title: Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs.
abstract: Amorphous solid dispersions (ASDs) give rise to supersaturated solutions (solution concentration greater than equilibrium crystalline solubility). We have recently found that supersaturating dosage forms can exhibit the phenomenon of liquid-liquid phase separation (LLPS). Thus, the high supersaturation generated by dissolving ASDs can lead to a two-phase system wherein one phase is an initially nanodimensioned and drug-rich phase and the other is a drug-lean continuous aqueous phase. Herein, the membrane transport of supersaturated solutions, at concentrations above and below the LLPS concentration has been evaluated using a side-by-side diffusion cell. Measurements of solution concentration with time in the receiver cell yield the flux, which reflects the solute thermodynamic activity in the donor cell. As the nominal concentration of solute in the donor cell increases, a linear increase in flux was observed up to the concentration where LLPS occurred. Thereafter, the flux remained essentially constant. Both nifedipine and felodipine solutions exhibit such behavior as long as crystallization is absent. This suggests that there is an upper limit in passive membrane transport that is dictated by the LLPS concentration. These results have several important implications for drug delivery, especially for poorly soluble compounds requiring enabling formulation technologies.
authors.affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana.
authors.forename: Shweta A
authors.initials: SA
authors.lastname: Raina
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois.
authors.forename: Geoff G Z
authors.initials: GGZ
authors.lastname: Zhang
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois.
authors.forename: David E
authors.initials: DE
authors.lastname: Alonzo
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wu
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois.
authors.forename: Donghua
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Catron
authors.affiliation: Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois. Electronic address: 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, West Lafayette, Indiana. Electronic address: lstaylor@purdue.edu.
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
mesh_terms: D001692:Biological Transport / Q000502:physiology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D004058:Diffusion; D016503:Drug Delivery Systems / Q000379:methods; D015736:Felodipine / Q000737:chemistry; D008566:Membranes / Q000378:metabolism*; D009543:Nifedipine / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D019999:Pharmaceutical Solutions / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D019999:Pharmaceutical Solutions; D014867:Water; D009543:Nifedipine; D015736:Felodipine
keywords: absorption; amorphous; bioavailability; crystallization; diffusion; dispersion; liquid-liquid phase separation; passive; uptake