Role of Self-Association and Supersaturation in Oral Absorption of a Poorly Soluble Weakly Basic Drug.
OBJECTIVE
Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated.


METHODS
Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables.


RESULTS
Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data.


CONCLUSIONS
Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.
Drug Product Science and Technology, One Squibb Dr., New Brunswick, New Jersey, 08901, USA, ajit.narang@bms.com.
Ajit S
AS
Narang
Sherif
S
Badawy
Qingmei
Q
Ye
Dhaval
D
Patel
Maria
M
Vincent
Krishnaswamy
K
Raghavan
Yande
Y
Huang
Aaron
A
Yamniuk
Balvinder
B
Vig
John
J
Crison
George
G
Derbin
Yan
Y
Xu
Antonio
A
Ramirez
Michael
M
Galella
Frank A
FA
Rinaldi
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D002021:Buffers; D002151:Calorimetry; D002626:Chemistry, Pharmaceutical; D003102:Colloids; D003198:Computer Simulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010316:Particle Size; D012995:Solubility; D013500:Surface Tension; D014227:Triazines / Q000737:chemistry* / Q000493:pharmacokinetics*
D002021:Buffers; D003102:Colloids; D014227:Triazines; C509922:brivanib; D000409:Alanine