PHYSICOCHEMICAL

INCOMPATIBILITIES

Drug Incompatibility
Problems that arise during the dispensing and
compounding of the Rx or administration of the drug

Types of Incompatibilities

Therapeutic
Physical
Chemical

Therapeutic Incompatibility

1. Pharmacokinetics:
ADME
2. Pharmacodynamics
synergism.antagonism, altered cellular transport,
effect on the receptor

Therapeutic Incompatibility
Pharmacokinetic interactions
1. Altered GIT absorption
2. Displaced protein binding
3. Altered metabolism
4. Altered renal excretion

Therapeutic Incompatibility
Pharmacodynamic interactions
a. Additive
b. Synergism
c. Potentiation
d. Antagonism

Therapeutic Incompatibility

Probenecid + Penicillin
Caffeine + Ergotamine tartrate
Antiparkinson drugs + Antipsychotic drugs

Physical Incompatibility

Interaction between two or more substances which

lead to change in color, odor, taste, viscosity
Incomplete solution- production of non-homogenous
product due to insolubility or immiscibility
Ex: resins in H2O, oils+silicones+H2O

Physical Incompatibility
Precipitation= materials in solution

forced out of
solution due to dehydration or salting out, change in
solvent system and temperature
salting out- aqueous solutions of slightly soluble
non-electrolyte + electrolyte
ex: hydroalcoholic solution + electrolytes; sugars +
hydrophilic colloids; NaCl/KCl benzoic acid
salting in- increased solubility of organic
compounds + salt
ex: globulins + dilute salt solutions

Factors affecting solubility (for Ca/PO4

mixture)

Concentration of Ca
Salt form of Ca
Concentration of amino acids
Amino acids decomposition
Concentration of dextrose
Temperature of solution
pH of solution
Presence of other additives
Order of mixing

Physical
occurs when electrolyte
Salting-out-Incompatibility

is added to an
aq. solution. The salt competes with the solute for
water molecule to allow hydration reduced
solubility of the dissolved material
Liquefaction eutexia or formation of eutectic
mixture
Ex: phenol, menthol, salol, thymol, ASA +
paracetamol; ibuprofen stearic acid; stearyl
ROH,/Ca or Mg stearate
- Release of H2O of hydration (atropine SO4, FeSo4,
citric acid and MgSO4) -- efflorescent
water
(hygroscopic)
- Absorbs

Physical Incompatibility

Incorrect form prescribed

Ex: AtSO4
liquid petrolatum
*Alkaloidal salt is insoluble in liquid petrolatum free
alkaloid is soluble
Vaporization
volatilization (drug loss-volatile oils, NTG, alcohols)
Remedy: dispersion of solid drug in macromolecule,
packaging (NTG tablets)

Physical Incompatibility
Polymorphism polymorphs with

lowest free energy

has the highest melting point and most stable and
lowest dissolution rate
Ex: steroids, chloramphenicol palmitate, theobroma
oil/cacao butter- 2 polymorphs ()
Water loss- evaporation of H2O from liquid
preparation - crystallization
Ex: water loss from o/w creams - surface rubbery
feel, cracking of emulsion
Remedy: store in well-closed containers

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

Unintended and undesirable chemical changes or

reaction

Types:
a.
Immediate
(precipitation,
color
change,
effervescence)
(DO NOT DISPENSE)
b. Delayed
mixtures react at a slower rate; may or may not
result to a loss in therapeutic activity
dispense if to be consumed before 10% of
therapeutic activity is lost

Classification:
1. Oxidation- gain of O, removal of H, loss of e Accelerated by light, trace metal ions, coinage
metals, O2 from air,
Ex: stannous salts -- stannic form (anticariogenic)
Fe in Fe +3 --- OA in organic compounds
Fe +2 --- RA

Chemical Incompatibility
2. 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

Chemical Incompatibility
3. Polymerization
small repeating units called monomers are bonded to form
a long chain polymer.
Ex:
Formaldehyde Paraformaldehyde (Polymer: white precipitate )
To avoid this formaldehyde must be stored in suitable
temperature and addition of methanol 15%.

Chemical Incompatibility
4. Isomerization:
Optical isomerization:
Conversion of optical active drug into less active
Ex: L-adrenaline to D-adrenaline
5. Decarboxylation:
Ex.: NaHCO3 Na + CO2

Chemical Incompatibility
6. CO2 absorption:
Ex: Ca(OH)2 + CO2 CaCO3
7. Combination:
Ex.: Surfactants with positive and negative charges
8. Formation of insoluble complexes:
Ex.: Tetracycline + heavy metals