Physicochemical basis of increased bioavailability of a poorly water-soluble drug following oral administration as organic solutions.
The physicochemical basis of improvement of the bioavailability of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] after oral administration as organic solutions was investigated. The drug, which exists in solid and metastable liquid forms, had a pKa value of 3.7 and a solubility of approximately 0.002 mg/mL in water (pH approximately 6) at 37 degrees C. It had appreciable aqueous solubility only at pH values less than 2. The dissolution rate of 1 at pH values greater than 3 was practically zero. On dilution of the water-miscible organic solutions (polyethylene glycol 400 and polysorbate 80) of 1 with aqueous media, the drug instantaneously formed saturated solutions and the excess drug separated as emulsified oily globules. The dispersibility of the globules improved in the presence of surfactants. The average globule size of the oily form of 1 was 1.6 micron or less, as compared with a particle size of 5-10 microns for the solids. Thus, a high surface area of 1 was obtained after oral intake of water-miscible organic solutions. Although 1 was practically insoluble under intestinal pH conditions, its solubility was greatly increased in the presence of bile salts, lecithin, and lipid-digestion mixtures. The high surface area of 1 separating from organic solutions would facilitate its dissolution rate in the presence of biological surfactants and lipids and, therefore, would increase its bioavailability.
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; D001647:Bile Acids and Salts / Q000378:metabolism; D001682:Biological Availability; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D008297:Male; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D012997:Solvents; D013535:Suspensions
D001647:Bile Acids and Salts; D004364:Pharmaceutical Preparations; D010713:Phosphatidylcholines; D012997:Solvents; D013535:Suspensions