Solvates

In additions to polymorphs, solvates (inclusion of the solvent of crystallization) are also often formed during the crystallization process. These forms are also called psudopolymorphs. The solvent molecules fill spaces in the crystal lattice and generally reduce the solubility and dissolution rates. This phenomenon is thermodynamically driven. If the solvate contains an organic solvent, this would not be admitted by regulatory authorities. According to the

TABLE 10 Effects of Salvation on Drug Activity

Example

Explanation

Ampicillin Hydrocortisone Caffeine, theophylline Glutethimide Mercaptopurine, Prednisolone Griseofulvin

Citric acid

Anhydrate shows higher bioavailability compared to trihydrate (?) Hemiacetone solvates show higher absorption compared to asolvates Increased dissolution of anhydrous forms Compared to hydrates

Higher dissolution and activity of asolvate from pellets implanted

Chloroformate solvate gives higher bioavailibility compared to asolvate, also solvation-desolvation results in increased surface area Hydrate used to provide mole of water as granulating agent in effervescent preparations

International Conference on Harmonization guidelines, the Class I solvents must be avoided as these are carcinogenic such as benzene, carbon tetrachloride, and 1,2-dichloromethane; the Class II solvents should be limited and include non-genotoxic animal carcinogens such as cyclohexane, acetonitrile; the Class III solvents have low-toxicity potential including acetic acid, alcohol, and acetone, which are allowed as long as the daily permissible dose does not exceed 50 mg. Generally, an allowed solvate would likely be removed during the manufacturing process but in some instances, the presence of solvate is desired like in beclomethasone dipropionate product of Glaxo that includes trichlorofluoromethane solvate; this solvate prevents crystal growth in sprays containing trichlorofluoromethane as propellant.

During seeding, crystals may incorporate one or more of the molecules of the solvent into their structure and the resultant forms are referred to as SOLVATES. The solvates themselves may exist in various polymorphic forms and are referred to as pseudopolymorphs. Some examples of pseudopolymorphs include mercaptopurine, fluprednisolone, and succinylsulfathiazole. The number of drug solvates is well over 100 and some of the most common examples include steroids, antibiotics, sulfonamides, barbiturates, xanthines, and cardiac glycosides.

The use of a solvates in increasing bioavailability is on the premise that some anhydrates dissolve faster than their corresponding hydrates in aqueous media. However, the relationship becomes much more complex when alcohlates or other nonaqueous solvate are dissolved in water. Table 10 lists several examples of effect of solvation on drug and dosage form.

Whereas the selection of an appropriate solvate or asolvate form can be advantageous in increasing the dissolution rates and bioavailability in some instances, their use requires careful monitoring of manufacturing and storage conditions because of the possibility of inadvertent solvation or desolvation.

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