Inkompatibilitas

Afifah Machlaurin

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 Isi Materi

Pengertian Inkompatibilitas

Tipe-tipe inkompatibilitas

Pengatasan Inkompatibilitas

Inkompatibilitas yang disengaja

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 Pengertian Inkompatibilitas

Ketidakmampuan suatu bahan atau

proses bersatu/bergabung dengan
bahan atau proses lain

Inkompatibiitas farmasetik 
proses peracikan dan penyiapan obat

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 Dampak Inkompatibilitas

Safety

purpo
se

Dampak Inkomp’
Appea
rence
Undesire
efficacy

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 Mengapa
penting ????
 Dengan memahami inkompatibilitas 
 menghemat waktu compounding
 memastikan efisiensi terapi suatu produk

 easier to prevent an incompatibility rather than to correct it

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 Tipe inkompatibilitas

Therapeutic
Tipe
Physical
Inkomp’
Chemical

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 Type of incompatibility

1 2 3
They exist when failure of the react chemically
the response to drugs to combine when mixed,
one or more drug properly. altering the
is different nature composition of
or intensity than one or more of the
that intended by constituents
the prescriber

Therapeutic Physic Chemist

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 Therapeutic Incomp’

Synergistic (or additive) combination

Antagonistic combinations

Contraindication

Dosage Error

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 Therapeutic incompatibility

 1. Synergistic (or additive) combination

 When certain drugs having the same
pharmacologic action are prescribed together, the
combined action they produce is greater than the
sum of their individual actions.
 Such combinations should be in reduced amount.
 The synergistic action will sometimes be desired
to decrease toxicity or reduce cost of prescription
 Therapeutic incompatibility

Synergistic (cont.); examples of useful

synergistic effecta
 Combinations of sulfonamides show less
nephrotoxicity than a single sulfonamide.
 Neomycin – erythromycin combination has a
broader spectrum than either antibiotic alone.
 Aspirin – codeine combination reduces the
amount of expensive codeine required.
 Therapeutic incompatibility

 2. Antagonistic combinations
When two or more drugs having opposite
pharmacological action are prescribed together,
their actions cancel each other and the resulting
prescription will have no therapeutic action.
 Stimulants with sedatives (hypnotics) e.g. caffeine
with chloral hydrate.
 Purgatives with antidiarrheals e.g. MgSo4 with tannins
 Acidifiers with alkalinizers e.g. aspirin with AL(OH)3.
 Therapeutic incompatibility

 3. contraindication
 Are drugs when prescribed together
may lead to increased toxicity or
decrease activity.
 Tetracycline is contraindicated with
any drug containing Ca2+ ions as it
form non-absorbable complex.
 Inactivation of sulfa drugs by
procaine HCI.
 Therapeutic Incompatibility
 4. Dosage Error:
can result from the administration of a single
high dose, or the too frequent administration.
R/
Atropine sulphate 6 mg
Phenobarbital 360 mg
Ft. caps, i mitte xii
sig. caps, i t.d.s
- Dosing errors, unclear prescription
 Therapeutic Incompatibility
 Dosage errors
Rx
Codeine phosphate 15 mg
Ammonium chloride 500 mg
Ft. caps, i mitte xx
sig; caps, ii q.h

What’s different ??
qd vs q.d.s ???
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 Physical Incompatibility

Physical incompatibilities are often called:

pharmaceutical incompatibilities

 This type of incompatibility results by the slow or

immediate formation of decomposed solutions or
precipitates, when the drugs are combined in a pharmacy
setup or laboratory.

 Def.: Interaction between two or more substances which

lead to change in color, odor, taste, viscosity and
morphology.

11/02/2022 19 PHR 416

 Manifestation of Physical incomp’

Insolubility/Immiscibility

Adsorption-complexation

Liquification

Precipitation

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 Insolubility

 Insolubility  When 2 or more substances are

combined they do not give homogenous product
Factors affect the solubility :
1. Change in pH
2. Milling
3. Surfactant
4. Chemical reaction
5. Complex formation
6. Co-solvent

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 Example Insolubility

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 Example Insolubility

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 Example Insolubility

Example of prescription:
    Terpine hydrate ……………… 3g
    Simple syrup ………………… q.s
to make 120ml
        MFT solution.
Terpine hydrate is insoluble in simple syrup then
how we make solution? So in this case ½ of the
syrup may be replace by alcohol or iso-alcohlic
elixirs or the drug may be suspended with
accasia tragacanth and dispense with a shake
label.
11/02/2022 24 PHR 416
 Example Insolubility

Example of prescription:
     Magnesium carbonate ……….. 3.75g
     Citric acid ……………………. 7.5g
     Sodium bicarbonate …………. 7.5g
     Boiled water ………………… q.s to make 250ml
MFT solution or MFT citrate solution.

Hint :
Magnesium Carbonate  insoluble
Magnesium citrate  soluble
Na bicarbonate  soluble
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 Example Insolubility

Example of prescription:

Rx/
Sulphamethoxazole 4.0g
Trimethoprim 0.8g
Na- CMC 0.5g
Purified water qs to 100ml

11/02/2022 26 PHR 416

 Another common insolubility drug…

 Sulphur
 Corticosteroids (hydrocortisone acetate)
 Antibiotics
Suspending agent

thickening agent Sulphamethoxas

Wetting Agent
indiffusible solids ole, phenacetin
e.g. saponins for + a suspending
sulphur such as chalk,
aromatic chalk agent (CMC-Na
containing or Tragacanth)
lotions powder, succinyl
sulfathiazole (in
polysorbates for mixtures) and
parenteral calamine and
suspensions of zinc oxide (in
corticosteroids lotions)
and antibiotics
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 Immiscibility

 Immiscibility  Separation in two phases liquid

The following factors lead to immiscibility:
1. Incomplete mixing
2. Unproper surfactant
- Unsuitable concentration
- False time of addition
- Unsuitable for the type of emulsion
3. Presence of microorganisms
4. Temperature

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 Adsorption and Complexation

 Certain substances including drugs and excipients may

interact to form physical complex which may alter the
appearance or activity of the medicament,

 For example, mixtures containing clays such as

Kaolin, Attapulgite or suspended antacids may pose
incompatibility problems due to adsorption

 Adsorption of Cyanocobalamin by Talc, a tablet lubricant

may decrease the absorption from GIT.

 Similarly Adsorption of antimicrobial preservatives such

as parabens on to the drugs or excipients may lead to
loss of their antimicrobial activity.
 Liquification (eutectic)

Def.: it means that when two solid substances are

mixed together, conversion to a liquid state take
place.

It happens through the following methods:

1. Formation of liquid mixture:
decrease of melting point  liquid in certain ratio
2. Exit of crystalline water
By mixing hydrated crystals and dry crystals 
crystalline water diffuse to dry crystals.

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 Examples:
Camphor ,menthol, phenol, thymol ,chloral
hydrate, sodium salicylate, Aspirin ,
phenazone.

Methods Of Rectifying Liquefaction:
       By the use of absorbent like kaolin, light
magnesium carbonate.

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 Example of Liquification

Rx/
Thymol 250 mg
Camphor 2 mg
Menthol 2 mg
Make powder.

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 Methods Of Rectifying Liquefaction

Methode

All the ingredients Each ingredient

are triturated 
is triturated
eutectic mixture
triturate with separately with
enough absorbent small amount of
powder e.g. light adsorbent 
kaolin or light these powders
magnesium are lightly mixed
carbonate  free
flowing powder

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 Example of Liquification

Rx/
Chloral hydrate 250 mg
Prepare capsules. Supply 10 capsules.
Label: Take the capsules at night time.

Comment: Chloral hydrate is hygroscopic in nature. It will

absorb moisture and soften the hard gelatin capsule shells
and the shape of the capsule may change physically.
Remedy: An equal quantity of light magneisum oxide should
be mixed with chloral hydrate. Other adsorbents those
may be used are kaolin, talc, starch etc.
 
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 Precipitation

Precipitation can result when the solvent in which

the solute is insoluble is added to the solution.
Resins are normally not soluble in water. So, the
tinctures of resins may form precipitate on
addition to water

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 Methods for rectifying physical incompatibility

Alternate Solvent

Modified
order of
Mixing A C Changing the
form
Concept

Surfactant E D Complexation

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 Question…

Rx
Olive oil                                             30 ml
 Water                                       up to 120 ml
Directions for Pharmacist:
          Make an emulsion.
Comments:
Physical incompatibility.

11/02/2022 37 PHR 416

 Question…

Rx
Phenacetin                                    3 gm
Caffeine                                         1 gm
Orange syrup                               12 ml
Water  up to 90 ml
Directions for Pharmacist:
        Make a mixture. Send 25 ml
Comments:
Physical incompatibility.

11/02/2022 38 PHR 416

 Question…

Menthol                                                  5 gm
Camphor                                                 5 gm
Ammonium chloride                               30 gm
Light magnesium carbonate                  60 gm
Directions for Pharmacist:
           Make an Insufflations. Send 40 gm.
Comments:
Correct prescription.

11/02/2022 39 PHR 416

LOGO
 Two types of chemical incompatibility

1. Tolerated
In this type of incompatibility, chemical reaction can be
reduced by mixing the solution in dilute forms or by
changing the order of mixing.

2. Adjusted
In this type of incompatibility, change in the formulation
is needed with a compound of equal therapeutic value
e.g. in the mixture of caffeine citrate and sodium
salicylate, caffeine citrate is replaced with caffeine.

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 Chemical incompatibilities often occur due to
oxidation-reduction, hydrolysis or combination
reactions.
 A chemical incompatibility, which is visualized
rapidly by effervescence, precipitation or colour
change, is called immediate incompatibility.
 An incompatibility without immediate and visible
physical change is known as delayed
incompatibility and may or may not result in loss
of therapeutic activity.

11/02/2022 42 PHR 416

 Chemical Incompatibility

Classification 4
1
Racemization
3
Oxidation-
reduction 2 Hydrolisis

Acid-Base Reaction
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 Oxidation-reduction

 Oxidation refers to the loss of electrons and

reduction to the gain of electrons.
 Prescription mixtures are usually oxidized on
exposure to air, higher storage temperatures,
light, over dilution, incorrect pH adjustment or in
presence of catalysis.
 Use of antioxidants such as ascorbic acid,
sodium sulphite or sodium metabisulphite is
often helpful.

11/02/2022 44 PHR 416

  Trace metal ion catalysis may be counteracted
by complexing agents such as disodium edetate
and sodium calcium edetate.
 Auto-oxidation in fats and oils, phenolic
substances, aldehydes and vitamins is
controlled by agents such as propyl gallate,
thymol, butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), and
hydroquinone etc.
 Silver, mercury and gold salts may be reduced
by light to the metallic form although such
reactions are rare in prescriptions.
11/02/2022 45 PHR 416
 Acid-base reactions

Such reactions result into precipitation, gas

formation, colour development or colour
change.
Change in or Development of Colour:
Most of the dyes employed in pharmaceutical
practice and their colour are influenced by their
ionization depending on pH of the solution.
Laxative phenolphthalein is colourless in acid
solution but red in alkaline mixtures.

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 Gentian violet is a basic purple compound but
on addition of acid, the compound changes the
colour through green to yellow.
 Such incompatibilities are corrected by the
addition of a buffer or change of the vehicle to
prevent formation of free acid or base from the
salt.

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 Hydrolysis

Many substances hydrolyze in water and their

reaction may be facilitated by heat catalysts,
hydrogen ions and hydroxyl ions.
Esters, amides and metals like Zn and Fe etc.,
are common examples.
Soluble salts of barbituric acid derivatives and
sulphonamides hydrolyze in water and yield
insoluble free acids.
Phenyl salicylate hydrolyses in basic media to
salicylic acid and phenol.

11/02/2022 48 PHR 416

  Addition of any of the species formed as a result
of hydrolysis is a common method employed to
prevent or reverse the ionic hydrolysis.
 Examples of drug substances which may
undergo hydrolytic decomposition include
procaine, sulphonamides, chlorothiazide,
barbituric acid derivatives, aspirin, some
alkaloids, and penicillin.
 Similarly gelatin, sucrose, sodium acetate,
flavouring oils and chlorobutanol; some of the
common ingredients in prescriptions; are also
liable to decomposition by hydrolysis.
11/02/2022 49 PHR 416
 Racemization
 It is the conversion of an optically active form of
a drug substance to an optically inactive form
without a change in chemical constitution but is
usually associated with a reduction in
pharmacological activity.
 Examples of substances undergoing
racemization are adrenaline, ephedrine,
norephedrine.
 In alkaline solution but not in acid solutions, 1-
hyoscyamine may undergo racemization to
form atropine.

11/02/2022 50 PHR 416

Intentional incompatibilities
 Intentional Therapeutic incompatibilities

 Such circumstances rarely occur, but when they do it

does not necessarily indicate a moment of forgetfulness
on the part of the physician. Such agents may have been
used together in order for one agent to modify the
activity of the other.
 Examples:
 Atropine should antagonize the depressant effect of
morphine to the respiratory tract.
 Central nervous system stimulants may be used to
overcome the drowsiness produced by anti-histaminic.
 A mild laxative antacid such as Mg(OH)2 may be used to
overcome the constipating effect of an astringent antacid
such as AL(OH)3.
 Intentional Chemical Incompatibility

 Strong iodine solution U.S.P. (Lugol’s solution)

 R/
Iodine 50 gm
Potassium iodide 100 gm
purified water ad 1000 ml
Iodine dissolves in potassium iodide to form the
water soluble I3 complex.
 Intentional chemical incompatibles
 Carbonaeous mixture
(Postion Revier Mixture):
Solution A: R/ Sodium bicarbonate 3.5 gm
Simple syrup 30.0 ml
Water to 150 ml

Solution B: R/ Citric acid 4.0 gm

Syrup lemon 30.0 ml
Water to 150 ml

Fait Mist. A and B, Mitte 50 ml of each

Sig.: one tablespoonful from solution A is mixed with an

equal volume of solution B and the mixture is
taken when effervescence is about to cease
 Intentional Physical incompatibilities

 Tincture myrh is diluted with water to give a

precipitate which is used as a gargle in the
treatment of tonsillitis.
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