TY - JOUR

T1 - Effect of centrifugation speed on the measured equilibrium solubility of poorly water-soluble compounds in viscous solvents

AU - Liu, Xiaona

AU - Mullertz, Anette

AU - Bar-Shalom, Daniel

AU - Berthelsen, Ragna

PY - 2020

Y1 - 2020

N2 - Lipid based drug delivery systems (LbDDSs) present an effective solution for increasing the apparent solubility and eliminating the slow dissolution process of many poorly water-soluble compounds. Typically, an initial step in designing a LbDDS is to measure the equilibrium solubility of the compound in various LbDDS excipients, which often are viscous. Equilibrium solubility is usually measured by the classical saturation shake-flask (SSF) method with centrifugation for phase separation. The concentration of the compound in the supernatant is determined as the solubility. As complete phase separation is necessary to determine the equilibrium solubility, but difficult to achieve in viscous solvents, the aim of the present study was to evaluate the effect of centrifugation speed on the measured solubility.In the present study, the solubility of seven poorly water-soluble compounds: amphotericin B, nystatin, beta-carotene, curcumin, itraconazole, cinnarizine and fenofibrate was measured in five viscous solvents using the SSF method. For five out of the seven compounds (amphotericin B, nystatin, beta-carotene, curcumin and itraconazole) the centrifugation speed had a significant effect on the measured solubility, i.e. different centrifugation speeds led to differences in the measured solubility. The supernatants of all the tested samples, following 15 min of centrifugation at 900 x g (3K RPM), 4.7K x g (7K RPM) and 17K x g (13.3K RPM), were evaluated for particle presence by polarized light microscopy. Presence of particles in the supernatants of the five affected compounds indicated that complete phase separation was not obtained, and that the measured solubility did not represent the true equilibrium solubility. Studying the physicochemical properties of the tested compounds, it was found, that the compounds, for which the measured solubility was affected by the centrifugation speed, all display high melting points. In conclusion, to avoid overestimating the equilibrium solubility, especially for compounds with high melting points, it is recommended to use the highest possible centrifugation speed, and to evaluate the effect of centrifugation speed on the solubility measurement, when conducting solubility experiments in viscous solvents using centrifugation for phase separation.

AB - Lipid based drug delivery systems (LbDDSs) present an effective solution for increasing the apparent solubility and eliminating the slow dissolution process of many poorly water-soluble compounds. Typically, an initial step in designing a LbDDS is to measure the equilibrium solubility of the compound in various LbDDS excipients, which often are viscous. Equilibrium solubility is usually measured by the classical saturation shake-flask (SSF) method with centrifugation for phase separation. The concentration of the compound in the supernatant is determined as the solubility. As complete phase separation is necessary to determine the equilibrium solubility, but difficult to achieve in viscous solvents, the aim of the present study was to evaluate the effect of centrifugation speed on the measured solubility.In the present study, the solubility of seven poorly water-soluble compounds: amphotericin B, nystatin, beta-carotene, curcumin, itraconazole, cinnarizine and fenofibrate was measured in five viscous solvents using the SSF method. For five out of the seven compounds (amphotericin B, nystatin, beta-carotene, curcumin and itraconazole) the centrifugation speed had a significant effect on the measured solubility, i.e. different centrifugation speeds led to differences in the measured solubility. The supernatants of all the tested samples, following 15 min of centrifugation at 900 x g (3K RPM), 4.7K x g (7K RPM) and 17K x g (13.3K RPM), were evaluated for particle presence by polarized light microscopy. Presence of particles in the supernatants of the five affected compounds indicated that complete phase separation was not obtained, and that the measured solubility did not represent the true equilibrium solubility. Studying the physicochemical properties of the tested compounds, it was found, that the compounds, for which the measured solubility was affected by the centrifugation speed, all display high melting points. In conclusion, to avoid overestimating the equilibrium solubility, especially for compounds with high melting points, it is recommended to use the highest possible centrifugation speed, and to evaluate the effect of centrifugation speed on the solubility measurement, when conducting solubility experiments in viscous solvents using centrifugation for phase separation.

KW - Viscous solvents

KW - Solubility measurement

KW - Shake-flask method

KW - Poorly water-soluble compounds

KW - Centrifugation

KW - Phase separation

KW - DRUG-DELIVERY SYSTEMS

KW - PERFORMANCE LIQUID-CHROMATOGRAPHY

KW - ORAL DELIVERY

KW - CINNARIZINE

KW - FORMULATION

KW - SEPARATION

KW - STABILITY

KW - CURCUMIN

KW - SNEDDS

KW - ASSAY

U2 - 10.1016/j.jddst.2020.101853

DO - 10.1016/j.jddst.2020.101853

M3 - Journal article

VL - 59

JO - Journal of Drug Delivery Science and Technology

JF - Journal of Drug Delivery Science and Technology

SN - 1773-2247

M1 - 101853

ER -