The central role of excipients in drug formulation
Active substances are rarely administered alone. For example, levothyroxine, a synthetic form of the thyroid hormone, indicated in the treatment of hypothyroidism, is administered at a very low dosage, ranging from 15 μg to 200 μg. These very small amounts of powder mean that it is not possible to manufacture tablets containing only this drug. Hence, the formulation of levothyroxine tablets requires the combination of the hormone with one or more non-medical agents known as pharmaceutical inactive ingredients or excipients that serve varied and specific pharmaceutical functions.
Excipients play a central role in the drug development process, in the formulation of stable dosage forms and in their administration. A bad choice of excipient can even lead to severe intoxications, as experienced by epileptic patients in Australia in the late 1960s who were taking phenytoin capsules2. The calcium sulphate used as a diluent in the capsule had been replaced by lactose and this substitution, considered to be harmless, resulted in an increase of the mean serum phenytoin concentration by a factor of 4.5, which is considerable for an active substance with a narrow therapeutic index such as phenytoin. The explanation lies in the solubility of the excipient: lactose is freely soluble in water, whereas calcium sulphate (dehydrate) is very slightly soluble in the same medium. Thus, in the original formulation, calcium sulphate acted as a matrix former and prolonged the release of the drug, whereas lactose provoked an immediate and massive release of phenytoin above the toxic threshold. Confusion between excipients can also have a fatal outcome: in 2007, pharmaceutical manufacturers in Panama used diethylene glycol, which they believed to be glycerine, for the formulation of a cough syrup. Diethylene glycol, which is used in antifreeze, is nephrotoxic and hepatotoxic and can result in multiple organ dysfunction syndrome, especially in children.
Definition of an excipient
The word excipient originates from the Latin excipere, which means to receive; hence, the excipient receives the active substance. Generally, excipients are defined exclusively: an excipient contained in a dosage form is something other than the active substance. According to the World Health Organisation – WHO – (Technical Report Series, No. 961, Annex 10 (Procedure for prequalification of pharmaceutical products), an active pharmaceutical ingredient (API) is “a substance used in a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.”
The European Pharmacopoeia (Ph. Eur.) 4 gave the following definition of an excipient: “An excipient is any component, other than the active substance(s), present in a medicinal product or used in the manufacture of the product. The intended function of an excipient is to act as the carrier (vehicle or basis) or as a component of the carrier of the active substance(s) and, in so doing, to contribute to product attributes such as stability, biopharmaceutical profile, appearance and patient acceptability and to the ease with which the product can be manufactured. Usually, more than one excipient is used in the formulation of a medicinal product.” The terms vehicle and base are further defined in the same pharmacopoeia: “A vehicle is the carrier, composed of one or more excipients, for the active substance(s) in a liquid preparation” and “A basis is the carrier, composed of one or more excipients, for the active substance(s) in semi-solid and solid preparations.” Tables 1 and 2 give an example of a vehicle and a basis respectively.
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