, , , ,

Ajit NarangAjit Narang, Ph.d., works for the Drug Product Science & Technology Department of Bristol-Myers Squibb Co. in New Brunswick, N.J. on oral solid dosage forms after receiving his doctorate from the University of Tennessee, Memphis.

In a pharmaceutical dosage form, excipients are often characterized as an inactive or inert ingredient. Although such nomenclature is important in distinguishing excipients from the targeted pharmacologically active pharmaceutical ingredient (API), it may inadvertently underestimate their bioavailability impact in dosage forms.

In fact, excipients impact all the three critical aspects of drug products: bioavailability, stability, and manufacturability.

The bioavailability impact of excipients can be mediated through their effect on drug release, originating in their functional role, as disintegrants or binders, or their physicochemical properties, such as the hydrophobicity of magnesium stearate. In addition, excipients can affect drug bioavailability through different mechanisms. Excipients such as surfactants (e.g., Tween-80) and hydrophilic polymers [e.g., polyvinyl pyrrolidone and polyethylene glycol] can act as wetting agents. Excipients such as kaolin and microcrystalline cellulose can act as substrates for adsorption of micro or nano-sized drug. Viscosity-inducing hydrophilic macromolecular excipients such as povidone, carboxymethyl cellulose, pectin, and gelatin, can minimize polymorphic conversion of a drug in the dosage form.

Some excipients, such as cyclodextrins, can complicate the drug, resulting in altered physicochemical and biopharmaceutical properties. Intimate co-processing of drugs with excipients such as by spray drying, co-precipitation, co-grinding, or the formation of solid dispersions can also lead to improvement in drug solubility and/or dissolution rate. Excipients can also affect the pH of the GI fluid and/or microenvironmental pH of the dosage form—both of which can affect drug release.

Certain excipients interact directly with the physiology to impact gastro-intestinal transit time. For example, nonabsorbable sugar alcohol, monosaccharides mannitol and xylitol, and the disaccharide lactulose can decrease small intestinal transit time. High lipid containing dosage forms can impact gastric emptying in ways similar to the fat content in food. The effect of excipients such as mannitol and PEG 400 on gastro-intestinal motility is often due to concentration and a possible overlap of multiple mechanistic pathways of the excipient’s influence on drug absorption. In addition, excipients, such as surfactants and polymers, can also impact the metabolizing cytochrome p-450 enzymes or the P-glycoprotein multi-specific efflux transporter. Tween 20/80, Span 20, Poloxamer, and Pluronic have been used as P-gp inhibitors.

These considerations in excipient interactions leading to bioavailability impact from a dosage form are significant in preclinical drug development, where the exposures and activity of the drug are sought to be evaluated, ideally with no impact of the excipient(s) used in the formulation. Minimal use of excipients—both in the number and concentration—to simplify the formulation contrasts with the need for enabling formulations and novel excipients for the increasing highly insoluble drug candidates that can benefit from drug delivery technologies during early development. These highlight the potential opportunities that exist in the development of excipient free or simpler enabling technologies to support new drug discovery research.