Chapter 46: Pharmaceutical Additives

HISTORY AND EPIDEMIOLOGY

During the last century there were several outbreaks of toxicity in the United States associated with pharmaceutical additives (Chap. 2). The 1937 Massengill sulfanilamide disaster is the most notorious of these epidemics. Diethylene glycol, an excellent solvent and potent nephrotoxin, was substituted for the additives propylene glycol and glycerin in the liquid formulation of a new sulfanilamide antibiotic because of lower cost.^27,64,73 As a result, more than 100 people died from acute kidney failure.²⁷ Outbreaks of acute kidney failure occurred when diethylene glycol was used to solubilize acetaminophen in South Africa, Bangladesh, Nigeria, and Haiti, cough syrup in Panama, and teething powder in Nigera.^{22,30,75,87,133,143}

In December 1983, a new parenteral vitamin E formulation (E-Ferol) was introduced. It contained 25 units/mL of α-tocopherol acetate, 9% polysorbate 80, 1% polysorbate 20, and water for injection. At the time, no premarketing testing was required for new formulations of an already approved drug. Several months after its release, a fatal syndrome in low-birth-weight infants, characterized by thrombocytopenia, acute kidney injury, cholestasis, hepatomegaly, and ascites, was described.^1,119 Thirty-eight deaths and 43 cases of severe symptoms were attributed to E-Ferol. Vitamin E was thought to be the cause and E-Ferol was recalled from the market 4 months after its release. It is now believed that the polysorbate emulsifiers were responsible.¹

Although these additive-related occurrences are rare, relative to the frequency of pharmaceutical additive use, they illustrate the potential of pharmaceutical additive toxicity.

Pharmaceuticals are labeled specifically to focus attention on the active ingredient(s) of a product, thus giving the misimpression that additive ingredients are inert and unimportant. Additives, or excipients as they are more properly termed, are necessary to act as vehicles, add color, improve taste, provide consistency, enhance stability and solubility, and impart antimicrobial properties to medicinal formulations. Although it is true that most cases of excipient toxicity involve exposure to large quantities, or to prolonged or improper use, these adverse events are nonetheless related to the toxicologic properties of the excipient.

Prior to selecting the specific additives and quantity necessary for a drug formulation, the drug manufacturer must consider several factors, including the active ingredient’s physical form, its solubility and stability, the desired final dosage form and route of administration, and compatibility with the dispensing container materials. Often, the same active ingredient requires different excipients to impart appropriate pharmacokinetic characteristics to different dosage forms, such as in long-acting and immediate-release formulations. Similarly, multiple-dose injection vials containing the same active ingredients as single-dose vials specifically require the addition of a bacteriostatic xenobiotic not necessary for single-dose vials.

Unlike requirements for active ingredients, there is no specific US Food and Drug Administration (FDA) approval system for pharmaceutical excipients. As such, the FDA determines the amount and type ...