Anhydrous metronidazole benzoate

Caira, M.R. Nassimbeni, L.R. van Oudtshoorn B. X-Ray structural characterization of anhydrous metronidazole benzoate and metronidazole benzoate monohydrate. J. Pharm. Sci. 1993, 82, 1006-1009. 

Hydrates can sometimes be obtained by simply suspending the anhydrous material in water, whereupon a form of Ostwald ripening occurs. For instance, aqueous suspensions of anhydrous metronidazole benzoate are metastable, and storage at temperatures lower then 38°C leads to monohydrate formation accompanied by crystal growth [65]. Sorbitol provides another example of this behavior, where slow cooling of a saturated aqueous solution yields long thin needles of sorbitol hydrate [66]. When suspended in water, anhydrous carbamazepine is transformed to carbamazepine dihydrate [67]. In other instances, hydrates can be obtained from mixed solvent systems. 

Grant et al. 1984), from which the enthalpy of solution can be calculated from the slope. If the lines intersect, it is known as the transition temperature, and one consequence of this is that there may be a transition from one polymorph to another, depending on the storage conditions. For example, the formation of the monohydrate of metronidazole benzoate from a suspension of the anhydrate was predicted from such data (Holgaard and Moller 1983). 

The instability of many anhydrate phases with respect to water has been long known. For instance, it was shown by Shefter and Higuchi that hydrate phases of cholesterol, theophylline, caffeine, glutethimide, and succinyl sulfathiazole would spontaneously form during dissolution studies [32]. Similar behavior has been reported for metronidazole benzoate [33] and carbamazepine [34]. In each of these systems, the integrity of the anhydrous phases can be maintained only as... 

A monohydrate phase of metronidazole benzoate exhibited solubility properties different from those of the commercially available anhydrous form [37], The monohydrate was found to be the thermodynamically stable form in water below 38°C. The enthalpy and entropy changes of transition for the conversion of the anhydrate to the monohydrate were determined to be -1200 cal/mol and -3.7 cal/K mol, respectively. This transition was accompanied by a drastic increase in particle size and caused physical instability of oral suspension formula-... 

A similar conclusion was reached regarding the relative stability of the monohydrate and anhydrate phases of metronidazole benzoate [37]. The enthalpy term (-1.20 kcal/mol) favored conversion to the monohydrate, but the strong entropy term (-3.7 cal/K mol) essen-... 

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