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Abstract
Slight dissolution rates related to poor water-solubility are one of the well-known
difficulties to be covered during the development of new drug substances. The poorly
water-soluble drug ECU-01, a low molecular enzyme-inhibitor with anti-inflammatory
properties for oral administration, shows a poor dissolution rate. This study is intended
to enhance the drug dissolution rate by using microcrystals. The common way for micronization
is the milling of previously formed larger crystals. However, milling shows several
disadvantages as the newly created surfaces are thermodynamically activated due to
the high energy input and not naturally grown. In this study microcrystals were not
produced using any cutting up techniques, but only by association. Naturally grown
microcrystals were prepared by a precipitation method in the presence of stabilizing
agents (e.g. gelatin, chitosan, different types of cellulose ethers) followed by spray-drying
of the formed dispersion. First the drug was dissolved in acetone and then precipitated
by rapid pouring an aqueous solution of the stabilizer into the drug solution. Particularly,
cellulose ethers were able to form stable and homogeneous dispersions of microcrystals
(mean particle size = 1 microm) showing a tight particle size distribution. By spray-drying,
the drug powder was obtained. The dissolution rate is significantly enhanced (common
drug: 4% after 20 min/microcrystals 93% after 20 min) due to the large surface, which
is hydrophilized by adsorbed stabilizers as shown by the decreased contact angle (65
and 30 degrees, respectively).
Copyright 2003 Elsevier Science B.V.