Finished pharmaceutical formulations often contain agents that have a variety of purposes, including improvement of the appearance, bioavailability, stability, and palatability of the drug. Excipients (substances added to confer a suitable consistency or form to a drug, such as the vehicle, preservatives, or stabilizers) frequently make up the majority of the mass or volume of oral and parenteral drug products. These pharmaceutical adjuvants are usually considered to be inert and do not add to or affect the intended action of the therapeutically active ingredients. Most of the so called inactive ingredients added to food and drugs to make them more appealing can have as many side effects as drugs themselves.

More than 800 chemical agents have been approved by the Food and Drug Administration (FDA) for use as inactive ingredients in drug products. Pharmacopeial guidelines, enforceable under the Food, Drug and Cosmetic Act, do require labelling of inactive ingredients for topical, ophthalmic and parenteral preparations; however, orally administered products are exempted. On pressurization by professional and consumer organizations asking the FDA to require complete disclosure of all ingredients, voluntary labelling was adopted by the two major pharmaceutical industry trade associations. These voluntary guidelines contain an exemption for “trade secret” components and do not require complete disclosure of all fragrance and flavouring ingredients.

Major problems encountered with “inactive” ingredients include benzalkonium chloride-induced bronchospasm from anti asthmaticccc drugs, aspartame-induced headache and seizures, saccharin-induced cross-sensitivity reactions in children with sulfonamide allergy, benzyl alcohol toxicity in neonates receiving high-dose continuous infusion with preserved medications, dye-related cross-reactions in children with aspirin intolerance, lactose-induced diarrhea and propylene glycol-induced hyperosmolality and lactic acidosis. Although many other excipients have been implicated in causing adverse reactions, these are the most significant in the paediatric population.

The pharmaceutical excipients market has seen tremendous developments in recent times. Pharmaceutical excipients are increasingly being considered as functional ingredients in contrast to their earlier status as non-functional additives. Consequently, drug product manufacturers are now seeking novel, value-added excipients for new product development. The established markets, including the US, UK, and Japan, together account for 30 per cent  of the global demand for excipients.

The US recorded the largest single demand for pharmaceutical excipients, representing 15.9 per cent of the global demand in 2009. It is expected that global excipients demand by volume will grow at a CAGR of 4.9 per cent  till 2015. The US, UK and Japan will demonstrate a growth of 3.8 per cent  whereas the emerging markets especially China, India and Brazil will grow at a faster pace of 6.3 per cent. Recent advances in nanotechnology have redefined excipients, imparting new functions to them. Thus, an excipient can also act as a carrier of drug particles that are coated on it using nanotechnology for improved stability and release. Combination excipients are tremendously being used by formulators as they bypass regulatory and processing hurdles.

Although listed as inactive ingredients by FDA, excipients generally have well-defined functions in a drug product. The excipients may be small molecule or complex and may vary in terms of degree of characterization. They may be chemically synthesized or may be either natural source or biotechnology-derived (recombinant). In contrast to active ingredients, minor components of an excipient may have significant impact on its pharmaceutical performance. One interesting fact is that an excipient in a drug product may be an active ingredient in another formulation, depending on its intended use.

Currently, control of excipient manufacturing and distribution is not the priority for regulatory authorities or pharmaceutical manufacturers, perhaps due to the fact that most of these excipients originated from the food industry and have generally recognised as safe (GRAS) status. However, with the emergence of novel excipients and delivery systems, better control of these materials becomes increasingly important.Now -a- days, regulatory bodies and manufacturing facilities are paying a whole lot more attention to excipient issues, as these supporting actors play a crucial role in the final drug formulation and in ensuring patient safety. The wrong excipient can interact with an active ingredient, hurting patients, while a contaminated or fake one can lead to adverse patient responses, or worse. Consider natural products, starch processed from corn grown during a dry season may bear little resemblance, when its physical properties are measured, to starch made from corn grown from a rainy season. Lactose made from the milk of cows who have been fed on winter sileage will differ dramatically from that made from the milk of cows fed on grass. But still, in both cases, the materials are considered to be similar when formulating.

It started in the 1980s when physicians began to explore the excipients’ role in adverse patient responses. An article, published in 1994, in the Canadian Medical Association Journal  opined for complete disclosure of all ingredients, active and inactive in any drug formulation, something that we now take for granted.

Each and every component of prescription drug formulations - excipients, additives and active ingredients - should be listed on the label, where they can be read by physicians, nurses, pharmacists and patients. Without easy access to this information one cannot recognize and appropriately treat adverse reactions and the safety and efficacy of any drug formulation cannot be established. It is unacceptable that health care professionals or patients must query a third party (the manufacturer) to determine the ingredients in a drug formulation.

Adverse drug reactions (ADRs) were studied extensively from the 1960s through the early 1980s, primarily in hospitals. The problem of ADRs was found to be widespread and serious enough that in 1968 the World Health Organization (WHO) started ADR surveillance program, which continues till today.

Canada was one of the 10 countries that founded the program. ADRs are a widespread and serious problem, but what portion of the problem is due to excipients is not known, but it is much larger than generally thought. Very rarely is a patient given a pure chemical or "active ingredient" as a therapeutic agent.

ADRs caused by excipients
A huge number of serious Adverse Drug Reactions (ADRs) are caused by excipients. Some 76 deaths were reported from acidosis and renal failure following the use of elixir of sulfanilamide; for this, the excipient diethylene glycol was found to be the cause. There were later reports of more than 100 deaths. The toxic nature of diethylene glycol was noticed again some 50 years later by Cantarell and collaborators. They described oliguria and acidosis in patients with burns who were treated with topical antibacterials containing diethylene glycol.

One could easily assume that adverse reactions to diethylene glycol had continued during the intervening 50 years; failure to diagnose these reactions may have resulted from diverse factors, including the belief that excipients were safe and ignorance about which excipients were found in drug formulations. Dilantin, a brand of phenytoin, had been sold for many years in Australia and New Zealand when the manufacturer decided to change the formulation to the one used in the United States. Consequently, 51 patients whose epilepsy was stable with the use of the old formulation had severe and serious adverse reactions, including coma, with the new product. The reformulation involved replacement of calcium sulfate dehydrate with lactose, a seemingly innocuous change. However, it appeared that the calcium salt slowed absorption of the phenytoin, whereas lactose speeded it up. It was in 1982 when benzyl alcohol was implicated in the “gasping” syndrome as well as the deaths of premature infants who received the medication containing this excipient. Benzyl alcohol was also the involved in the exacerbation of asthma following intravenous administration of a hydrocortisone formulation.

In a number of investigations of an ADR, when the patient showed a positive sign of a challenge with the suspected drug formulation, investigators concluded that the cause of the reaction was the active ingredient because it was the only constituent known; the rest of the formulation was considered inert. Luckily, a few sceptics in the medical community investigated not only the drug formulation but also each substance in it and combinations of ingredients. In 1984, advice was taken for the management of a recurrent upper respiratory tract infection in a child. The infection tended to be refractory because the patient was hypersensitive to penicillin and its derivatives. A liquid oral erythromycin preparation (125 mg/mL) was prescribed. Just after the first dose, the patient suffered severe abdominal pain, nausea and vomiting. It was doubted that the child had an allergy to erythromycin, and so the physician prescribed another formulation of erythromycin (250 mg/mL). With this formulation the child suffered no adverse reaction; but; some time later, a local pharmacist disregarded the physician's "no substitution" order and substituted the 125 mg/mL formulation. The child again experienced the pain, nausea and vomiting. When informed about the consequences, the pharmacist said, "The active ingredient is the same; the colouring and flavour don't matter." Actually, the child had reacted to the tincture of orange used as a colouring and flavouring agent in the 125 mg/mL formulation. The 250 mg/mL preparation did not contain tincture of orange, although the products were manufactured by the same company.

Future prospects
Commercially available excipients provide a variety of required functions, from processing aids that increase lubricity, enhance flowability, and improve compressibility and compatibility to agents that impart a specific functional property to the final product. There are currently 1,200 or so excipients on the market and they fulfil the needs of the majority of finished pharmaceutical products.

There is no unmet need in immediate-release dosage forms for new excipients, although the big exception here is for modified-release dosage forms. The constant drive for new drug candidates in the pharmaceutical industry will result in a growing number of finished products entering the market. There is a strong need for additional information and guidelines regarding the development, characterization, and quality of new excipients and new applications of the current excipients.

The pharmacopoeias and international councils have spearheaded some efforts to develop and harmonize the standards as well as to provide guidelines on good manufacturing and distribution practices for excipients. However, additional efforts are necessary to develop comprehensive and authoritative standards to promote innovation in the area of excipients in order to improve the understanding of the importance of excipients in the global market.

In general, there is an increased recognition of the role of excipients in the drug delivery process along with an increased research on the impact of excipients to enhance the bioavailability of active ingredients. Thus, there is also an resistance from pharmaceutical companies we well as manufacturers to double their risk by using a novel excipient. At the same time, developing a novel excipient is long and expensive (€ 30 mio). More than 50 per cent  of the world’s consumption of medicinal products is in the form of tablets. This provides lactose with a very stable market, in which it continues to be the leader.