The use of ordered mixtures for improving the dissolution rate of low solubility compounds&

Abstract

The dissolution rate of micronized griseofulvin has been investigated, both for the agglomerated raw material and the material formulated as an ordered mixture, by means of the USP XX paddle method. During the experiments, which were performed at sink condition and constant temperature, the effects of adding a surfactant and of agitation were tested. The ordered mixture with sodium chloride gave a fast dissolution rate, practically independent of the test parameters. Micronized griseofulvin alone gave dissolution profiles that were improved by adding polysorbate 80 and by increased agitation, but the dissolution rates obtained were much lower than those for the ordered mixture. It was concluded that the rate limiting step in the dissolution of griseofulvin as the raw material is the penetration of the dissolution medium into the agglomerates. With an ordered mixture, these agglomerates were deaggregated during the mixing process, producing a system in which the entire external surface area of the primary particles was exposed to the dissolution medium. This conclusion was supported by calculation of the contact surface areas taking part in the dissolution process for the systems tested. The procedure developed in this study could be applied to preformulation work where a cohesive, low solubility drug of hydrophobic nature is to be formulated.

Investigation into process-induced de-aggregation of cohesive micronised API particles

“…Incomplete de-aggregation has previously been observed despite the use of much higher mixing speeds (Kale et al, 2009) and significantly longer mixing durations , Olusanmi et al, 2014. Very long blending times may indeed be necessary to fully remove such aggregates in formulations containing poorly water-soluble drug compounds (Nystrom & Westerberg, 1986) which would dramatically reduce the efficiency of the manufacturing process.…”

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“…Ordered mixing yields nearly the perfect mix and may be obtained in a number of ways like mechanical means, adhesion, coating and other methods 64 . Prerequisite for fast dissolution from an ordered mixture includes that the carrier particle should dissolve rapidly, delivering a fine particulate suspension of drug particles 65 . Higher concentration of drug shows reduced dissolution rates particularly at loadings above monolayer coverage.…”

Dissolution Enhancement of Drugs. Part II: Effect of Carriers

“…Ordered mixtures of griseofulvin were prepared using sodium chloride as a carrier material. Dissolution rate was increased due to soluble nature of sodium chloride, thereby rapid delivery of drugs in the form of discrete primary particles (37).…”