The document discusses the various types of incompatibilities in pharmaceutical formulations, including physical, chemical, and therapeutic incompatibilities. It explores definitions, manifestations, and correction methods for each type, providing examples and factors that lead to incompatibilities, such as changes in solubility and drug interactions. The importance of recognizing and correcting potential incompatibilities during drug formulation to ensure safety and efficacy is emphasized.

1. UNIT-8: Incompatibilities In
Formulation
1
BY: FM
FANTAHUN M.

2. Contents
2
BY: FM
 Introduction
 Types of incompatibilities
 Physical incompatibilities
 Chemical incompatibilities
 Therapeutic
incompatibilities
 Correction of incompatibilities

3. Introduction
3
BY: FM
 Incompatibility is defined as a result of mixing of two or
more
antagonistic substances and undesirable product is formed,
 which may affect the safety
, efficacy
, appearance and stability
of the pharmaceutical product.
 Incompatibilities may be detected by changes in
 the physical, chemical and therapeutic qualities of the medicine.
 Incompatibility arise during
 compounding, manufacturing, packaging, dispensing, storage or
administration.

4. Types of Incompatibilities
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BY: FM
1. Physical Incompatibilities
2. Chemical Incompatibilities
3. Therapeutic
Incompatibilities

5. 1. Physical Incompatibilities
5
BY: FM
 Physical incompatibilities are those in which
 the physical properties of the ingredients produce a mixture
or
preparation that is
 unacceptable in the appearance or accuracy of dosage,
 non-uniform, or
 unpalatable mixtures,
 which pose the potential danger of non-uniform
dosage.
 form various physical changes in final product.
 Such as color, odor, taste, viscosity and morphology.
 usually involve properties such as solubility, melting
point, polymorphic forms, freezing point, dielectric
constant, etc.

6. Cont. . .
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BY: FM
 Physical incompatibilities may be corrected by any of the
following
methods
 Change the order of mixing
 Emulsification
 Addition of suspending agent
 Addition, substitution or omission of any ingredient

7. Cont. . .
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BY: FM
 Manifestations of physical incompatibility:
 Insolubility: Insolubility of prescribed agent in vehicle
 Immiscibility: Immiscibility of two or more liquids
 Precipitation: occurs due to solvents is insoluble when it
is added to solution
 Liquefaction: Liquefaction of solids mixed in a dry state
(called
eutexia)

8. Cont. . .
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BY: FM
Insolubility:
 Inability of material to dissolve in a particular solvent system.
 The majority of incompatibilities are due to insolubilities of
the organic as well as inorganic compounds in particular
solvents.
 Incomplete solution can occur when two or more substances
are combined and may not give a homogeneous product because
of immiscibility or insolubility.

9. Cont. . .
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BY: FM
 Example of prescription containing
 Ephedrine sulfate 0.25g
 Menthol 0.02mL
 Liquid paraffin qs 30mL
 Make a nasal drop
 Cause
 ephedrine sulfate is a salt which is soluble in water but
insoluble in organic solvents, liquid paraffin.
 Solution
 Anhydrous ephedrine sulfate is soluble in liquid paraffin
and hence it can be used to prepare clear solution.

10. Cont. . .
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BY: FM
 The following factors affect the solubility of prescribed agent
in
vehicle and may render it less soluble:
1.Change in pH
2.Milling
3.Surfactant
4.Chemical reaction
5.Complex formation
6.Co-solvent
 Any change in previous factors may lead to precipitation of
drugs
and change in their properties.

11. Cont. . .
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BY: FM
Precipitation
 can occur when a vehicle is added to a substance that is soluble
in
one solvent and is not soluble in this second vehicle or solvent.
 An example would be the addition of water to compound
benzoin tincture.
 Tincture of benzoin is a solution of benzoin resin in ethanol.

12. Cont. . .
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BY: FM
 Example of prescription
containing
 Tincture benzoin 5g
 Glycerin
 Rose water
qs
10mL
100mL
 Compound tincture benzoin lotion
 Cause
 Tincture benzoin compound contain resins, change in
solvent system results in an unavoidable precipitate.
 Solution
 Addition of tincture with rapid stirring yields a fine
colloidal dispersion.

13. Cont. . .
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BY: FM
Immiscibility:
 The inability of two or more substances or liquids to
readily dissolve into one another.
 Immiscibility occurs when a vehicle is added to a solution of
something like an oil but the oil is not soluble in the second
vehicle.
 This manifestation appears clearly in emulsion, creams,
lotions, some types of ointments.
 Separation in two phases is noticed in these pharmaceutical
dosage forms
 Example would be the addition of water to peppermint spirit
 where the peppermint oil may come out of solution.

14. Cont. . .
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BY: FM
 Example of prescription
containing
Castor
oil
Water
15mL
60mL
 Make emulsion
 Cause
 In this prescription castor oil is immiscible with water due
to
high interfacial tensions, which is a sign of incompatibility.
 Solution
 To overcome this type of incompatibility, emulsification
is necessary with the help of emulsifying agent and
vigorous shaking.

15. Cont. . .
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BY: FM
 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 microorganisms
 Some bacteria grow on constituents of mixture
 Temperature
 Storage must be in room temperature to prevent
separation

16. Cont. . .
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BY: FM
Liquefaction
 Liquefaction of solids mixed in a dry state.
 It means that when two solid substances are mixed
together, conversion to a liquid state take place.
 It happens through the following methods:
 Formation of liquid or soft mass (known as eutectic
mixture): when the solid substance is soluble in another solid
substance which lead to decrease of its melting point of the
mixture to below room temprature and conversion to a liquid
in certain ratios.
 Exit of crystalline water: By mixing hydrated crystals and
dry crystals, crystalline water diffuse to dry crystals.

17. Cont. . .
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BY: FM
 The medicaments showing this type of behavior are camphor,
menthol, phenol, thymol, chloral hydrate and aspirin.
 If such conditions take place,
 compounding such powders becomes difficult since the
ultimate
mixture turns to liquid.

18. Cont. . .
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BY: FM
 Example of prescription
containing
 Menthol
 Camphor
 Ammonium chloride
 Light magnesium carbonate
 Prepare 100g insufflation
 Cause
5g
5g
30g
60g
 In this prescription menthol, camphor and ammonia chloride
get liquefied on mixing with each other.
 Solution
 To dispense this prescription, menthol camphor and
ammonium chloride are triturated together to form liquid.
 Then, add light magnesium carbonate and mix it thoroughly to
make free flowing powder

19. 2. Chemical Incompatibilities
19
BY: FM
 Chemical incompatibilities are those in which
 the ingredients interact or decompose to give new
compounds;
these may or may not produce visible changes.
 Chemical incompatibilities are reaction between two or
more substances which lead to change in chemical
properties of pharmaceutical dosage form.
 Some of these incompatibilities are also instabilities.
 Instability describes degradation, including hydrolysis,
oxidation, and covalent chemical reactions that may be
slowed but not stopped.

20. Cont. . .
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BY: FM
 It should be noted that some incompatibilities are
 intentional,
 as in the preparation of a product called White Lotion,
 and others are not intentional,
 as in the lowering of the pH of a dissolved sodium or
potassium salt of the drug with the precipitation of the
free form of the drug.
 These incompatibilities may be instantaneous (precipitate, color
change, effervescence) or delayed (drug stability, precipitate) and
occur at such a slow rate that no visible change occurs for a
time.
 These incompatibilities should not be dispensed without
correction.
 Chemical incompatibilities may involve different types of chemical
interactions e.g. oxidation, hydrolysis, polymerization,
isomerization

21. Cont. . .
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BY: FM
Oxidation
 is defined as loss of electrons or gain of oxygen.
 Factors lead to oxidation:
 Presence of oxygen, Light, Temperature, PH, Pharmaceutical
dosage form, Type of solvent used, and Presence of
unsaturated bonds.
 How to identify oxidation in pharmaceutical dosage form?
 Change of color, odor, viscosity of dosage form

22. Cont. . .
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BY: FM
Protection of drugs from oxidation:
 Addition of Antioxidants: Vitamin E, vitamin C and
inorganic
sulfur compounds: thiosulfate and polysulfide
 Addition of chemicals which form complexes with metals
e.g. Benzalkonium chloride
 Protection from light:
 Using of dark container
 Storage in dark places
 Packaging with substances which absorbed light

23. Cont. . .
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BY: FM
 Choice of suitable pharmaceutical dosage forms which
reduce the possibility of oxidation process (solid dosage
forms are better than solutions)
 Maintenance of pH by using buffer solution
 Choice of suitable solvent (rather than water)
 Storage in low temperature
 Protection from air by:
 using good closed containers
 Replacement of oxygen by nitrogen

24. Cont. . .
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BY: FM
Hydrolysis
 A chemical reaction in which water is used to break down a
compound;
 this is achieved by breaking a covalent bond in the compound
by inserting a water molecule across the bond.
 Factors induce hydrolysis:
1. Presence of water
2. pH (E.g. Atropine: optimal pH=3.1-4.5)
3. High temperature (Problem by autoclave E.g. procaine)

25. Cont. . .
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BY: FM
Protection from hydrolysis:
1. Protection from moisture by:
 Packaging with substances impermeable for moisture
 Addition of substances that absorb water (CaCO3)
2. Using of solvent rather than water
3. Maintenance of pH by using buffer system
4.Formation of complexes: which protect the drug from the
effect of water
5.Reducing of solubility of substance (i.e. Suspension instead of
solution)

26. Cont. . .
Polymerization
 In polymerization, small repeating units called monomers are
bonded to form a long chain polymer.
 E.g.: Formaldehyde Paraformaldehyde (Polymer:
white
precipitate )
 To avoid this formaldehyde must be stored in
suitable temperature and addition of methanol 15%.
 Ampicillin in high temperature forms polymers which
cause allergy.
 Factors induce Polymerization: Temperature, Light, Solvent, pH
and impurities 26
BY: FM

27. Cont. . .
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BY: FM
Isomerization:
 It means conversion of drug to its isomer
 Isomers have:
 Identical molecular formulas but different arrangement of
atoms.
 E.g. in Geometric isomerization, Cis is more therapeutically active
than trans (e.g: Vitamin A)
 E.g. L-Adrenaline is converted to d-adrenaline by change of pH
or temperature.
 L-Adrenaline is more therapeutically active than d-
adrenaline,
 this is not general for other drugs, d-tubocurarine is more
active than l-type.

28. 3. Therapeutic incompatibilities
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BY: FM
 Therapeutic incompatibilities are now often referred to as
drug
interactions.
 It is the modification of the therapeutic effect of one drug by
the concomitant administration of another.
 A therapeutic incompatibility has been defined as an
undesirable
interaction between two or more ingredients that leads to:
1. Potentiation of the therapeutic effects of the ingredients.
2. Destruction of the effectiveness of one or more of the
ingredients.
3. Occurrence of a toxic manifestation within the patient.

29. Cont. . .
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BY: FM
 Mechanisms of therapeutic incompatibility
 They are divided into two groups:
1.Pharmacokinetics interactions:
 are those in which one agent alters the absorption,
distribution, metabolism and excretion of a second drug
with a resultant change in the plasma concentration of the
later agent.
2.Pharmacodynamics interactions
 are related to the pharmacological activity of
the interacting drugs
 e.g. synergism, antagonism, altered cellular
transport, effect on the receptor site.

30. Cont. . .
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BY: FM
 Different kinds of drug
interaction
 Drug - Drug interaction
 Drug - Excipient interaction
 Excipient - Excipient
interaction
 Drug - Food interaction
 Excipient - Packaging
interaction

31. Cont. . .
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BY: FM
Drug-drug interaction
 Drug-drug interactions occur when a drug interacts, or
interferes,
with another drug.
 This can alter the way of one or both of the drugs act in
the body, or cause unexpected side effects.
 This action can be synergistic (when the drug's effect is
increased) or antagonistic (when the drug's effect is decreased)
or a new effect can be produced.

32. Ont. . .
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BY: FM
Synergism
 Many drugs shows the synergistic effect,
 when two drugs are given together the effect of each drug
is increased
 E.g. Aspirin and Paracetamol increase analgesic activity
Penicillin and streptomycin increase the antibacterial
activity.
 Example of prescription
containing
 Amphetamine sulphate 20 mg
 Ephedrine
sulphate
 Simple syrup qs
100
mg
100 ml
 Make a mixture. Both are sympathomimetic drugs that use
additive effects.
 Hence of individual drugs dose should be reduced to avoid the
therapeutic incompatibility.

33. Cont. . .
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BY: FM
Antagonism
 When two drugs are given together and one drug opposes the
pharmacological activity of another drug it is known as
antagonism.
 Example of prescription containing
 Aspirin
 Probenecid
0.6
g
0.5
g
 When prescribed together their combination produces
antagonistic
effect on probenecid.

34. Cont. . .
34
BY: FM
Drug-excipient Interaction
 Drug-excipient interaction occurs between the API and
excipient.
 E.g. Certain amine drugs (paracetamol) react with lactose
(diluent) in the presence of Magnesium stearate to form
brown color compound.
 This may cause darkening of the tablets and the integrity
of
the tablet maybe loss.

35. Cont. . .
35
BY: FM
Excipient-excipient Interaction
 This type of interaction occurs between two or more excipients
in
a drug molecule.
 E.g. In proper addition of electrolyte such as- Ca++ or Mg++
ion in suspension containing sodium carboxymethyl cellulose
(Na CMC) which will cause formation of Calcium/Magnesium
CMC.
 The suspending agent will be destroyed and cannot
perform its function.

36. Cont. . .
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BY: FM
Drug-food interaction
 A drug-food interaction happens when the food affects the
ingredients in a medicine.
 Example-
 Blood-thinning drugs such as Coumadin® (warfarin)
interfere
with vitamin K-dependent clotting factors.
 Eating too much green leafy vegetables, which are high
in vitamin K, can decrease the ability of blood-thinners
to prevent clotting.
Excipient-packaging material interaction
 In some pharmaceutical formulation excipient and
packaging material may interact with each other.

37. Correction of Incompatibilities
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BY: FM
 Incompatibilities are easier to prevent than to correct.
 If one can recognize a potential incompatibility and correct it,
then it can save time, materials, and money.
 One must be cautious to not "imagine" incompatibilities
where
they may not exist.
 If one cannot be certain,
 it may be beneficial to prepare a small quantity of a
preparation for observation.

38. Table: Methods and techniques used to correct
incompatibility
38
BY: FM

39. Cont. . .
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BY: FM
 Typically, physicochemical stability is assessed at the pre-
formulation stage of development.
 A drug substance candidate is treated with acid, base, heat,
light, and oxidative conditions to assess its inherent chemical
stability.
 Binary mixtures of the drug substance with individual
excipients are also investigated at the pre-formulation stage.
 These tests are performed to determine the drug substance
sensitivity to degrade or reactivity with common
pharmaceutical excipients.
 With an understanding of the stability/reactivity of a drug
substance in the preformulation stage, it is possible to formulate
the drug product to minimize drug decomposition.

40. 40
BY: FM