434 PHT Sterile Dosage Forms 1432-1431 Nahla S. Barakat, Ph 434 PHT Sterile Dosage Forms 1432-1431 Nahla S. Barakat, Ph.D King Saud University College of Pharmacy Dept. of Pharmaceutics 4/21/2017

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. 4/21/2017

The following IV fluids are not recommended for any drug admixture 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 4/21/2017

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 4/21/2017

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. 4/21/2017

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) 4/21/2017

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. 4/21/2017

The volume-control sets, or plastic burette chamber should be avoided. 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. 4/21/2017

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. 4/21/2017

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. 4/21/2017

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. 4/21/2017

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. 4/21/2017

Sodium chloride is the IV fluid of choice for sodium ampicillin. 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. 4/21/2017

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. 4/21/2017

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. 4/21/2017

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. 4/21/2017

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. 4/21/2017

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. 4/21/2017