Review of Current Issues in Pharmaceutical Excipients - Pharmaceutical Technology

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Review of Current Issues in Pharmaceutical Excipients
Excipients facilitate formulation design and perform a wide range of functions to obtain desired properties for the finished drug product. The article reviews excipient development and functionality of these materials, including their importance in formulation design, potential processing challenges directly related to excipients, and therapeutic benefits.

Pharmaceutical Technology

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 references
Conducting 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

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).


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