Gefitinib-cyclodextrin inclusion complexes: physico-chemical characterization and dissolution studies.
BACKGROUND
Gefitinib, an anticancer drug, has an extremely low aqueous solubility, and its oral absorption is limited by its dissolution rate. The solubility and dissolution of gefitinib can be improved by complexation with cyclodextrins (CDs).


METHODS
Phase solubility studies of gefitinib with hydroxypropyl betaCD (HPbetaCD) and randomly methylated betaCD (RMbetaCD) in n various aqueous systems was conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were prepared by freeze-drying method and characterized by X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC).


RESULTS
Gefitinib formed stable complexes with HPbetaCD and RMbetaCD in distilled water as indicated by the association rate constants (Ks) of 458.9 and 1096.2 M(-1) for HPbetaCD and RMbetaCD, respectively. The complexation of gefitinib with CDs in pH 4.5 acetate buffer indicated an A(N) type of phase-solubility diagrams, whereas gefitinib and HPbetaCD in distilled water in the presence of polymers such as polyvinyl pyrrolidone K-30 (PVP) or hydroxypropyl methylcellulose E3 (HPMC) resulted in A(P)-type phase-solubility diagrams. The solid-state amorphous complexes (as described by DSC and X-RD) showed substantial increases in the solubility and dissolution rate of gefitinib with both CDs. Further increases in the solubility and dissolution rate of the gefitinib-HPbetaCD freeze-dried complex were obtained by physically mixing the complex with PVP and HPMC.


CONCLUSIONS
Gefitinib formed stable inclusion complexes with HPbetaCD and RMbetaCD, and the solubility and dissolution rate of the drug was significantly increased.
Phillip Lee
Y-H
YH
Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
Sathigari
Sateesh
S
Jean Lin
Y-J
YJ
Ravis
William R
WR
Chadha
Gurkishan
G
Parsons
Daniel L
DL
Rangari
Vijay K
VK
Wright
Nydeia
N
Babu
R Jayachandra
RJ
D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins; D000077156:Gefitinib; D006863:Hydrogen-Ion Concentration; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D011799:Quinazolines; D000077156:Gefitinib