Influence of the presence of trace amounts of metals on the polymorphism of tolbutamide.
The polymorphism phenomenon causes an important problem in the preparation of many pharmaceutical dosage forms, including oral suspensions, tablets, creams and suppositories. In this work the influence of the presence of certain metallic elements (Ca(II), Fe(III), Mn(II), Zn(II), Cd(II), Ni(II) and Co(II)) in trace amounts on the polymorphism of tolbutamide is described. For these studies, known amounts (5-500 ppm) of different cations were added to ethanol-water solutions of the pharmacologically active polymorph A of tolbutamide prior to its crystallization. These cations were chosen as being among those that commonly appear in drug solutions as a consequence of elution from glass containers. IR studies show that the presence of cations prevents the appearance of the polymorph B of the tolbutamide. Thus, the peaks at 2980, 2940, 2890, 905, 851, 816 and 727 cm-1 (polymorph A) appeared but not the ones at 1045 and 847 cm-1 corresponding to polymorph B. Scanning electron microscopy studies reveal that, in the presence of Ca2+, a third kind of crystal different from polymorphs A and B appears. This form of olbutamide cannot be identified with "polymorph III" of Al-Saieq and Rileys [S.S. Al-Saieq and G.S. Riley, Pharm. Acta. Helv., 56 (1981) 125-129] due to their different IR data. Dissolution rate tests and X-ray diffractometry were also employed in this study. All these results showed that divalent cations partially avoid the transformation of polymorph A into polymorph B.
Olives
A I
AI
Sección Departamental de Química Analítica, Facultad de Farmacia, Universidad Complutense de Madrid, Spain.
Martin
M A
MA
del Castillo
B
B
Barba
C
C
D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003460:Crystallization; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007501:Iron / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D008670:Metals / Q000494:pharmacology*; D008855:Microscopy, Electron, Scanning; D009532:Nickel / Q000494:pharmacology; D012995:Solubility; D013054:Spectrophotometry, Atomic; D013055:Spectrophotometry, Infrared; D014044:Tolbutamide / Q000737:chemistry*; D014961:X-Ray Diffraction; D015032:Zinc / Q000494:pharmacology
D002412:Cations; D007004:Hypoglycemic Agents; D008670:Metals; D002104:Cadmium; D003035:Cobalt; D008345:Manganese; D009532:Nickel; D014044:Tolbutamide; D007501:Iron; D015032:Zinc; D002118:Calcium