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Incompatibilities

COMPOUNDING INFORMATION SOURCESOMPATIBILITIES

Inability of a substance to maintain its identity or to exercise its inherent properties


when brought into contact with or into the sphere of influence of another substance
or a physical force.

Two classes (from viewpoint of compounder):


(1) Desirable
(2) Undesirable

INCOMPATIBILITIES
Three classes (based on cause and manifestations):

• Physical incompatibilities
physical or chemical interaction between 2 or more ingredients that lead to a
visibly recognizable change
(2) Chemical incompatibilities
involves a reaction in which change is not visible

INCOMPATIBILITIES
Three classes (based on cause and manifestations):
(3) Therapeutic incompatibilities
involves an undesirable interaction between 2 or more ingredients

PHYSICAL INCOMPATIBILITIES
Physical stability is the assurance that the product retains its original physical properties,
including appearance, palatability, uniformity, dissolution and suspendability, during its
shelf-life.

PHYSICAL INCOMPATIBILITIES

• Liquefaction of solid ingredients


(a) Efflorescent powders
contain water of hydration that may be released when powders are triturated or
stored in a low humidity environment which may cause powders to
become damp or pasty, or become powdery
Examples: alums
ferrous sulfate
terpin hydrate

PHYSICAL INCOMPATIBILITIES

• Liquefaction of solid ingredients


(a) Efflorescent powders
Remedies:

≈ Store & dispense in tight containers.

≈ Use anhydrous drug form with appropriate dose correction.

PHYSICAL INCOMPATIBILITIES

• Liquefaction of solid ingredients


(b) Hygroscopic & Deliquescent powders
solids that absorb moisture from the air, which may or may not dissolve to form
a solution
Examples: calcium chloride
ephedrine sulfate
phenobarbital Na
PHYSICAL INCOMPATIBILITIES

• Liquefaction of solid ingredients


(b) Hygroscopic & Deliquescent powders
Remedies:

≈ Store and dispense in tight containers.

≈ Add an inert, powdered ingredient that will preferentially absorb


water, like lactose or light magnesium oxide.
PHYSICAL INCOMPATIBILITIES

• Liquefaction of solid ingredients


(c) Pharmaceutical eutectic mixtures of drugs
refer to 2 or more substances that may liquefy when intimately mixed at room
temperature
Examples: acetaminophen
aspirin
camphor
menthol
PHYSICAL INCOMPATIBILITIES

• Liquefaction of solid ingredients


(c) Pharmaceutical eutectic mixtures of drugs
Desirable eutexia:
≈ High concentration of lidocaine and prilocaine in EMLA Cream is achieved by
forming a liquid eutectic mixture of the components.
≈ Used to facilitate reduction in particle size of crystal without need for
pulverizaton by intervention.
PHYSICAL INCOMPATIBILITIES

• Liquefaction of solid ingredients


(c) Pharmaceutical eutectic mixtures of drugs
Remedies:
≈ Force the liquid eutectic to form, then sorb the liquid onto an inert,
high-melting, finely-divided solid.
≈ Triturate potential eutectic former separately with an inert powder, then mix by
gentle spatulation.
PHYSICAL INCOMPATIBILITIES
(2) Changes in crystal form
Metastable polymorphs are sometimes used in manufacturing solid dosage forms to
give more rapid dissolution and improved bioavailability. Manipulation in
compounding may result in reversion to the more stable, less soluble, less available
polymorph.

PHYSICAL INCOMPATIBILITIES
(2) Changes in crystal form
Specific remedy depends on what caused the change in crystal form.
Example:
Cocoa butter is readily overheated and solidifies as one of the lower melting
polymorphs, which may melt at room temp., or suppositories may liquefy when
handled by patient during insertion. Remedy is to melt cocoa butter slow and
carefully, at temperatures below 340C.
PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
Influenced by specific manufactured drug product, drug concentrations, base
solutions or diluents and their manufacturers, order of mixing, time frames,
temperature and test methods.

PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(a) Solvent effects
When a drug is dissolved in a solvent and a second solvent, one in which the
drug is poorly soluble, is added, the drug may precipitate.
Example: Addition of water or aqueous solution to an alcoholic solution of
salicylic acid. (Solubility - 1:2.7 alcohol and 1:460
in water)

PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(a) Solvent effects
Example:
Addition of aqueous solution or syrup to Phenobarbital elixir.
Dilution of digoxin injection with an aqueous injectable solution will alter
cosolvent system composition (40% PPG and 10% alcohol) and result in
precipitation due to poor water solubility of 0.08 mg/mL.

PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(a) Solvent effects
Remedies:
≈ Choose appropriate solvent system.
≈ Follow manufacturer’s instruction when diluting preparations using cosolvent
system.
Example:
A manufacturer recommends dilution of Digoxin Injection with at least
fourfold volume of Sterile Water for Injection or the equivalent.

PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(a) Solvent effects
Remedies:
≈ Decrease the drug concentration so the drug is soluble in the solvent system.
≈ For oral or topical products, a suspension may be prepared by adding a
suspending agent. Include “shake well” label.

PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(b) pH effects
Most drugs are weak electrolytes and their degree of ionization depends on the
pH of the solution. When there is a big difference in the solubilities of
two drug forms, a problem may occur when the pH is altered (i.e. drug
solutions with differing pH are combined or when a drug that generates a
different pH is added to the original drug solution).

PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(b) pH effects
Example:
Chlorpromazine HCl (protonated salt form) – solubility 1g / 2.5 mL water
Chlorpromazine base (neutral unchanged form) – insoluble in water

PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(b) pH effects
What to consider:
≈ Check solubilities of all drugs in the solvents to be used.
codeine and morphine
ephedrine and ephedrine HCl
phenobarbital Na and
phenobarbital
PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(b) pH effects
What to consider:
≈ Determine the salt type of the drug, whether salt of a neutral weak acid or a
neutral weak base.
≈ Estimate the resultant pH of the solution.
≈ Calculate the pH of the precipitation as a function of the pKa and drug
solubility.
PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(b) pH effects
Remedies:
≈ Control the pH at a desirable level using pH adjusting agents or buffers.
≈ Keep drug solutions with incompatible pH’s separate. For IM injections, draw
solutions in separate syringes and give in different sites. For IV
injections, give at different times and flush the IV line between
additions of incompatible drug solutions.
PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(b) pH effects
Remedies:
≈ With oral or topical solutions, a cosolvent may be used if a suitable one that is
available will keep the free form of the drug in solution. Or check
possibility of making a suspension.
PHYSICAL INCOMPATIBILITIES
(3) Precipitation from solution
(b) pH effects
Remedies:
≈ Dilute the final solution so that drug concentration is below the precipitation
concentration of the neutral free form.
≈ For injectable drugs, like Phenytoin Na Inj. and Aminophylline Inj., that are
sensitive to pH changes caused by absorption of CO2, use short
expiration times.
PHYSICAL INCOMPATIBILITIES
(4) Precipitation from solution
(c) Colloids and polymers
Solutions of hydrophilic polymers such as methylcellulose and acacia depend on
hydration through hydrogen-bonding and ion-dipole interactions.
These polymers may be dehydrated and precipitated by concentrated
electrolyte solutions or phenolic compounds.
PHYSICAL INCOMPATIBILITIES
(4) Precipitation from solution
(c) Colloids and polymers
Remedies:
≈ Decrease concentration of electrolyte.
≈ Substitute with polymer gum that is not easily dehydrated.
PHYSICAL INCOMPATIBILITIES
(4) Precipitation from solution
(c) Colloids and polymers
For some viscosity-increasing polymers, interactions are required to form the
desired gel.
Example:
Sodium alginate is gelled with calcium ions.
Carbomer is gelled by addition of an inorganic (e.g.NaOH) or organic (e.g.
Triethanolamine) base.
PHYSICAL INCOMPATIBILITIES
(4) Precipitation from solution
(d) Effect of temperature
Solubility of most drugs decreases with decrease in the temperature of the
solution.
Remedies:
≈ For injectable solutions, check warnings concerning temperature effects. If an
extemporaneously prepared sterile product cannot be refrigerated,
the beyond-use date should be adjusted.
PHYSICAL INCOMPATIBILITIES
(4) Precipitation from solution
(d) Effect of temperature
Remedies:
≈ For oral or topical solutions, be aware of possible problems when handling
solutions near the saturation point. If such a solution must be stored
or used at temperatures different from that at which it was made,
steps to prevent or handle precipitation should be undertaken.
PHYSICAL INCOMPATIBILITIES

• Sorption and Leaching


Sorption is dependent on the hydrophilic/ lipophilic nature of the drug and the binding
site or the material in the capillary space of the interface.
Drugs that are poorly water-soluble or lipophilic have a greater tendency to sorb to
PVC or dissolve in its plasticizer.
Examples: lorazepam, amiodarone, diazepam,
isosorbide dinitrate, vitamin A
PHYSICAL INCOMPATIBILITIES

• Sorption and Leaching


Remedies for sorption:
≈ Special tubing or containers may be used.
≈ Use shorter run-times for IVs containing drugs with potential sorption problems.
≈ Add the drug just before the time of administration.
≈ Consider giving the drug by IV push, if possible.

PHYSICAL INCOMPATIBILITIES
• Sorption and Leaching
Remedies for sorption:
≈ Use short administration-set tubing (with less binding sites).
≈ Store product in the refrigerator until administration.

PHYSICAL INCOMPATIBILITIES

• Sorption and Leaching


Drug solutions containing surfactants or cosolvents are more at risk, because some of
these have been found to extract plasticizer from the plastic and contaminate the
drug solution.
Example: Approved labeling for paclitaxel which uses dehydrated
alcohol-polyoxyethylated castor oil solvent system, requires
use of non-PVC containers and administration sets.
PHYSICAL INCOMPATIBILITIES

• Sorption and Leaching


Remedies for leaching:
≈ Containers, administration sets and device components that do not contain
DEHP-plasticized materials, like glass, polyolefin, ethylene vinyl acetate,
silicone, polyethylene and polyurethane, can be used.

CHEMICAL INCOMPATIBILITIES
The following reactions usually cause loss of active drug content, and do not provide obvious
visual or olfactory evidence of their occurrence:

• Oxidation

• Hydrolysis

• Epimerization

• Decarboxylation

• Dehydration

• Photochemical decomposition
CHEMICAL INCOMPATIBILITIES
The chemical reactions are enhanced by the following factors:
(a) adverse temperatures
(b) light
(c) humidity
(d) oxygen
(e) carbon dioxide
CHEMICAL INCOMPATIBILITIES

• Oxidation
Drugs susceptible to oxidation:
- catecholamines, e.g. epinephrine
- phenolics, e.g. phenylephrine, morphine
- phenothiazines, e.g. chlorpromazine
- olefins
- steroids
- tricyclics
- thiols, e.g. captopril
- miscellaneous, e.g. amphotericin B, tetracycline, nitrofurantoin, furosemide,
ergotamine)

CHEMICAL INCOMPATIBILITIES

• Oxidation
Remedies:
≈ Protect from oxygen by using tight containers and limiting storage time through
conservative BUDs
≈ Protect from light by using light-resistant containers and syringes, and wrap
containers with light-resistant wrappings.
CHEMICAL INCOMPATIBILITIES

• Oxidation
Remedies:
≈ Add a metal-chelating agent like edetate disodium.
≈ Add an antioxidant.
≈ Control storage temperature.
≈ Control pH.
≈ Separate drugs that are easily oxidized with those that are readily reduced.
CHEMICAL INCOMPATIBILITIES
(2) Hydrolysis
Drugs susceptible to hydrolysis:
- esters, e.g. procaine, tetracaine, aspirin, compounds with lactone rings
- amides, e.g. penicillins
- imides, e.g. barbiturates
- thiolesters

CHEMICAL INCOMPATIBILITIES
(2)Hydrolysis
Remedies:
≈ For solids, control exposure to moisture by using tight containers and dessicants.
≈ Control the pH of aqueous formulations.
≈ Check effect of general acids or bases and drug concentration.
≈ Control storage temperature.
CHEMICAL INCOMPATIBILITIES
(3) Evolution of gas (usually CO2)
Representative drugs:
- sodium bicarbonate and carbonate buffers
- ortho- and para-substituted benzoic acids, like p-aminosalicylic acid

CHEMICAL INCOMPATIBILITIES
(3)Evolution of Gas
Remedies:
≈ Do not combine drug products that generate acid pH with sodium bicarbonate or
drug products that contain carbonate buffers.
NaHCO3 + H+ → H2CO3 → H2O + CO2↑
≈ For vulnerable solid dosage forms, store and dispense in tight containers.
CHEMICAL INCOMPATIBILITIES
(4) Displacement
- Cisplatin is the best known example.

- Maintain 0.2% NaCl solution for cisplatin.


- Use stainless-steel needles for drawing and administering the drug.

CHEMICAL INCOMPATIBILITIES
(5) Complexation
Representative drugs:
- tetracycline by multivalent ions like calcium, magnesium, iron and aluminum
Remedy: Keep drug from offending ions.
(Note: Patients should be counseled to avoid taking drug with food or drugs
containing multivalent ions, including milk, iron-containing
foods/drugs and antacids.)
CHEMICAL INCOMPATIBILITIES
(5) Complexation
Representative drugs:
- Aminophylline is a complex with 2:1 ratio of theophylline and ethylenediamine.
Theophylline may precipitate out of solution.
Remedy: Addition of excess ethylenediamine to keep theophylline in the complex.
Maintain pH of 8.6 to 9 using ethylenediamine.

CHEMICAL INCOMPATIBILITIES
(5) Racemization
A mixture of equal parts of enantiomers is called a racemate, and the conversion
of one enantiomer to a racemate is known as racemization.
Examples: epinephrine
mepivacaine and bupivacaine
amphetamine and dextroamphetamine
albuterol and levalbuterol
omeperazole and esomeprazole
CHEMICAL INCOMPATIBILITIES
(5) Racemization
Problems exist only when one enantiomer is much more physiologically active
than the other one and when racemization takes place easily.
CHEMICAL INCOMPATIBILITIES
(6) Epimerization
A pair of diastereomers that differ only in the configuration about one carbon atom
are called epimers.
Examples:
Tetracycline epimerized to epitetracycline (with little antibacterial activity)
Remedy: Formulation of suspension.
Control of pH with buffers.
CHEMICAL INCOMPATIBILITIES
(7) Formation of sparingly soluble salts
(a) Inorganic precipitates

CHEMICAL INCOMPATIBILITIES
(7) Formation of sparingly soluble salts
(b) Precipitation of large cation/large anion compounds
Examples:

Remedy:
≈ Keep solutions separate.
≈ Administer at different sites or different times.
CHEMICAL INCOMPATIBILITIES
(7) Formation of sparingly soluble salts
(c) Drugs with unusual counter ions
Organic salts with a special or unusual counter ion, such as mesylate, lactate,
succinate should be added with caution to another salt.

CHEMICAL INCOMPATIBILITIES
(7) Formation of sparingly soluble salts
(d) Alkaloidal precipitants
Precipitation of alkaloids caused by citrate salts, tannins, iodide and picric acid.
Remedy:
≈ Addition of alcohol or glycerin to prevent precipitation.

THERAPEUTIC INCOMPATIBILITIES
Effects of Therapeutic Incompatibilities:

• Potentiation of therapeutic interactions between 2 or more ingredients.

• Destruction of effectiveness of one or more ingredients.

• Occurrence of toxic manifestations within the patient.

REFERENCES