Dissolution behavior of a poorly water soluble compound in the presence of Tween 80.
OBJECTIVE
To investigate the mechanism by which Tween 80 impedes the dissolution of CI-1041, a poorly water-soluble compound in its free form.


METHODS
Bulk powder and intrinsic dissolution (ID) of CI-1041 in 0.1 N HCl with various concentrations of Tween 80 were conducted. The residual solids of the dissolution experiments were characterized. The surface tension and the critical micellar concentration (CMC) of Tween 80 in 0.1 N HCl were determined.


RESULTS
CI-1041 underwent solvent mediated conversion to its chloride salt (CS) in 0.1 N HCl. The coating of the CS on the surface of the CI-1041 pellet decreased the ID rate 20 to 30 fold. When the Tween 80 concentration in 0.1 N HCl was below 0.5 mg/ml, the CS formation rate increased with increasing Tween 80 concentration. Above 0.5 mg/ml of Tween 80 in 0.1 N HCl, opposite trend was observed. The change in trend at 0.5 mg/ml Tween 80 coincided approximately with the CMC of Tween 80 in 0.1 N HCl.


CONCLUSIONS
The authors propose the following mechanism mediated by Tween 80. Below CMC, reduced surface tension caused by addition of Tween 80 increases the rate of nucleation of insoluble CS, causing the formation of CS on the surface of the CI-1041 free form. This, in turn, decreases the dissolution rate by decreasing the release of compound into solution. Above CMC, the effect of reduced surface tension on the CS nucleation and therefore its formation may be negated by other factors, such as an increase in viscosity or adsorption of surfactant on the crystal surface.
Chen
Linna R
LR
Pharmaceutical Sciences, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105, USA.
Wesley
James A
JA
Bhattachar
Shobha
S
Ruiz
Bienvenido
B
Bahash
Korey
K
Babu
Suresh R
SR
D001583:Benzoxazoles / Q000737:chemistry* / Q000378:metabolism*; D002214:Capsules; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism*; D011136:Polysorbates / Q000378:metabolism* / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D014867:Water / Q000378:metabolism*
D001583:Benzoxazoles; D002214:Capsules; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011136:Polysorbates; D014867:Water; C481484:besonprodil