Download 434 PHT incompatibil..

434 PHT
Sterile Dosage Forms
1432-1431
Nahla S. Barakat, Ph.D
King Saud University
College of Pharmacy
Dept. of Pharmaceutics
5/25/2017
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Compatibility and stability

Instability is defined as “a phenomenon which occurs
when LVP or LVP drug product (IV admixture) is
modified due to storage conditions (time, temp., light,
sorption). An unsuitable product may be formed.

Incompatibility is defined as “ a phenomenon which
occurs when one drug is mixed with others and produces
an unsuitable product by some physicochemical means.
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The following IV fluids are not recommended for any drug admixture.
These infusions are unstable by nature and drug admixtures could trigger
adverse reactions such as coagulation, coalescence, or gas evolution,
therefore rendering the IV infusion potentially hazardous.
Blood, plasma and blood products
plasma substitutes
protein hydrolysates
Amino acid solutions
sodium bicarbonate
Fat emulsion
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Factors affecting IV incompatibility

pH

Light exposure

Temperature, generally increased storage temperature speeds drug
degradation.

Length of time in solution

Degree of dilution, generally, the more diluted the drugs are in a
solution, the less chance there is for an ion interaction leading to
incompatibility

Type and order of additives to a solution
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
Drug adsorption
Non-polar, sparingly soluble drugs stored in plastic containers tend to
partition into the plastic container wall. A classical example is
nitroglycerin. Nitroglycerin has low water solubility, approximately
0.1%, which suggests that it has high non-polar solubility.
Indeed, if nitroglycerin in aqueous solution is placed in a
polyvinylchloride IV bag (non-polar medium) or is delivered through a
polyvinylchloride IV set, the drug will be lost by adsorption to the
plastic.
Since the dosing of nitroglycerin is critical, it should be dispensed in
glass IV bottles and infused with a special, non-adsorbing infusion set.
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Adsorption of insulin to infusion containers

10-33% of insulin in solution was adsorbed in infusion bottles and
tubing. This adsorption decreased with increasing concentrations
of insulin.
Adsorption of insulin to glassware and tubing depends on:

Concentration of insulin

Contact time of insulin in glass and tubing

Flow-rate of infusion solution

Presence of negatively charged protein such as human serum
albumin (HSA)
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
The use of in-line filters and PVC bags resulted in greater loss of
insulin

Insulin binds to peritoneal dialysis solution and this binding was
an instantaneous phenomenon not influenced by time.

Insulin adsorption is greater in an electrolyte solution than in
dextrose.

Insulin was found to be more readily adsorbed to glass surfaces
than to plastic surfaces.

Addition of HSA and gelatin to the parenteral solutions reduced
adsorption.

Flushing the infusion set with 50 ml of insulin solution reduced the
adsorption.
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
Mixtures of diazepam in plastic containers significantly reduce the
diazepam concentration. No visual incompatibility was observed when
diazepam was infused in glass or polyolefin IV bottles.
The volume-control sets, or plastic burette chamber should be avoided.

The leaching effect of diethylhexyl phthalate (DEHP) from PVC bags
mixed with cyclosporin show significant leaching within 48 h.
It is recommended the IV cyclosporin be prepared in glass containers to
minimize DEHP leaching,
or the admixture should be used immediately if plastic IV bags are
utilized.
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
Interaction with Antioxidants
Several parenteral products contain sulfites to prevent
oxidative degradation. Sulfites, however, may chemically
react with other drugs.
For example, fluorouracil and thiamine hydrochloride react
with bisulfites which can lead to inactive products.
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

Other Interactions
In general monovalent cations are usually compatible.
However, divalent cations like calcium and magnesium can be
troublesome in the presence of bicarbonate, citrate, and
phosphate, reacting to form insoluble complexes.

When bicarbonate reacts, it will decompose to release CO2 gas,
which can have devastating clinical effects.
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Physical Incompatibility
When the combination of two or more drugs in solution results in a
change in the appearance of the solution, change of color, formation of
turbidity or precipitate, or the evolution of gas.



Ex.: Sodium salt of weak acids such as sodium diphenylhydantoin or
sodium Phenobarbital precipitate as free acids when added to IV fluids
having an acidic pH.
Calcium salts precipitate in the presence of sodium bicarbonate, and
acid salts such as dimenhydrinate precipitate when added to an alkaline
medium.
Diazepam precipitate when added to aqueous solutions because of their
low water solubility.
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Chemical Incompatibility

Degradation of drugs in solution resulting from the combination of
parenteral dosage forms is called “chemical incompatibility”.

Penicillin in solution remains active for 24 h at pH 6.5, but at pH
3.5 is destroyed in a short time.

Adding drugs, such as ascorbic acid, or tetracycline HCL that have
a low pH to the IV fluid containing penicillin may lower the pH to
a point which the penicillin may be inactivated.

The same can happen if the reconstituted penicillin solution is
added to IV fluids of high buffering capacity that have a pH <6.0,
such as lactaated Ringer’s injection or protein hydrolysates.
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
The stability of ampicillin sodium is also pH dependent. When
reconstitued ampicillin sodium is added to 5%D/W, its period of stability
is 4 hours. (Dextrose solutions should be avoided)

When added to sodium chloride Inj., its loss in activity is less than 10% in
8 hours.
Sodium chloride is the IV fluid of choice for sodium ampicillin.

Aminophylline injection added to sodium chloride already containing
vitamin B complex and vitamin C as additives results in an alkaline
solution unfavorable to the stability of the vitamin.
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
Calcium and phosphate in TPN solutions require special care in
mixing.

Amino acid-containing IV solutions may degrade acid-labile drugs,
bind drugs, or form complexes.

No drug additive should be mixed with fat emulsion (Intralipid).

Calcium also forms complexes with tetracyclines resulting in an
inactivated product.
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Therapeutic (pharmacologic) Incompatibility

The antagonism between chloramphenicol and penicillin.
Penicillin should be given before tetracycline.

Penicillin or cortisone may antagonize the effect of heparin
and produce a misleading picture of the anticoagulant effect
of heparin.

Antagonism of folic acid to methotrexate

Inactivation occurs with aminoglycosides and penicillins and
mixing should be avoided.
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Minimization of incompatibilities

Use freshly prepared solutions if possible.

Discard any unused solution after 24 h.

Refrigeration may be required if it is necessary to prepare admixture in
advance.

Encourage the use of few additives as possible in infusion fluids.

Dilution may prevent incompatibility.

Each drug should be mixed thoroughly after it is added to the
preparation.

Incompatibilities can be avoided by selecting another route or site of
administration for one of the drugs involved.
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Keep a compatibility chart handy in your medication room to re-verify
compatibility if two medications are to be given concurrently into the same
iv line.
Don’t forget to check for any incompatibilities with additives that have
already been added to the patient’s primary IV solution (e.g. potassium
chloride, multivitamins), these can be incompatible with many medications
because of pH.
If a prescription calls for unfamiliar drugs or IV fluids, compatibility
references should be consulted.
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Don’t piggyback any medications into parenteral nutrition
lines unless the pharmacy verifies the safety of doing so.
 Many of the electrolytes added to the mixture are
incompatible when they come contact with many common
infusion medications.
 Be on alert for medication with a known history of frequent
incompatibilities when come in contact with other drugs.
 Among
the drugs most often increminted in
incompatibilities are furosedime, phenytoin, heparin,
diazepam when used in IV admixture.

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