9/7/20151 434 PHT 434 PHT Sterile Dosage Forms 1432-1431 Nahla S. Barakat, Ph.D King Saud University College of Pharmacy Dept. of Pharmaceutics.

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434 PHT434 PHT

Sterile Dosage Forms1432-1431

Nahla S. Barakat, Ph.D

King Saud University College of Pharmacy

Dept. of Pharmaceutics

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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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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Adsorption of insulin to infusion containers

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. 04/19/23 15

Minimization of incompatibilitiesUse 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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