Bioavailability Challenges

90% of New Chemical Entities (NCEs) in today’s development pipeline suffer from either poor aqueous solubility or poor permeability, or both. 1

Fig 1: Disposition of NCEs within the Biopharmaceutics Drug Disposition Classification System (BDDCS)

NCE’s with low solubility and/or poor permeability often result in:

  • • Insufficient drug reaching the bloodstream and target tissues
  • • Significant food effects potentially resulting in altered bioavailability
  • • Bioavailability that can be significantly altered by food effects
  • • More difficult, costly, and lengthy development programs due to high inter-patient response variability

Thus, modifying a drug’s solubility and permeability are important considerations for improving bioavailability. Often the bioavailability of a drug can be enhanced by modifying the drug substance, the formulation, or both. Selection of an appropriate strategy for enhancing the oral bioavailability of a poorly-soluble and/or poorly-permeable drug depends on the unique properties of each drug, for example:

  • • Molecular attributes: molecular weight, functional group composition, structure, pKa
  • • Physical attributes: solid form, particle-size distribution, particle surface area, physical stability, hygroscopicity, intrinsic dissolution rate, solubility
  • • Chemical attributes: stability, compatibility (in vivo and with excipients)
  • • Biological properties: mechanism of absorption (passive diffusion or active transport); site of absorption; first-pass metabolism; efflux; enterohepatic circulation; drug dosing requirements

The solubility of the active pharmaceutical ingredient (API) in gastric and/or intestinal fluid is a significant factor in achieving adequate absorption (Table I). Compounds with poor solubility in these media (e.g., <0.1%) are likely to exhibit poor bioavailability.

Formulation strategies for enhancing a drug’s permeability , modulating drug transport processes, or altering absorption pathways represent areas of active research. This website will primarily focus on technologies to improve bioavailability through solubility enhancement.

1Benet, L. Predicting Drug Disposition by Application of BDDCS, AAPS (2008)

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