Drug dosage forms can be rather complex systems containing many components in addition to active pharmaceutical ingredients (APIs). Formulators apply practical understanding of pharmaceutical excipients to develop optimal, robust formulations and the appropriate manufacturing processes. Technical information about these excipients is readily available (1–2). The authors review some of the important issues regarding pharmaceutical excipients, current industry trends in using pharmaceutical additives, and basic principles of formulation design.
Overview of pharmaceutical excipients
The International Pharmaceutical Excipients Council (IPEC, http://www.ipec.gov/) 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.