Imprudent selection of excipients and excipient vendors may lead to process-development problems (see sidebar "Potential problems
related to excipients").
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 (IPEA,
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.
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)).
Table I: Examples of modified excipients.