An inactive pharmaceutical ingredient is not a passive ingredient

An excipient (the inactive pharmaceutical ingredient) is any component of a medicine other than the active substance. In most tablets, excipients make up the bulk of the mass, with the API sometimes a few milligrams of a much larger dosage form.

The word "inactive" invites the assumption that these are filler. They are not. The term means no intended therapeutic effect; it does not mean inert, and excipient selection frequently determines whether a medicine works at all.

What excipients do

• Binders and fillers. Binders hold a tablet together so it survives packing and handling; fillers bring a few milligrams of API up to a tablet large enough to manufacture and swallow. Microcrystalline cellulose, lactose and starch are typical.

• Disintegrants. Arguably the most consequential class. A tablet that does not break apart cannot dissolve, and a drug that does not dissolve cannot be absorbed, so disintegrants such as croscarmellose sodium and sodium starch glycolate swell on contact with fluid and burst the tablet open. This is the mechanism behind the observation that an insoluble tablet still delivers its drug.

• Coatings and release modifiers. Enteric coatings resist stomach acid so the tablet dissolves in the intestine, protecting an acid-sensitive drug, or protecting the stomach from an irritant one. Modified-release matrices spread absorption over hours, turning a four-times-daily drug into a once-daily one. Entirely excipient-driven.

• Preservatives. Essential in multi-dose liquids, syrups and eye drops, where microbial growth after opening is a genuine hazard.

• Stabilisers, buffers and antioxidants. These keep the API chemically intact to its expiry date: buffering pH to the range where it is most stable, and scavenging oxygen for oxidation-prone drugs.

• Flavours and sweeteners. Mostly a compliance question rather than a comfort one. A paediatric antibiotic a child refuses is not an effective treatment.

• Vehicles and bases. For creams, ointments, gels and lotions, the base determines spreadability, occlusivity and how much drug penetrates. The same corticosteroid in an ointment and in a lotion behaves differently on skin: a formulation choice, not a marketing one.

• Colourants and shape. Colour, size and shape allow patients and pharmacists to identify a medicine at a glance, which is a real safety function for anyone managing several at once.

Many excipients serve more than one purpose (an antioxidant may also buffer, a filler may aid compression), which is part of the formulator's craft.

Regulation

Excipients are regulated. They must meet pharmacopoeial specifications where a monograph exists, are declared on the label, and are assessed as part of the marketing authorisation for the finished product. Excipient manufacture is subject to GMP appropriate to its use, and a change of excipient supplier can require regulatory notification, because it can change how the product performs.

Excipient reactions

Reactions to excipients are uncommon, and the honest position is that they are neither a general worry nor something to dismiss. Specific examples matter to specific people:

• Lactose, a very common filler, at levels usually tolerated even by people with lactose intolerance, but relevant in severe cases.
• Starches derived from wheat, worth checking in coeliac disease.
• Certain azo colourants, which carry warning-label requirements in the EU.
• Sulfites, used as antioxidants, which can trigger reactions in sensitive asthmatics.
• Propylene glycol, benzyl alcohol and some parabens, occasionally implicated in contact reactions with topical products.

Anyone who suspects a reaction to a medicine should speak to a pharmacist or doctor rather than stopping treatment unilaterally. An alternative formulation of the same drug, with a different excipient profile, is very often available. That is a more useful answer than either alarm or reassurance.

For the active side of the same formulation, see the role of APIs in drug formulations.