Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions.
Solid dispersions of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] in an amphiphilic vehicle [Gelucire 44/14; 2] and in polyethylene glycol (PEG) 1000, PEG 1450, and PEG 8000 were prepared. The vehicle 2 was a mixture of hydrogenated fatty acid esters with a mp of 44 degrees C, and had a HLB value of 14. Compound 1 was dissolved or dispersed in molten vehicles at elevated temperatures. The pulverization and compression of solid dispersions were avoided by encapsulating the hot solutions directly into hard gelatin capsules. At room temperature, the dispersions solidified forming plugs inside the capsules. On storage, greater than 180 mg of 1 remained dissolved per gram of vehicle, while the excess drug formed fine crystals (less than 20 micron). When mixed with water, the dissolved drug separated as a metastable liquid. Due to the surfactant property of 2, the oily form of 1 that separated from this vehicle formed an emulsified system with a globular size of less than 1 micron, while greater than 80% of 1 that separated from the other three formulations coalesced to form large oily masses. As a result of the large difference in surface area, the dissolution rate of 1 in simulated gastric fluid from capsules containing 2 was much higher than that of a PEG-based formulation. The bioavailability (AUC) of 1 in dogs from capsules containing 2 was also higher than that from PEG 1000-based capsules.
Serajuddin
A T
AT
Rorer Central Research, Horsham, PA 19044.
Sheen
P C
PC
Mufson
D
D
Bernstein
D F
DF
Augustine
M A
MA
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002214:Capsules; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D006912:Hydroxyquinolines / Q000378:metabolism; D008297:Male; D010316:Particle Size; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D011804:Quinolines; D012995:Solubility
D002214:Capsules; D006912:Hydroxyquinolines; D014677:Pharmaceutical Vehicles; D011804:Quinolines; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; D011092:Polyethylene Glycols