Method for screening of solid dispersion formulations of low-solubility compounds--miniaturization and automation of solvent casting and dissolution testing.
An efficient method has been developed for screening solid dispersion formulations that are intended to enhance the dissolution of poorly soluble compounds. The method is based on miniaturization and automation of sample preparation by solvent casting, and dissolution testing, in a 96-well plate format, using less than 0.1mg of compound per well. To illustrate the method, six polymers and eight surfactants were screened, individually and in combination, for their ability to dissolve a compound with aqueous solubility of < 1 microg/ml in simulated intestinal fluid. Screening was performed at an excipient/compound ratio of 10:1, and a polymer/surfactant ratio of 3:1 for ternary formulations. Sixteen of the 48 ternary formulations dissolved the compound to a level > 100 microg/ml, i.e. at least a 100-fold increase over the aqueous solubility. A number of synergies were observed wherein the performance of a ternary formulation greatly exceeded that of either of the corresponding binary formulations. Thirteen 'hits' from screening were scaled up with melt methods, and approximately 2/3 of these showed comparable dissolution enhancement when tested at larger scale. Five of these were administered to rats, and the absolute oral bioavailability ranged from 10 to 23%, versus less than 1% for the unformulated compound.
Oral Products R&D, ALZA Corporation, 1015 Joaquin Road, Mountain View, CA, USA.
Anant
A
Shanbhag
Shelley
S
Rabel
Ewa
E
Nauka
Gemma
G
Casadevall
Padmaja
P
Shivanand
Gary
G
Eichenbaum
Paul
P
Mansky
D000818:Animals; D001331:Automation / Q000379:methods; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D005079:Excipients / Q000737:chemistry; D008297:Male; D008904:Miniaturization / Q000379:methods; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods*
D005079:Excipients; D004364:Pharmaceutical Preparations; D011108:Polymers; D012997:Solvents; D013501:Surface-Active Agents