Effect of crystal size on the in vitro dissolution and oral absorption of nitrendipine in rats.
OBJECTIVE
To investigate the effect of crystal size on the dissolution and oral absorption of nitrendipine, a poorly soluble drug, in rats.


METHODS
Five types of nitrendipine crystal suspensions with different particle sizes (200 nm, 620 nm, 2.7 microm, 4.1 microm, 20.2 microm) were prepared either by the precipitation-ultrasonication or the anti-solvent precipitation method. The simulated intestinal fluid in the fasted state (FaSSIF) was selected as the dissolution medium, and the dissolution behaviors of different nitrendipine crystals were simulated based on a Noyes-Whitney type equation. The in vivo absorption and the absolute bioavailability of the different nitrendipine crystals were evaluated in Wistar rats.


RESULTS
The dissolution rate of nitrendipine was significantly increased by a reduction in particle size. The dissolution test in FaSSIF could discriminate between the differences in the dissolution rates of the different particle sizes, and the simulated results were in agreement with the observed dissolution curves. From the simulated T(50%) values (50% dissolution time), the dissolution rates of crystals with particle sizes of 200 nm, 620 nm, 2.7 microm, 4.1 microm and 20.2 microm were calculated to be 5.1 x 10(4), 1.0 x 10(4), 237, 64 and 11-fold greater than that of the raw crystals and resulted in absolute bioavailability of 61.4% 51.5%, 29.4%, 26.7%, 24.7%, respectively. The reduction in the drug particle size correlated well with incremental improvements in oral absorption. A good linear relationship was observed between the Log (T(50%)) and the absolute bioavailability of nitrendipine.


CONCLUSIONS
The dissolution rate and the oral bioavailability of nitrendipine were significantly affected by the crystal size, and the oral bioavailability could be improved significantly by preparing it as nanocrystals. FaSSIF can be used to predict differences in oral absorption of crystals with different particle sizes.
Xia
Dengning
D
Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
Cui
Fude
F
Piao
Hongze
H
Cun
Dongmei
D
Piao
Hongyu
H
Jiang
Yanbo
Y
Ouyang
Mei
M
Quan
Peng
P
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D008297:Male; D008855:Microscopy, Electron, Scanning; D009061:Mouth Mucosa / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry; D009568:Nitrendipine / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D010316:Particle Size; D033362:Powder Diffraction; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013499:Surface Properties; D014961:X-Ray Diffraction
D002121:Calcium Channel Blockers; D009568:Nitrendipine