title: Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs.
abstract: OBJECTIVE
  Many enabling formulations give rise to supersaturated solutions wherein the solute possesses higher thermodynamic activity gradients than the solute in a saturated solution. Since flux across a membrane is driven by solute activity rather than concentration, understanding how solute thermodynamic activity varies with solution composition, particularly in the presence of solubilizing additives, is important in the context of passive absorption.
  
  
  METHODS
  In this study, a side-by-side diffusion cell was used to evaluate solute flux for solutions of nifedipine and felodipine in the absence and presence of different solubilizing additives at various solute concentrations.
  
  
  RESULTS
  At a given solute concentration above the equilibrium solubility, it was observed that the solubilizing additives could reduce the membrane flux, indicating that the extent of supersaturation can be reduced. However, the flux could be increased back to the same maximum value (which was determined by the concentration where liquid-liquid phase separation (LLPS) occurred) by increasing the total solute concentration. Qualitatively, the shape of the curves of solute flux through membrane as a function of total solute concentration is the same in the absence and presence of solubilizing additives. Quantitatively, however, LLPS occurs at higher solute concentrations in the presence of solubilizing additives. Moreover, the ratios of the LLPS onset concentration and equilibrium solubility vary significantly in the absence and presence of additives.
  
  
  CONCLUSIONS
  These findings clearly point out the flaws in using solute concentration in estimating solute activity or supersaturation, and reaffirm the use of flux measurements to understand supersaturated systems. Clear differentiation between solubilization and supersaturation, as well as thorough understanding of their respective impacts on membrane transport kinetics is important for the rational design of enabling formulations for poorly soluble compounds.
authors.affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.|Manufacturing Science and Technology, Operations, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA.
authors.forename: Shweta A
authors.initials: SA
authors.lastname: Raina
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Geoff G Z
authors.initials: GG
authors.lastname: Zhang
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois, USA.|Formulation & Process Development, Gilead Sciences Inc., Foster City, California, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Alonzo
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois, USA.|Center for Drug Evaluation and Research, FDA, Silver Spring, Maryland, USA.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wu
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois, USA.|Pharmaceutical Development Manufacturing & Science, Janssen R&D China, Johnson & Johnson, Shanghai, China.
authors.forename: Donghua
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Catron
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois, USA. gao.yi@abbvie.com.|Manufacturing Science and Technology, Operations, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA. gao.yi@abbvie.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA. lstaylor@purdue.edu.
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
mesh_terms: D001692:Biological Transport / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004058:Diffusion; D015736:Felodipine / Q000737:chemistry; D007408:Intestinal Absorption / Q000187:drug effects; D007700:Kinetics; D009543:Nifedipine / Q000737:chemistry; D019999:Pharmaceutical Solutions / Q000737:chemistry*; D012995:Solubility
chemical_list: D019999:Pharmaceutical Solutions; D009543:Nifedipine; D015736:Felodipine
keywords: membrane transport; solubilization; supersaturation; surfactants