INCOMPATIBILITIES

N.SANTHI PRIYA
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES
 DEFINITION
• The undesired change taking place in the physical ,
chemical or therapeutic properties of the
medicament of a prescription are mixed together , is
termed as INCOMPATIBILITY
• While handling a prescription containing
combinations many a times problems
asscociated with therapeutic ,physical and
chemical properties of the drugs arise
UNINTENTIONAL INCOMPATIBILITY
• TOLERATED – interaction is minimized but composition of the
prescription is not altered
• ADJUSTED – interaction is prevented by addition or substitution of
constituents without affecting the medicinal action of the preparation

INTENTIONAL INCOMPATIBILITY
The prescriber wants that the prescription , be dispensed as it is
 3 CLASSES
• THERAPEUTIC INCOMPATIBILITY
• PHYSICAL INCOMPATIBILITY
• CHEMICAL INCOMPATIBILITY
 THERAPEUTIC INCOMPATIBILITY
• When the response to one or more drugs in the
patient is of a nature or intensity different from that
intended , it is known as therapeutic incompatibility
REASONS
1. Dosage errors
2. wrong dose or dosage form
3. Contraindicated drug
4. Synergistic or antagonistic drugs
5. Drug interactions
 DOSAGE ERROR
• Dispensing of an overdose of prescription
• Any experienced pharmacist should be able to detect such an error
while checking the prescription
Ex:
 Atropine sulphate-0.06gm
 Phenobarbital-0.015gm
 Asprin-0.300gm
If the quantity of atropine sulphate for a single capsule is more than the
recommended maximum dose,The physician should be contacted
EX-2
Codeine phosphare-0.5gm
ONE POWDER TO BE TAKEN AT BED TIME
 Wrong dose or dosage form
• Possibility of dispensing the wrong drug
because of confusingly similar names
• Ex:
1. Prednisone and prednisolone
2. Protamine and protamide
3. Digoxin and disgitoxin
 Contraindicated drugs
• Certain drugs are contraindicated in a particular
disease or when a particular patient is allergic to it
1. Corticosteroids-contraindicated to patients having
peptic ulcer
2. Morphine,barbiturates-dangerous in severe asthma
3. Pencillin and sulphur drugs - allergic to patients
4. Vasoconstrictors-should not be given to
hypertensive patients
 Example-contraindication
Sulphadiazine-0.25gm
Sulpharmerazine-0.25gm
Ammonium chloride -0.5gm
Ammonium chloride being a urinary acidifier , would
cause deposition of sulphonamide crystals in kidney
Hence this contraindicated combination should
be avoided
 Synergistic or antagonistic drugs
Synergistics:
• Penicillin derivatives+probenicid
• Aspirin +paracetamol
Antagonistics:
Amphetamine X barbiturate
Stimulants X sedatives
Cholinergic drugs X anticholinergic drugs
Purgatives X antidiarrhoeals
Antacids X antibiotics
 CHEMICAL INCOMPATIBILITY
• Chemical changes which occour due to the
interaction of the prescribed substances
leading to the formation of a harmful or
dangerous product
• They often occour by
1. OXIDATION – REDUCTION
2. HYDROLYSIS
3. COMBINATION OF BOTH
 Oxidation – reduction
1. Oxidation -Loss of electrons
2. Reduction - Gain of electrons
Oxidization of prescriptions
• On exposure to air
• Higher storage conditions
• Light
• Over dilution
• Incorrect pH adjustments
• Presence of catlysis
• Trace metal ion catalysis - complexing agents
like disodium edetate , sodium calcium
edetate
• Autooxidation of fats and oils
,phenols,aldehydes,vitamins - antioxidants
like propyl gallate,
thymol,BHT,BHA,hydroquinone
• Light Reduces siver,mercury,gold salts to
metallic form
Example Problem Remedy

Sodium salicylate-8g Solution darkens due to Antoxidant prevents

Sodium bicarbonate-16g alkali catalysed oxidation development of color
Pepperment water -18ml

Potassium chlorate -4m Ferric oxide is oxidised to Dispense the reactant

Syrup ferric chloride -15ml postassium chlorate substances seperately
Purified water -18ml CLEAR –fresh solution
Iodine deposts -
Onstanding

Mild mecurous chloride DUE TO PRESENCE OF THE PRESECRIPTION

Potassium bromide MOISTURE incompatibility SHOULD NOT BE
Sucrose occours DISPENSED
 Acid base reactions
I. Precipitation
II. Gas formation
III. Color development or color change
 Precipitation
EXAMPLE PROBLEM REMEDY

Cocaine HCl Sodium borate imparts ELIMINATE SODIUM

Boric acid alkalinity and water BORATE
Sodium borate insoluble cocaine base is
Purified water precipitated
 Evolution of gas
• Gas may be evolved due to a chemical
reaction between ingredients
EXAMPLE PROBLEM REMEDY
Sodiumbicarbonate -1.5 Boric acid in the The substances should
Borax -1.5 presence of glycerin be mixed with water in
Phenol -0.75 forms glyceroboric acid an open vessel until
Glycerin -25ml effervescence ceases

Reacts with bicarbonate

gas is evolved
Reaction of alkali Double decomposition The resulting mixture
bicarbonates with reaction occours should not be packed
soluble calcium and resluting the the until the reaction is
magnesium salts formation of insoluble complete
carbonate and CO2
 Breaking of structure of disperse systems

• Gelling agents like carbomers , sodium cmc

lose viscoisty by change in pH outside an
optimum range
• Carbomer pH< 5 and pH> 10 liquify
• Alginic acid at pH< 3 precipitates sodium
alginate to form sodium derivative
Change in or development of color
• Dyes – color -IONIZATION DEPENDING ON pH

DYE CHANGE WITH pH

GENTIAN VIOLET ( ANTISEPTIC) In acidic Green to Yellow

IS
BASIC PURPLE IN COLOR

IN ACIDIC
PHENOPHTHALEIN ( LAXATIVE ) COLORLESS
IN ALKALINE
RED
 HYDROLYSIS
DRUGS PRONE TO HYDROLYSIS : GELATIN- SUCROSE
Procaine FLAVORING OILS
Sulphonamides CHLOROBUTANOL
Chlorothiazide Hydrolysis promoters :
Barbituric acid
Aspirin • Heat catalysts
Alkaloids • Hydrogen ions
Penicillin • Hydroxyl ions
ADDITIVES PRONE TO HYDROLYSIS : Ex: ESTERS, AMIDES, METALS like Zn,
Fe
EXAMPLE PROBLEM REMEDY

Sodium salicylate Alkalinity causes SALTS SHOULD BE

Phenobarbital decomposition of DISPENSED
sodium Bvitamin SEPERATELY
Vitamin B complex Precipitation of
elixer acids from sodium
salt
 EXPLOSIVE COMBINATIONS
EXAMPLE PROBLEM REMEDY
Potassium chlorate Explosion may takes Powder each
Tannic acid place if the ingredient
sucrose ingredients are seperately
mixed by simple Minimize rubbing
trituration in mortar during
and pestle compounding
Tumble the
powders on a sheet
of paper is
satisfactory
 Racemization
• Conversion of optically active form of a drug
substance to an optically inactive form without a
change in chemical constitution associated with
reduction in pharmacological activity
Examples
• Adrenaline
• Ephedrine
• Norephedrine
• HYOSCYMINE – racemizes to atropine
 Complexation
• The medicaments or excipients get bound to
or trapped inside the macromolecules
• The complexes are too large to penetrate cell
membranes
• Reversible complexation is useful
• POVIDONE – IODINE Complex : useful to
reduce the irritancy and stability of the drug
 Other changes
1. Cementation
2. Polymerization
3. Development of heat
4. Lowering of temperature
5. Double decomposition
6. Substitution
7. Addition
 PHYSICAL INCOMPATIBILITIES
• They are easier to PREDICT, DETECT AND
CORRECT by applying proper technique ,
mixing, selection of additives etc
• They are manifested by
1. Non-uniform
2. Unsighty
3. Unpalatable products
 CLASSIFICATION
• INSOLUBILITY
• PRECIPITATION
• SEPERATION OF IMMISCIBLE LIQUIDS
• LIQUEFACTION OF SOLID
• PHYSICAL COMPLEXATION
• MISCELLANEOUS
 INSOLUBILITY
• When a drug is insoluble in a solvent , it may
create in proper administration of the dose
• Ex:
• Solubility enhancers
• Alteration in the volume
• Settling - suspending agents
• Poor wettability – levigating agents
 Precipitation of the drug
• A Solubilized substance may precipitate from its solution if a non
– solvent for the substance is added to the solution
• Poor solvent – order of mixing
• Precipitation – suspension
• Cap locking – co-solvents
• Grainy semisolids – non uniform cooling
EX:
1. HYDROCOLLOIDS +ALC addition --> PPTS
2. Aromatic waters + electrolytes addition -> VOLATILE OILS
precipitates
3. ELECTROLYTES + in SOAP EMULSIONS -> cracking
 Liquefaction
Eutectic substance (LOW MELTING SOLIDS )such as camphor,
menthol, thymol if mixed together undergo liquefaction ex:
• Eutectic powders
• Insufflations
• Siedliz powder
TO OVERCOME:
1. Mixtures dispensed separately
2. Triturate separately with adsorbent to give free flowing
product
3. If already liquefaction occurred -> adsorbed on powder ->
filled in capsules -> dispensed
 Example – Liquefaction
 Menthol – 2g
 Camphor -2g
 Ammonium chloride – 20g
 Make a powder
1. If the ingredients are triturated together , they shall liquefy
due to the formation of eutectic mixture
2. Powder form is obtained by mixing them separately in
suitable adsorbent like Mg Co3
3. 3 mixtures dispensed separately to obtain a powder
 Adsorption and complexation
Drug + excipient Physical complexes
1. Alter appearance
2. Alter medicament activity
ex :

Adsorption of cyanocobalamin by talc as tablet

lubricant decrease the adsorption of this
vitamin in GIT
Adsorption of preservatives like parabens onto
drugs lead to loss of antimicrobial activity
INORGANIC INCOMPATIBILITIES
1. Incompatibilities of metals and their salts
2. Incompatibilities of acids
3. Incompatibilities of alkalies
ORGANIC INCOMPATIBILITIES
BY
4. Purine bases
5. Alkaloids
6. Pyrazolone derivatives
7. Amino acids
8. Quaternary ammonium compounds
9. Glycosides
10.Anesthetics
 INCOMPATIBILITIES OF THE METALS AND THEIR SALTS

GROUP 1A ( Li,Na,K,Rb,Cs,Fr)
1. sodium salicylate + potassium bicarbonate – sodium bicarbonate
ppt , darkening due to salicylates
2. K+ Tartaric acids- ppt , Sulfurated potash incompatible with acids
and liberate H2S
3. Lithium carbonate – in alkaline or neutral solutions
GROUP 1 B (CU,Ag,Au)
4. Copper salts ppts tannic acid ,arsenates , alkalis etc
5. Cupric salts – iodides, acetates
6. Silver salts decomposed by light and form metallic silver
7. Ago – powerful oxidizing agent and causes explosion when
triturated with reducing agents
8. Gold salts +weak reducing agents - gold metal
 INCOMPATIBILITIES OF THE METALS AND THEIR SALTS

• Group II- A ( Be,Mg,Ca,Ba,Ra)

Mg-
1. Mg.trisilicate,adsorbs alkaloids , dyes, toxins
2. MgO – adsorbs moisture,co2 when exposed to air
3. Mg.sulfate – water soluble salt , but ppts on addition on soluble
phosphates,carbonates ,salicylates
4. Mg.salts react with bromide reacts with ammonia –( ANTACIDS X
Bromide preparations)
Ca-
Incompatible with hydroxides , citrates , carbonates , oxalates
,tartrates, phosphates ,forms precipitates except in acids
 INCOMPATIBILITIES OF THE METALS AND THEIR SALTS

Group II – B: ( Zn, Cd , Hg)

Zinc :
1. Soluble zinc salts incompatible with alkali hydroxides,carbonates, phosphates and converts
into insoluble zinc compounds
2. They also precipitates fatty acids , acacia , proteins , tannins

Mercury :
Mercury salts reduced to free metals by light , moisture , trituration

Mercurous salts oxidizing agents Mercuric salts

Hgcl2 + 4KI Hg + K2HgI4 +2KCl
3. Mercurous salts ppts alkaloids proteins tannins organic acids
4. Yellow HgO gets pptd from alkali hydroxide solutions
5. Combined use of ammoniated mercury + salicylic acid in ointments causes
severe irritation due to the formation of mercuric salicylate
6. Calomel decomposes into mercuric chloride and free mercury when exposed
to sunlight or triturated excessively
 INCOMPATIBILITIES OF THE METALS AND THEIR SALTS

Group III –A ( B,Al , Ga, In Ti )

1. Aluminium solutions are acidic
2. Incompatible to weak acids , borax
3. Produce effervescence with carbonates
4. Complexes the penicillin , sulphonamides
when mixed with organic salts
5. Alum incompatible with soluble sulfates
 INCOMPATIBILITIES OF THE METALS AND THEIR SALTS

Group VII – B( Mn ,Tc ,Re)

1. Mn hypophosphite ,Mn salts ppt out as
Mn.hydroxide
2. These ppts darkens on standing due to
absorption of oxygen
3. MnO2 is a strong oxidizing agent and causes
explosion if triturated with reducing agents
like phosphides , hypophosphites and organic
substances
 INCOMPATIBILITIES OF THE METALS AND THEIR SALTS

Group VIII ( Fe, Ru ,Os ,Co ,Rh, Ir ,Ni , Pd, Pt )

Ferrous salts in aqueous solutions are unstable
They gets oxidized to ferric state by precipitation of a basic ferric salt
4FeSO4 + 2H2O+ O2 4Fe(OH)SO4
Oxidation reaction can be prevented by adding iodides and hypophosphites
Incompatible with alkali hydroxides – white ppt of Fe(OH)2 – green – brown
due to oxidation
Ferric salts gets reduced to ferric state by iodides and hypophosphites
2Fe 3+ + 2I- 2 Fe 2+ + I2
Precipitation can be prevented by addition of organic hydroxy acids or their
salts such as tartrates, citrates etc or polyhydric alcohols such as glycerin
and sugars
 INCOMPATIBILITIES OF NON METALS

• Most of the non-metallic elements form acids

and exhibit acidic incompatibilities
• Other non-metal incompatibilities include –
 Carbon
 Sulphur
 Iodine
 INCOMPATIBILITIES OF NON METALS

Carbon –
• Charcoal gets easily oxidized , - so don't triturate with oxidizing agents
• High adsorptive characteristics – so dispensed separately if potent drugs
are present since they may get inactivated
SULPHUR –
Sulphur gets readily oxidized in presence of water
On heating with fixed hydroxides – solubilizes forming metal thiosulphates
14S + 12 KOH K2S3+2K2S3O3+2K2S+K2S5+6H2O
Iodine-
1. Iodine acts as an oxidizing agents in alkaline solution
2. Incompatible with reducing agents like hypophosphite's , arsenites
I2+H3AsO3+H2O 3HI+H3AsO4
3. Iodine + turpentine oil - gives explosive combination
4. Iodine + potassium iodide – precipitates alkaloids
5. Iodine + oxidizing agents – gives iodates
 INCOMPATIBILITIES OF ACIDS

• ALL ACIDS EXHIBIT INCOMPATIBILITIES

 Strong acids
 Weak acids
 Oxidizing acids
 Reducing acids
 Acidic preparations
 INCOMPATIBILITIES OF ACIDS

• Strong acids highly ionize in aq.solutions

• Sulphuric acid chars many organic substances ,
forming carbon , charring of sugar
C6H1206 6C + 6H20
• Hot,concentrated sulphuric acid acts as a strong
oxidizing agent for metals,non-metals
Hg+ 2H2SO4 HgSO4 + SO2 + 2H20
• Orthophosphoric acid reacts with salts of lead and
silver to give precipitates
 INCOMPATIBILITIES OF ACIDS

• Weak acids slightly ionize in aq.solutions

• All weak acids reacts with alkali carbonates to give CO2
Oxidising acids -incompatible with org.sub and give explosive
combinations
• Reducing acids - incompatible with oxidising agents and give
explosive combinations
D
 Ergot fluid extracts O
N Carbonates
 Nux vomica fluid extracts T
Bicarbonates
C
 Compound pepsin elixer O Chorates
 Ammonium acetate solution M Hypochlorites
B nitrates
 Ferric chloride solution I
 Citric acid syrup N
E
 INCOMPATIBILITIES OF ALKALIES

• Metallic alkaloids precipitate due to solubility

changes and salt formation
1. Strong alkali hydroxides – soluble in water
2. Weak alkali hydroxides – insoluble in water
3. Amphoteric alkali hydroxides-soluble in water by addition with acid

 Fluid extract of senega INCOMPATIBLE

WITH
 Ammonium valerate elixer ALKALIES
 Calcium hydroxide solution
 Aromatic spirit of ammonia
1. Neutralizes acids
2. Precipitates alkaloids
3. Precipitates heavy metals
from salt solutions
 ORGANIC INCOMPATIBILITIES
Some specific incompatibilities include :
 Purine bases (xanthines)
 Alkaloids
 Pyrazolone derivatives
 Amino acids
 Quaternary ammonium compounds
 Glycosides
 Anaesthetics
 Xanthines
• Weak basic properties
• Scarcely available in the form of salts with
acids
• Salts so formed are weak mixtures
 Alkaloids
ALKALOIDAL COMPONENT INCOMPATIBILITY

Alkalies and alkaline reactants like borax, Free alkaloids precipitates

potassium citrate

Tannins and its preparations Insoluble tannates

Picric acid Free alkaloid precipitates

cocaine ,colchicine,atropine Hydrolysed by acids and alkalies

Pyrazolone derivatives Produce color with oxidizing agents

Aminoacids Free aminoacids form internal salts

between NH2 and COOH groups

Quaternary ammonium compounds