Solubilization of two structurally related anticancer drugs: XK-469 and PPA.
The efficiency of a solubilization technique is determined by the physical-chemical properties of the drug. This study investigates the solubilization on two structurally related anticancer drugs, XK-469 and PPA. XK-469 is much less polar than PPA with an intrinsic solubility of 0.000274 mg/mL, which is about 10,000 fold less than that of PPA. Fortunately, its physical-chemical properties make it much more formulatable. An ionizable drug can be solubilized by pH adjustment with cosolvency, micellization, or complexation. Both XK-469 and PPA are weak acids with pKa values of 2.7 and 2.9, respectively. Thus, they can be solubilized by pH adjustment. At pH 4.55, neither cosolvency, micellization nor complexation has much effect on the solubility of PPA. However, these techniques can significantly increase the solubility of XK-469. In fact, the solubility of XK-469 in 20% HPbetaCD at pH 4.55 is 5.85 mg/mL, which is more than 20,000 times greater than its intrinsic solubility. With the solubilization descriptors obtained from the experimental data for both unionized and ionized drug species at pH 1.0 and pH 4.55, the solubility of each drug at any pH and excipient concentration can be estimated. Then, a solubilization technique can be chosen for preparing a desired final drug concentration.
He
Yan
Y
College of Pharmacy, the University of Arizona, Tucson, 85721, USA. yhe@rdg.boehringer-ingelheim.com
Tabibi
S Esmail
SE
Yalkowsky
Samuel H
SH
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000970:Antineoplastic Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D000431:Ethanol / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D011136:Polysorbates / Q000737:chemistry; D011422:Propionates / Q000737:chemistry*; D019946:Propylene Glycol / Q000737:chemistry; D011810:Quinoxalines / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
D000970:Antineoplastic Agents; D008823:Micelles; D011136:Polysorbates; D011422:Propionates; D011810:Quinoxalines; D012997:Solvents; D013501:Surface-Active Agents; C118180:XK 469; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C093196:SBE4-beta-cyclodextrin; D000431:Ethanol; D019946:Propylene Glycol; C408480:2-phenoxypropanoic acid