The theoretical aspects of solid solutions and eutectic mixtures as well as their application to pharmaceutical systems are discussed. A mechanism is considered by which such solid systems may enhance dissolution rates and, in turn, the gastrointestinal absorption rate and availability of poorly soluble drugs. A degree of ambiguity exists in the literature published to date in this area. This report progoses that results previously attributed to eutectic mixtures are properly explained y the existence of solid solutions. The sulfathiazole-urea and chloramphenicolurea systems are examined in detail.
I
NUMBER of modern therapeutic agents are
A poorly soluble in the aqueous fluids of the gastrointestinal tract. Consequently, the in vivo dissolution rate of these compounds is low, and their gastrointestinal absorption tends to be incomplete and erratic (1). Since dissolution rate is directly proportional to surface area (2), one may increase the rate by decreasing the particle size of the drug. The greater surface area of drug in contact with biological fluids then will bring about more rapid dissolution and thereby more rapid gastrointestinal absorption, provided that absorption is rate limited by the dissolution process. Levy (1) notes that, "In those instances where the intrinsic dissolution rate is so low that the drug is ordinarily not completely absorbed when administered in solid form, the more rapid absorption attained by increasing the specific surface area will cause also an increase in the total amount of drug absorbed from a given dose."
Recent studies with sulfadiazine (3), sulfaethylthiadiazole (4), and griseofulvin (5) support these hypotheses. As a result of the lastmentioned investigation (5), manufacturers now market griseofulvin in a finely micronized form which permits 50% dosage reduction as compared to the original unmicronized form. At present, the degree of particle size reduction required to increase significantly the specific surface area of these drugs is usually attained by micronizing the material in a suitable fluid energy mill (6). In 1961, Sekiguchi and Obi (7) developed a unique technique to achieve particle size reduction and thereby permit sparingly water-soluble drugs to become dispersed finely in