Formulation-Related Problems Associated with Intravenous Drug Delivery

The intravenous route is the most rapid and the most bioavailable method of getting a drug into the systemic circulation. However, this route is prone to a number of problems. Some of the problems associated with intravenous drug delivery are independent of the formulation. These include hypersensitivity, microbiological contamination, particulate matter, and poor injection technique or burred needles. These have been discussed in detail by Turco1 and in books edited by Avis et al.2,3 Others are the result of design of the formulation itself and the rate at which it is injected. The major adverse effects of intravenous administration that result from the formulation are hemolysis, precipitation, phlebitis, and pain. These latter adverse effects are the subjects of this review. Each is discussed with respect to its relationship to the design of the formulation and the way in which it is injected. A single model of the injection site is presented to aid in the understanding of the causes of hemolysis, phlebitis and pain, and their relationship to precipitation of the active ingredient. Hemolysis is the loss of integrity of the red blood cell membrane with the release of the cellular contents into the plasma. The resulting increase in hemoglobin concentration can be particularly problematic. If the release of free hemoglobin into the circulation is more than the body can clear, a number of symptoms can result, including fever, chills, abdominal and back pain, shortness of breath, prostration, and shock. High plasma concentrations of hemoglobin can lead to plaque formation and the clogging of renal tubules, thereby affecting kidney function.4-6 Hemolysis may also produce congestion in the reticuloendothelial cells of the spleen and liver causing splenomegaly and jaundice, respectively.7 Hemolysis, or the lysis of red blood cells, can result from hypotonicity or from the effect of either the drug or the formulation components on cell membranes. The only purely physical problem associated with the intravenous injection of drugs is phase separation, i.e., the formation of oil droplets or crystals of drug upon mixing of the formulation with blood. Precipitation of solubilized drugs can also result in uneven or delayed bioavailability. In fact, the mere presence of a separate drug phase indicates a reduced concentration in the aqueous phase. If the second phase is rapidly redissolved there may be no loss in total efficacy. However, if it becomes embedded into or sorbed onto the cells of the vein wall and redissolution is gradual, either reduced or prolonged efficacy can result. If the precipitated material is crystalline, the particles can cause cellular abrasion as they move along the vein wall. Phlebitis (or thrombophlebitis) is an inflammation of the vein wall. It is similar to other inflammatory processes in that it is characterized by clinical observations of pain tenderness, edema, erythema, and a local temperature increase. In addition, phlebitis can cause thrombus formation which can ultimately lead to death. Phlebitis is a fairly common and potentially very serious side effect of intravenous therapy. Boon et al.8 found that drugs commonly used in anesthetic practice produce a 36% incidence of phlebitis. Phlebitis has also been reported as a common side effect of amiodarone,9 phenytoin,10 and diazepam.11 Phlebitis has long been associated with the mechanical and chemical effects of particulate matter introduced during injection. These particles may be present initially in the July 1998