The International Pharmaceutical Excipients Council defines an excipient as any substance other than the active drug or prodrug that is included in the manufacturing process or is contained in a finished pharmaceutical dosage form (3). Today's commercially available excipients provide a gamut 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 (e.g., modifying drug release). The US Pharmacopeia–National Formulary (USP–NF) categorizes excipients as binders, disintegrants, diluents, lubricants, glidants, emulsifying–solubilizing agents, sweetening agents, coating agents, antimicrobial preservatives, and so forth. In addition to their functional performance, ideally, excipients should be chemically stable, nonreactive with the drug and other excipients, inert in the human body, have low equipment and process sensitivity, have pleasing organoleptic properties, and be well characterized and well accepted by the industry and regulatory agencies. A limited choice of excipients with all of these attributes and presently available in the market can make formulation design and excipient selection challenging.
Excipients are categorized as compendial or noncompendial materials. Compendial excipients have composition consistent with monographs published in compendia such as USP–NF. Generally speaking, compendial excipients are the better characterized excipients and most likely to possess the desirable qualities previously stated. These materials are recognized as preferred excipients for pharmaceutical formulations. Noncompendial excipients might also be applied in pharmaceutical formulations. The use of these noncompendial materials is supported by Type IV drug master files (DMFs) in regulatory dossiers (i.e., new drug applications, abbreviated new drug applications, and investigational new drug applications). These files are maintained by excipient manufacturers with the agency and support the safety of the excipient as well as the quality and consistency of excipient manufacturing.
There may be approved drug products containing noncompendial excipients, thereby demonstrating the acceptance of these excipients by the US Food and Drug Administration or other agencies in the major markets. For materials in which toxicity is a possible concern, formulators can gain information about the excipient's regulatory acceptance and allowable amount by consulting with excipient manufacturers and toxicology experts. This information also may be found in the Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide (4), and other references. In addition, 21 CFR parts 182 and 184 list generally regarded as safe (GRAS) food ingredients.
Efficient pharmaceutical development
For lifecycle management, improved formulations replace or are marketed with already available products. By setting up an excipient formulary, which includes a sufficient number of carefully selected excipients and links to various unit processes, efforts can be geared toward a better understanding of excipients, functionality-test development, vendor relationships (e.g., vendor qualification), and second-vendor identification and qualification.The establishment of an excipient formulary can lead to more efficient use of available assets, decreased development times, harmonized specifications, worldwide formulation acceptance, and economy in product manufacturing.
Excipient selection in the drug product–development phase focuses on the desirable characteristics (e.g., functionality, material consistency, regulatory acceptance, cost, availability, and sources). Ingredients derived from natural animal sources (e.g., gelatin, starch) have raised concerns of transmissible spongiform encephalopathy/bovine spongiform encephalopathy/genetically modified organism (TSE/BSE/GMO). A verification letter from a vendor of these natural materials is sufficient to support non-GMO or TSE/BSE implication for consumer protection. Some vendors also provide prionics-check certification for ingredients from animal sources.
Potential problems related to excipientsImprudent selection of excipients and excipient vendors may lead to process-development problems (see sidebar "Potential problems related to excipients").
Excipient and vendor selections can greatly influence development time, performance, quality, and acceptance of final products. Consequently, quality excipient suppliers should:
maintain drug master files with FDA for noncompendial items;
consistently conform to monograph requirements;
manufacture in ISO 9000–certified facilities;
pass FDA inspection and auditing by either pharmaceutical companies or International Pharmaceutical Excipient Audit
Inattention to excipients, excipient suppliers, and regulations may lead to product development failure. Quality-by-design concepts, which have recently been initiated by FDA, emphasize the need for characterizing material properties (e.g., micromeritic, chemical, thermal, rheological, and mechanical properties) and elucidate their vital role in formulation and manufacturing processes (5–8).
Currently available excipients are sufficient to support typical formulation development. A significant number of drug entities under development, however, have physicochemical, permeation, and pharmacokinetic properties that are less than ideal. These drugs present formulation challenges and may require either the discovery of new excipients or new applications of existing excipients. Regulatory agencies require new excipients to undergo a series of toxicology tests, which may be costly.
Few new excipients of new chemical entity have been introduced into the market, primarily because of the economic hurdles associated with toxicology testing. Instead, excipient manufacturers have improved excipient performance and have expanded product lines by modifying already approved products (see Table I). Excipients undergoing these approaches may be advantageous in their formulation, manufacture, and marketing. In formulation, these excipients may decrease strain rate sensitivity, increase rework potential, increase dilution potential, decrease lubricant sensitivity, enhance flow properties, enhance the blending process, optimize content uniformity, increase compression ratio, facilitate material handling, require smaller quantities, decrease environmental concerns, and improve stability. These formulation benefits can lead to manufacturing advantages such as enable direct compaction to avoid time-consuming wet granulation, increase production capacity using excipients with enhanced flow and compaction behavior, reduce tablet tooling and machine wear, and eliminate the facility need of solvent recovery. Benefits such as rapid formulation development, smaller tablet size, better quality products, and no solvent residues may be possible by using these excipients with proven functionality.
Table I: Examples of modified excipients.Many APIs under development have less than ideal physicochemical and absorption properties, resulting in poor bioavailability. Excipient manufacturers have developed enabling excipients such as various solubilizers and absoption enhancers for these hard-to-deliver compounds (e.g., solubilizers hydroxyl propyl β-cyclodextrin; methylated β-cyclodextrin; sulfobutylether β-cyclodextrin; Cremophor RH40, Cremophor EL (BASF), and Solutol HS15 (BASF); Acconon and Captex (Abitec); as well as absorption enhancers Capmul MCM (Abitec); Gelucire 44/14, Gelucire 50/13, Labrasol, and Labrafil (Gattefosse); Imwitor 308 and Imwitor312 (Sasol), vitamin E TPGS (Eastman); and Galacticles (LipoCore)).
Because of a lack of enabling excipients in certain functionality areas, however, formulation scientists have explored several chemicals as unconventional excipients for special functions. Absorption promoters modulating epithelial tight junctions, mobilizing the lipid in epithelial cells, inhibiting P-glycoprotein efflux system, inhibiting proteolytic enzymes, or inhibiting cytochrome P-450, have been investigated (9–11). New solubilizers such as glucuronylglucosyl β-cyclodextrin (Takeda Chemical) and docosenoyloxypropyl phosphohomocholine (Genzyme Pharmaceuticals), new liquid vehicles such as tocopherol and pyrroles (BASF and ISP), polymeric micelles such as poly(ethylene glycol)-poly(lactic acid) (MacroMed) and poly(lysine) co-poly(glutamate) (Flamel Technologies), and new materials for colonic delivery based on enzymatic degradation by human colonic microflora such as amylose and pectin also were used in clinical trial formulations.
Guidance referencesConducting safety and toxicology evaluations of new excipients and generating DMF-required documents is costly. IPEC provides excipient guidance documents for the pharmaceutical industry (see sidebar "Guidance references").
Viewpoints on formulation design
Keep it simple. Simplicity is the basis of good formulation design. Formulators eliminate redundant elements and integrate components when applicable. If the API is not short of certain properties, then there is no need to incorporate any excipient to the formulation. In reality, however, APIs under development always lack certain properties and excipients facilitate manufacturing processes and enhance product performance. Nonetheless, fewer ingredients in the formulation are better for the following reasons:
Excipients are not completely inert. Even commonly used excipients that are deemed to be pharmaceutically inactive and nontoxic may cause adverse reactions (13, 14).
There is less ingredient variability to influence process and product consistency.
There is better economic efficiency in product manufacturing.
There are fewer excipients for releasing testing.
There is less probability of chemical or physical interactions between API and excipient and among excipients.
Multifunctional excipients can be beneficial in formulation design. For example, low-substituted hydroxypropyl cellulose can facilitate disintegration and prevent capping during tableting. Hydrogenated vegetable oil (e.g., Lubritab , Serotex ), distilled glyceryl monostearate (e.g., Myvaplex 600P), glyceryl behenate (Compritol 888 ATO), and glyceryl palmitostearate (Precirol ATO5) are promoted as tablet and capsule lubricants and sustained-release agents. Microcrystalline cellulose can be a bulking agent and compression aid to impart high compactibility–compressibility, good flow behavior, improve blending, and possibly enhance disintegration to drug formulations. Nonsoluble, high-swell, pregelatinized starch has been promoted as a carrier for hygroscopic ingredients, a stabilizer for moisture-sensitive drugs, and a granulation aid for high yield, fast disintegration, and dissolution enhancement.
Drug–excipient and excipient–excipient interactions
Interactions between drugs and excipients can occur by means of several possible mechanisms, including adsorption, complexation, chemical interaction, pH effects, and eutectic formation, resulting in drug products with desired or undesired properties.
Water-insoluble cellulose-type excipients such as microcrystalline cellulose and croscarmellose sodium can adsorb APIs during wet granulation or in dissolution testing, thereby leading to incomplete dissolution. This incomplete dissolution, however, usually is not present at an alarmingly high level when only van der Waals forces are operative. Substantial electrostatic interactions can occur between oppositely charged excipients and drugs, for example. Negatively charged excipients may not be compatible with positively charged drugs or excipients and positively charged excipients can interact with negatively charged drugs and excipients. Based on the Henderson-Hasselbalch equation, alkalinizing agents (e.g., sodium bicarbonate, calcium carbonate, magnesium oxide) and acidifiers (e.g., citric acid, tartaric acid, malic acid, fumaric acid) can influence the microenvironment pH significantly and may have a major influence on drug solubility or dissolution for acidic and basic drugs. Drug–excipient interaction examples have been reviewed (15).
Furthermore, formulation scientists should evaluate the possibility of excipient–excipient interactions and their influence on drug-product attributes. An excipient–excipient interaction sometimes can be used as a formulation strategy to achieve desired product attributes. For example, the viscosity of xanthan gum is increased in the presence of ceratonia (16), and the viscosity of non-ionic cellulose derivatives (hydroxypropyl methylcellulose and hydroxypropyl cellulose) is enhanced by the incorporation of sodium lauryl sulfate (17). These excipient–excipient interactions are used synergistically in controlled-release drug delivery systems.
Formulators must take all factors into consideration to design a holistic formulation, including physicochemical properties, stability and compatibility issues, pharmacokinetic attributes, permeation characteristics, segmental absorption behavior, drug delivery platforms, intellectual property issues, and marketing drive. Early characterization of these factors allows scientists to determine the absorption challenges and desired delivery platform for the API. Furthermore, excipients are not totally inert to the human body, and they may contribute significantly to therapeutics in ameliorating many disease symptoms, leading to a synergistic treatment with drugs or reduced side effects.
For example, oleic acid, a fatty acid found in olive oil, can help fight breast and other cancers, according to several published studies (18–20). Researchers at Northwestern University found that oleic acid inhibited expression of the breast cancer gene Her-2/neu by more than 46%. This gene is responsible for 25–30% of all breast cancers and begets a particularly aggressive form of the disease. Oleic acid also improved the efficacy of the drug Herceptin, which already is used to treat breast cancer. The accumulating evidence suggests that oleic acid may have a potential role in lowering the risk of several cancers. Both oleic acid and olive oil are used as GRAS-listed pharmaceutical excipients.
Researchers also found that the omega-6 polyunsaturated fatty acid gamma-linolenic acid has antitumor activity in vitro, and concurrent treatments of Her-2/neu overexpressing cancer cells with gamma-linoleic acid and the anti-Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation (20).
Several plant oils used in pharmaceuticals such as corn oil, almond oil, peanut oil, safflower oil, sesame oil, and soybean oil, contain a significant amount of linoleic acid (GRAS-listed material), which will be converted to gamma-linolenic acid by delta-6-desaturase in the body. For the other essential fatty acid family (omega-3 fatty acids), a growing body of research suggests the omega-3 fatty acids in fish oil benefit not only the cardiovascular system but also a range of psychiatric and neurological problems, inflammatory and autoimmune diseases, cancer, and bone health promotion.
Medium-chain triglycerides (e.g., glyceryl tricaprylate/caprate, glyceryl tricaprylate, glyceryl tricaprate) offer unique metabolic properties and nutritional potential for formulators to design a liquid product for a special patient population, including acquired immune deficiency disease and malabsorption disorders, to increase beneficial caloric intake. These oily liquid materials, which possess desired pharmacological or physiological effects, may be used as a liquid vehicle for other drugs.
It has been demonstrated that xylitol, a commonly used sweetener, inhibits the growth of certain bacteria and also helps prevent otitis media in a significant percentage of children (21). Xylitol is commonly used in oral pharmaceutical formulations, especially chewable tablets and syrups and is generally regarded as a nontoxic, nonallergenic, and nonirritant material. The combination of xylitol and an appropriate antibiotic in a formulation, especially liquid formulation, may provide a synergistic effect against otitis media. Other sugars such as lactulose and lactitol also are used therapeutically in the treatment of hepatic encephalopathy and as laxatives. The actions of these sugars, which are absorbed poorly after oral administration, depend on saccharolytic bacteria for breakdown in the colon to carbon dioxide, lactic acid, and small amounts of acetic acid and formic acid, which acidify the contents of the colon. This acidification of the colon area leads to retention of ammonia and removal of ammonia from the blood into the colon. The laxative action of these sugars and the metabolites then aid to expel the trapped ammonium ions from the colon. The laxative actions, ammonia-removing properties, and colonic acidification effect may help minimize the constipation side effect of certain drugs, to enhance other drugs for the treatment of hepatic encephalopathy, to create an acidic environment for improving solubility of basic drugs in the colon, or facilitate a formulation and drug delivery system.
Using absorbable sugar-based excipients for antidiabetic drugs may not be justifiable. Recently, FDA has warned healthcare professionals of the potential for life-threatening, falsely elevated glucose readings using glucose dehydrogenase pyrroloquinoline guinone-based glucose monitoring systems in patients who have received parenteral products containing maltose or galactose or oral xylose (22). Other excipients such as sodium docusate, polyethylene glycol, guar gum, methyl cellulose, polycarbophil, sodium phosphate, magnesium oxide, and magnesium carbonate, also possess laxative properties and may be used to counter the constipation side effect of some drugs. Furthermore, the magnesium mineral is an obvious powerhouse, which has the beneficial effects on many conditions, including heart attack, angina, arrhythmias, cardiomyopathy, mitral valve prolapse, intermittent claudication, low HDL, high blood pressure, diabetes, muscle cramps, kidney stones, fibromyalgia, and fatigue. In addition, magnesium may be just as important as calcium for the prevention of low bone density and osteoporosis.
Magnesium and calcium work synergistically, and both are needed for bone health, along with other cofactors of bone production, such as vitamin D and K, boron, and zinc. The calcium mineral is critical to bone strength. Calcium carbonate, dicalcium phosphate, calcium sulfate, and tricalcium phosphate can be used with a bisphosphonate drug (e.g., alendronate, risendronate, and ibandronate), a selective estrogen receptor modulator (e.g., raloxifene), or a drug with osteoporosis side effect (e.g., prednisolone) to treat and prevent osteoporosis. Long-term drug therapy for these conditions, in which the mineral can contribute significantly, is the prerequisite to consider using magnesium mineral as an excipient because mineral supplements can take as long as several weeks for results. In addition, these mineral excipients (e.g., calcium carbonate, sodium bicarbonate, and magnesium oxide can impart alkalinity to the drug microenvironment, which is another factor to be considered when using them in formulations. From the alkalinity aspect, these excipients with antacid function can be used with proton-pump inhibitors and H2 blockers to enhance the treatment additively or synergistically.
Amino acids such as glycine, lysine, isoleucine, leucine, arginine, and methionine have been used rarely in formulations as buffering agents, water-soluble lubricants, or for other functionalities. Amino acids may be used to treat certain diseases. For example, lysine is used in the treatment of cold sores and leucine may block the break down of muscle-building proteins at a lower rate. Furthermore, poly-L-lactic acid, a commonly used biodegradable polyester, is approved as an injectable implant for the restoration or correction of the sign of lipoatrophy in individuals with HIV (23). Even for a commonly used enteric polymer, preliminary data in mouse models suggest that properly formulated cellulose acetate phthalate may be an efficacious agent for preventing vaginal transmission of genital herpesvirus infections (24).
Along with the size, shape, name, and logo for drug products, formulation scientists must take the product's organoleptic attributes (i.e., visual, olfactory, and taste sensations) into consideration when formulating a drug. This organoleptic consideration is critical, especially for dosage forms designed to release the drug in the oral cavity (e.g., chewable tablets, fast disintegrating tablets, buccal tablets). First, the concept of aromatherapy, which relies on scented oils to help patients feel better physically and emotionally, may be applied to a formulation. Certain odors can have effects on mood, emotion, and behavior. For example, lavender is for relaxation and restful sleep; vanilla is for reducing anxiety; citrusy tang of lemon can be calming; rosemary is for alertness (25). Second, flavoring agents can be used for taste-masking and to produce a palatable product that can be readily consumed on a repetitive basis. Furthermore, natural spices such as cinnamon, parsley, sage, turmeric and rosemary contain many health-promoting antioxidants. This is especially true for cinnamon: the US Department of Agriculture found that half a teaspoonful a day lowered blood-sugar levels in patient with Type-2 diabetes and decreased levels of bad cholesterol (26). Third, tablet color helps in identification, branding, and reducing errors. Patients may respond better when color corresponds with the intended therapeutics of the medication, for example, calm blue for insomnia drugs, radiating yellow for depressants, and dynamic red for analgesics (27, 28). Formulation scientists rely heavily on marketing input to address product trade dress issues based on market research. The organoleptic properties of drug products can be used as a marketing strategy to ingrain a vivid product image to healthcare providers and patients.