Crystallization, tolbutamide

Tolbutamide exists in two polymorphs, one was obtained either by crystallization of tolbutamide from benzene solution after addition of hexane, or by precipitation from solution in aqueous ammonia by addition of acetic acid, and the other, metastable form was obtained from ethanolic solution after addition of water. The two forms were characterized by infrared spectroscopy, x-ray diffraction and d.t.a.(l)... 

Nirmala and Gowda (2) have reported that tolbutamide crystallizes in the orthorhombic space group Pn2 a, with a=20.16 (2), b=9.05 (1), C=7.85 (1) A0, Z=4, Dc=1.25, Dm=1.24 Mgm 3 and U (CuKa)=1.968 mm l. The structure was solved by the Patterson search method and refined to an R factor of 0.083 for 615 visually measured reflections. The structure is stabilized by hydrogen bonding between the polar group and Van der waals interactions between the non polar groups. The... 

While a number of sffidies of the connection between the crystal modification and bioavailability have been published, it is reasonable to assume that many more remain the intellectual property of pharmaceutical companies or in confidential documentation submitted to regulatory agencies. Also many in vitro studies, especially those of extent or rate of dissolution, are used to extrapolate to expected bioavailabilites (e.g. Chikaraishi et al. 1995 Shah et al. 1999), which is indeed proven in some cases such as the tetramorphic tolbutamide (Kimura et al. 1999). We cite here a few additional examples from the open literature, limiting ourselves (except for one example below) to cases in which the bioavailability does differ among crystal modifications. 

Kimura, K., Hirayama, F, Arima, H. and Uekama, K. (2000). Effects of ageing on crystallization, dissolution, and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex. Chem. Pharm. Bull, 48, 646-50. [254]... 

This amorphous solid did yield a crystalline structure after 5 months of storage, but the crystals were those of urea only. This is in contrast to simple physical mixtures of the two solids that clearly showed crystalline mixtures of both tolbutamide and urea. In contrast to the tolbutamide-urea system, the tolbutamide-PEG system showed similar degrees of crystallinity for both the rapid-cooled and slow-cooled systems. Dissolution profiles for this system were compared for the rapid-cooled, slow-cooled, and physical mixture samples. The profiles for all three samples were very similar however, the extent of release from the rapid-cooled sample was approximately 10% higher than that of the other two samples at any given time during the dissolution process. 

Sonoda, Y, Hirayama, R, Arima, H. etal. Selective crystallization of the metastable form IV polymorph of tolbutamide in the presence of 2,6-di-0-methyl-(3-cyclodextrin in aqueous solution. Cryst. Growth Des. 2007, 6,1181-1185. 

A further issue is the purity of the samples. Olives et al. (8) have demonstrated that the addition 5-500 ppm of metals, which are commonly eluted from glass containers to ethanol-water solutions of tolbutamide, can prevent the appearance of polymorph B. Furthermore, the addition of Ca2+ to the solution prior to crystallization... 

Crystal morphology or habit is important, since it can influence many properties of the compound. For example, powder flow properties, compaction and stability have all been found to be dependent on crystal morphology. It has been shown that tolbutamide B (platelike)... 

Examination by microscopy revealed that the thickening was due to partial conversion of the original platelike tolbutamide crystals to very fine needle-shaped crystals. The new crystals were identified as a different polymorphic form and did not correspond either to a solvate species or to crystals of a different habit. The crystalline conversion was observed to take place in a variety of solvents, the rate of conversion being faster in solvents where the drug exhibited appreciable solubility. Because the conversion rate in 1-octanol was relatively slow, use of this solvent permitted an accurate solubility ratio of 1.22 to be obtained (Form I being more soluble than Form III). 

Crystallization of tolbutamide from aqueous solution was significantly affected by CyD complexation (Fig. 14.8) [76]. When the supersaturated transparent tolbutamide solution was stored at 4 °C, the stable Form I crystallized exclusively. On the other hand, a solution containing 2 gave only the metastable Form IV of tolbutamide. DM-a-CyD with the smaller cavity gave the stable Form I crystals. Detailed investigation indicated that crystallization of tolbutamide proceeds via the metastable Form IV, which quickly converts to the stable Form I within 15 h at 4 °C. However, conversion of Form IV to Form I in 2 solutions was markedly suppressed, and continued for at least three more days. This suppression is attributable to inclusion complexation of tolbutamide with 2, because the addition of competitive inhibitors gave the stable Form I crystals. 2 seems to be effective in suppressing conversion of the metastable form to the stable form in the solution. 

Isolation of intermediate, metastable polymorphs can generally be achieved by inhibiting their transformation to stable forms through the mediation of additives. A recent report on tiie isolation of a metastable form (Form IV) of tolbutamide (Figure 1, 3) is a case in point [17]. This species crystallized exclusively from an aqueous solution containing dimethylated p-cyclodextrin (DMB), whereas tiie stable form (I) crystallized in the absence of DMB. The proposed mechanism involves inhibition of the solution-mediated transformation of Form IV to Form I by complexation of tolbutamide with DMB. While not yet established as a general method, it is likely that this approach will be applied to the isolation of metastable polymorphs of other organic substrates. 

Sano, A., Kuriki T., Kawashima Y., Takeuchi H., Hino T., and Niwa T. (1992). Particle design of tolbutamide by spherical crystallization technique. V. Improvement of dissolution and bioavailability of direct compressed tablets prepjared using tolbutamide agglomerated crystals. Chemical and Pharmaceutical. Bulletin, 40, 3030-3035. 

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