Chitosan-Based Gels for the Drug Delivery System - Chitosan Based Hydrogels: Functions and Applications - page 277

Chitosan solution
in acetic acid (5%)

Mechanical
stirrer

Cross-linker

Chitosan
microsphere

Microsphere formation
Petroleum ether

Mineral oil

Tw een-80
10-15 min mixing

2-4 h additional
mixing

Figure 6.12
Schematic representation of the suspension cross-linking technique. (From Denkbas, E. B. and Ottenbrite, R. M.
2006. J Bioact Compat Polym 21: 351-368. With permission.)

The inverse microemulsion method has been utilized to prepare ultrafine polymeric
nanoparticles with narrow size distribution [87,88]. Similar to the inverse (mini) emulsion
method, this method also involves a w/o dispersion. However, it requires the addition of a
large amount of oil-soluble surfactants above the critical threshold to prepare reverse
micelles, producing thermodynamically stable microemulsions [84,87]. The resulting
micellar droplets have nanometer-sized particles ranging from tens to hundreds of nano-
meters in diameter [87]. In a typical preparation [89], a lipophilic surfactant was dissolved
in hexane, and then aqueous solutions of chitosan and hydrophilic drugs were added with
continuous stirring to avoid any turbidity. The entire mixture solution was homogeneous
and optically transparent. An additional amount of water may be added to obtain nano-
particles of larger size. To this transparent solution, a cross-linking agent (glutaraldehyde)
was subsequently added with continuous stirring. It was reported that chitosan-based
nanoparticles containing doxorubicin-modified dextran have a diameter of 100 nm [89].

6.4.2.2 Coacervation

In this process, the polymer is solubilized to form a solution. This is followed by the addi-
tion of a solute, which forms insoluble polymer derivative and precipitates the polymer. As
for chitosan, the physicochemical property of its insolubility in an alkaline pH medium
but coacervating in contact with an alkaline solution is utilized to obtain microparticles.
This process avoids the use of toxic organic solvents in the other methods.
Berthold and Kreuter [90] prepared drug-loaded chitosan microspheres using sodium
sulfate as a precipitant. The addition of sodium sulfate to the aqueous acid solution of chi-
tosan containing a surfactant resulted in decreased solubility of chitosan, leading to pre-
cipitation of chitosan as a poorly soluble derivative. Microspheres were purified by
centrifugation and resuspended in demineralized water. It was reported that particles
produced accordingly have better acid stability than observed by other methods.
In addition, particles can also be produced by blowing chitosan solution into an alkali
sodium hydroxide solution using a compressed air nozzle to form coacervate droplets [18].