Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions.
The aim of this study was to investigate the impact of formulation excipients and solubilizing additives on dissolution, supersaturation, and membrane transport of an active pharmaceutical ingredient (API). When a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers, and cyclodextrins, have an effect not only on dissolution profile but also on the measured physicochemical properties (solubility, pKa, permeability) of the drug while the excipient is present, therefore also affecting the driving force of membrane transport. Meloxicam, a nonsteroidal anti-inflammatory drug, was chosen as a poorly water-soluble model drug and formulated in order to enhance its dissolution using solvent-based electrospinning. Three polyvinylpyrrolidone (PVP) derivatives (K30, K90, and VA 64), Soluplus, and (2-hydroxypropyl)-β-cyclodextrin were used to create five different amorphous solid dispersions of meloxicam. Through experimental design, the various formulation additives that could influence the characteristics of dissolution and permeation through artificial membrane were observed by carrying out a simultaneous dissolution-permeation study with a side-by-side diffusion cell, μFLUX. Although the dissolution profiles of the formulations were found to be very similar, in the case of Soluplus containing formulation the flux was superior, showing that the driving force of membrane transport cannot be simplified to the concentration gradient. Supersaturation gradient, the difference in degree of supersaturation (defined as the ratio of dissolved amount of the drug to its thermodynamic solubility) between the donor and acceptor side, was found to be the driving force of membrane transport. It was mathematically derived from Fick's first law, and experimentally proved to be universal on several meloxicam containing ASDs and DMSO stock solution.
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.
Enikő
E
Borbás
Pion Inc. , Billerica, Massachusetts 01821, United States.
Bálint
B
Sinkó
Pion Inc. , Billerica, Massachusetts 01821, United States.
Oksana
O
Tsinman
Pion Inc. , Billerica, Massachusetts 01821, United States.
Konstantin
K
Tsinman
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.
Éva
É
Kiserdei
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.
Balázs
B
Démuth
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.
Attila
A
Balogh
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.
Brigitta
B
Bodák
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.
András
A
Domokos
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.|Compound Profiling Laboratory, Gedeon Richter Plc. , Budapest 1103, Hungary.
Gergő
G
Dargó
Compound Profiling Laboratory, Gedeon Richter Plc. , Budapest 1103, Hungary.
György T
GT
Balogh
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics , Budapest 1111, Hungary.
Zsombor K
ZK
Nagy
D004121:Dimethyl Sulfoxide / Q000737:chemistry; D000077239:Meloxicam; D008962:Models, Theoretical; D015394:Molecular Structure; D057139:Nanofibers / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry; D011205:Povidone / Q000737:chemistry; D012996:Solutions / Q000737:chemistry*; D013843:Thiazines / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
D011108:Polymers; D011145:Polyvinyls; D012996:Solutions; D013843:Thiazines; D013844:Thiazoles; D047392:beta-Cyclodextrins; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D011092:Polyethylene Glycols; D011205:Povidone; D000077239:Meloxicam; D004121:Dimethyl Sulfoxide
DMSO; Soluplus; cosolvent; electrospinning; flux; in vitro dissolution−permeation test; meloxicam; microflux; nanofiber; supersaturation