Solubility increases associated with crystalline drug nanoparticles: methodologies and significance.
In this manuscript, the determination of solubility of crystalline drug nanosuspensions by a range of methods is critically investigated. As the determinations of solubility were performed in the presence of the solubilizing nanosuspension stabilizer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), the potential effects of this excipient on the measurements were studied first. Solubility data of nanosuspensions of itraconazole, loviride, phenytoin and naproxen were generated using different methodologies. Data obtained using separation-based methodologies (centrifugation, filtration and ultracentrifugation) proved to be of limited use, due to poor nanoparticle separation efficiencies and/or significant adsorption of TPGS onto the nanoparticle surfaces. Light scattering and turbidity were found to be more suitable for the determination of nanosuspension solubility. The obtained data show that, unlike earlier reports, the solubility increases due to nanosizing are small, with measured increases of only 15%. These solubility increases are in fair agreement with what would be predicted based on the Ostwald-Freundlich equation.
Van Eerdenbrugh
Bernard
B
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
Vermant
Jan
J
Martens
Johan A
JA
Froyen
Ludo
L
Humbeeck
Jan Van
JV
Van den Mooter
Guy
G
Augustijns
Patrick
P
D000081:Acetamides / Q000737:chemistry; D000098:Acetophenones / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D005079:Excipients; D017964:Itraconazole / Q000737:chemistry; D008027:Light; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D009288:Naproxen / Q000737:chemistry; D009391:Nephelometry and Turbidimetry; D010316:Particle Size; D010672:Phenytoin / Q000737:chemistry; D011092:Polyethylene Glycols; D012542:Scattering, Radiation; D012995:Solubility; D013535:Suspensions; D014810:Vitamin E / Q000031:analogs & derivatives
D000081:Acetamides; D000098:Acetophenones; D005079:Excipients; D008823:Micelles; D013535:Suspensions; D014810:Vitamin E; D017964:Itraconazole; C080073:loviride; D011092:Polyethylene Glycols; D009288:Naproxen; D010672:Phenytoin; C014225:tocophersolan