Spironolactone solvates

It may be instructive to consider some examples of solvate formation. The compound 5-methoxysulphadiazine forms 1 1 host-guest solvates with dioxane, chloroform, and tetrahydrofuran [78]. These were prepared by heating to boiling a solution of the sulfonamide in the appropriate solvent, followed by slow cooling to obtain large crystals. Spironolactone forms 1 1 solvates with methanol, ethanol, ethyl acetate, and benzene. It also forms a 2 1 spironolactone-acetonitrile solvate [79,80]. The spironolactone solvates were prepared by crystallization in a refrigerator from solutions that were nearly saturated at room temperature. 

Thermal analysis (TGA and DSC) of spironolactone and its ethanol, methanol, acetonitrile, ethyl acetate, and benzene solvates has been used to characterize the materials [61]. The analysis was carried out under dry nitrogen ( 50 mL/min), with the samples being contained in aluminum sample pans. Thermograms were obtained at a heating rate of 10°C/minute, with the final temperature being 230°C. Spironolactone and its methanol and ethanol solvates exhibited small exothermic transitions in addition to the anticipated endotherms. 

We will consider two drugs that exhibit this phenomenon. Spironolactone (I), which is a diuretic steroidal aldosterone agonist, crystallises as two polymorphic forms and also as four solvated crystalline forms depending on the solvents and methods used for crystallisation. We will consider the occurrence of solvated forms in section 1.4 at the moment we will concentrate on the two polymorphs only. Form 1 is produced when spironolactone powder is dissolved in acetone at a temperature very close to the boiling point and the solution is then cooled within a few hours down to O C. Form 2 is produced when the powder is dissolved in acetone, dioxane or chloroform at room temperature and the solvent is allowed to spontaneously evaporate over a period of several weeks. In both polymorphs the steroid nuclei (A, B, C and D rings)... 

By way of illustration of this phenomenon, we remm to the case of spironolactone which we considered earlier. As well as the two polymorphs, this compound also possesses four solvates, depending on whether it is crystallised from acetonitrile, ethanol, ethyl acetate or methanol. Each of these solvates is transformed to the polymorphic Form 2 on heating, indicating that the solvent is involved in the bonding of the crystal lattice. 

Spironolactone (17-hydroxy-7 a-mercapto-3-oxo-17 a-pregn-4-ene-21-carboxylic acid), a diuretic steroidal aldosterone agonist, has been obtained into anhydrous polymorphs as well as four solvated crystalline forms [38]. The compound shows variable and incomplete oral absorption due to its poor water solubility and dissolution rate, factors that are compounded by the existence of polymorphism and solvate formation. The two anhydrate forms (Forms I and II) both crystallize in orthorhombic space groups, and the crystallographic data for these are collected in Table 15. The spironolactone system exhibits the classic... 

However, it is clear that vibrational spectroscopy has considerable use beyond the identification of polymorphs and solvates. The infrared spectra obtained on the polymorphs of acetohexamide and selected derivatives has been used to study the tautomerism of the drug compound [127]. It was deduced in this work that Form A existed in the enol form, stabilized by the intramolecular bonding between the O—H and groups that produces a six-membered ring. Form B was characterized by the existence of the keto form, with the urea carbonyl group being intermolecular bonding to a sulfonamide N—H functionality. This behavior can be contrasted with that noted for spironolactone, where no evidence was found for the existence of enolic tautomers in any of the four polymorphs [128]. 

Even when Raman spectroscopy is used primarily as a means for the differentiation of polymorphs or solvates, the degree of spectral simplification associated with Raman data permits a more facile generation of band assignments. This feature has been successfully exploited in the cases of spironolactone [128], losartan [138], 3-(p-thioanisoyl)-l,2,2-trimethyl-cyclopentanecarboxylic acid [139], and tra 5-3,4-dichloro-A-methyl-A-[l,2,3,4-tetrahydro-5-methoxy-2-(pyrrolidin-l-yl)]-naphth-1 -ylbenzeneacetamide [ 140]. 

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