Spironolactone polymorphism

Fourier-transform Raman and Fourier-transform infrared spectroscopic methods were adapted for the analysis of spironolactone and differentiation of its polymorphic forms [31,32],... 

A typical example of the characterization of a polymorphic system by FT Raman spectroscopy has been given by Gu and Jiang (1995) while an application of the technique with near infrared excitation to the polymorphic cimetidine system has been described by Tudor et al. (1991). The FT Raman technique has been compared to infrared diffuse reflection spectroscopy in the study of the polymorphs of spironolactone (Neville et al. 1992), and the pseudopolymorphic transition of caffeine hydrate (i.e. loss of solvent) has been monitored using the technique (de Matas et al. 1996). 

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. 

GA Neville, HD Beckstead, HF Shurvell. Utility of Fourier transform-Raman and Fourier transform-infrared diffuse reflectance spectroscopy for differentiation of polymorphic spironolactone samples. J Pharm Sci 81 1141-1146, 1992. 

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]. 

No special sample preparation is required, in contrast to the grinding for x-ray studies or pressing into disks for IR work. This is especially important for examination of polymorphs Grinding can alter the solid state of, for example, di-goxin or spironolactone and compression can induce polymorphic conversion for phenylbutazone and some sulfonamides. 

A potential case of an interaction between quinidine and flucloxacillin was demonstrated in a 63-year-old patient with recently diagnosed dilated cardiomyopathy who was admitted to the hospital with polymorphic ventricular tachycardia and ventricular fibrillation episodes induced by bradycardia. The patient was on a heart failure regimen of furosemide, spironolactone and perindopril, and was initiated on oral quinidine in the hospital for the prevention of ventricular arrhythmias. The patient s temporary pacemaker lead was removed and an implantable cardioverter-defibrillator was placed due to continued ventricular fibrillation. The next day, the patient became febrile. Culture of pacemaker lead tip and blood cultures were positive for S. aureus. Flucloxacillin and rifampin were initiated, but rifampin was discontinued due to the development of renal insufficiency and liver test abnormalities. These were normalised after rifampin was discontinued. The patient required continuous pacing to prevent ventricular tachycardia episodes, and quinidine was increased to 2800 mg per day (maximum daily dose). Quinidine plasma levels were subtherapeutic at 1.1 mg/L. The authors speculate that this interaction was due to quinidine being a substrate of Pgp and CYP3A4, and flucloxacillin s ability to induce these enzymes. While this may be a potential mechanism, the authors do not comment on how long the patient received rifampin. Rifampin is also a CYP3A4 inducer and could have been parf of fhe reason for fhe decrease in quinidine level [46 ]. 

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