it.
b) Corticosteroids contraindicated in peptic ulcer patients
c)Morphine/barbiturates contraindicated in asthma patients

33. 33
33
2. Synergistic & antagonistic drugs
Many drugs exhibit Synergism & Antagonism when administered
in combination.
a) When the two drugs are prescribed together, they tend to
increase the activity of each other, called as synergism.
Example:
– A combination of aspirin & paracetamol increase the
analgesic activity.
– A combination of penicillin & streptomycin increases the
anti-bacterial activity

34. 34
34
b)When two drugs having the opposing pharmacological effects
are called antagonism.
Example:
A combination of acetyl salicylic acid and probenecid used in the
treatment of gout, where probenacid neutralize the action of
action of acetyl salicylic acid. Thus there is no action.

35. 35
35
3. Unintentional drug interaction
The effect of one drug is altered by the prior or simultaneous
administration of another drug.
Example:
Tetracycline hydrochloride 250mg
Direction –take one capsule with milk
But, Tetracycline inactive by calcium which is present in milk.

36. 36
36
4. Intentional
drug interaction
Rx
Acetophenetidin 150mg
Acetyl salicylic acid 200mg
Caffeine 30mg
Send 10 capsules.
Acetophenetidin & acetyl salicylic acid are analgesic.
– Acetophenetidin depresses the CNS & this effect is
undesirable.
– Caffeine is CNS stimulant to neutralise the side effect of
acetophenetidin.

37. 37
37
PHYSICAL INCOMPATIBILITIES
• When two or more than two substances are combined together,
a physical change takes place and an unacceptable product is
formed.
• Interaction between two or more substances which may lead to
change in color, odor, taste, viscosity and morphology. It is also
called as pharmaceutical incompatibility.

38. 38
38
Manifestations of physical incompatibility
The following list outlines the various ways incompatibility
between or among drug agents may be manifested.
• Insolubility:-insolubility of prescribed agents in vehicle
• Immiscibility:-Immiscibility of two or more liquids
• Precipitation:-It occurs due to solvent is insoluble when it is
added to solution.
• Liquefaction:-Liquefaction of solids mixed in a dry state (called
eutexia)

39. 39
39
INSOLUBILITY
• It means the inability of material to dissolve in a particular
solvent system.
• The majority of incompatibilities is due to insolubility of the
inorganic as well as organic compounds in particular solvents.

40. 40
40
The following factors affect the solubility of prescribed agent in
vehicle and may render it less soluble.
• Change in PH
• Milling
• Surfactant
• Chemical reaction
• Complex formation
• Co-solvent

41. 41
41
• Any change in previous factors may lead to precipitation of
drugs and change in their properties.
• Substances like chalk, acetyl salicylic acid, succinyl
sulphothiazzole, zinc oxide, and calamine are the common
examples of in diffusible solids.
• Some tinctures containing resins or chlorophyll may provide
precipitation when added to the aqueous system7 .

42. 42
42
E.g.:-Mixture of prepared chalk
Rx
Chalk powder –2g
Tincture catechu – 2ml
Cinnamon water – 2ml
Causes: - Chalk powder is not soluble in water. It gets precipitated
when added to aqueous medium. These precipitates are found in
diffusible in nature which results in physical incompatibility.
Remedy: - Use of suspending agents is necessary to suspend the
precipitated chalk particles.
Generally 2% W/V of compound tragacanth powder is
recommended as suspending agent.

43. 43
43
The corrected prescription is Mixture of prepared chalk
Rx
Chalk powder –2g
Tragacanth – 0.4g
Tincture catechu – 2ml
Cinnamon water up to 30ml

44. 44
44
2. IMMISCIBILITY
• When two such ingredients are combined resulting in a non-
homogenous product, such ingredients are called immiscible to
each other and the phenomenon is called immiscibility.
• This manifestation appears clearly in emulsions, creams,
lotions, some types of ointments.
• Separation in two phases is noticed in this pharmaceutical
dosage form.
• Storage must be in room temperature to prevent separation.

45. 45
45
The following factors lead to immiscibility
• Incomplete mixing
• Addition of surfactant with
– Unsuitable concentration
– False time of addition
– Unsuitable for the type of emulsion
• Presence of micro – organisms
– Some bacteria grow on constituents of mixture

46. 46
46
E.g.:- Gelatin Arabic gum
• Others produce enzymes which oxidize the surfactant.
• Temperature
• Oils and water are immiscible with each other which shows
physical incompatibility

47. 47
47
E.g.:- Castor oil emulsion
Rx
Castor oil – 15ml
Water – 60ml
Causes: -In this prescription castor oil is immiscible with water due to
high interfacial tensions, which is a sign of incompatibility.
Remedy:-To overcome this type of incompatibility emulsification is
necessary with the help of an emulsifying agent.
The corrected prescription is Castor oil emulsion
Rx
Castor oil – 15ml
Acacia – 2% W/V
Water– upto 60ml

48. 48
48
LIQUIFACTION
• When certain low melting point solids are mixed together, a
liquid or soft mass know as eutectic mixture is produced.
• This occurs due to the lowering of the melting point of the
mixture to below room temperature and liberation of hydrates.
• If such conditions take place, compounding such powders
becomes difficult since the ultimate mixture turns to liquid.
• The medicaments showing this type of behavior are camphor,
menthol, phenol, thymol, chloral hydrate, aspirin, sodium
salicylates, etc……

49. 49
49
E.g.:-Insufflations
Rx
Menthol – 5g
Camphor – 5g
Water – 60ml
Causes: - This mixture is a physical incompatibility because both
the ingredients in the prescription are liquefiable of mixed
together.

50. 50
50
Remedy:-
• These substances can be dispensed by any one of the following
method.
• Triturate together to form liquid and mixed with an absorbent (light
kaolin, magnesium carbonate) to produce the following powder.
• The individual medicaments is powdered separately and mixed with
an adsorbent and then combined together tightly and filled in a
suitable container.
Hence the corrected prescription is
Rx
Menthol – 5g
Camphor – 5g
Light kaolin– 0.2g

51. 51
51
PRECIPITATION
• Solubilized substances may precipitate from it solution if a non-
solvent for the substances is added to the solution.
• E.g.:- Resins are insoluble in water
• Alcoholic solution of resins + water =precipitated resins.
• Aqueous dispersions of hydrophilic colloids (polysaccharide
mucilage + high concentration of alcohol or salts) =precipitated
colloids.
– High concentration of electrolytes causes cracking of soap
emulsion by salting out the emulsifying agents.

52. 52
52
• Vehicles (one or more organic liquids) use to dissolve
medicaments of low solubility; water soluble adjuvant
practically inorganic salts may be precipitated in such vehicles.
• When tinctures containing resinous matter are added in water,
resin agglomerates forms in diffusible precipitates.
• This can be prevented by slowly adding the undiluted tincture
with vigorous shake.
• Suspension or by adding some suitable thickening agent.

53. 53
53
E.g.:- Lotion of compound tincture of benzoin
Rx
Tincture benzoin compound – 5g
Glycerin – 10ml
Rose water upto 100ml
Causes: - Tincture benzoin compound contain resins. This change
in solvent system results in an unavoidable precipitate.
Remedy: - Addition of tincture with rapid stirring yields a fine
colloidal dispersion. So there is no need of any suspending agents.