Chlorpropamide

Chlorpropamide is a sulfonylurea class drug for type 2 diabetes mellitus.

Crystallization and polymorphic transitions of chlorpropamide in aqueous 2-hydroxybutyl-beta-cyclodextrin solution.[Pubmed:20036739]

Eur J Pharm Sci. 2010 Feb 19;39(4):248-55.

Effects of cyclodextrins on crystallization of Chlorpropamide and the polymorphic transition mechanism of the drug in aqueous solution were investigated. In the presence of 2-hydroxybutyl-beta-cyclodextrin, Chlorpropamide was exclusively crystallized to metastable Form II and III polymorphs, whereas it was crystallized to stable Form A in the absence of the beta-cyclodextrin at 4 degrees C. The crystallization to metastable Form II or III polymorph was dependent upon 2-hydroxybutyl-beta-cyclodextrin concentrations employed, i.e. crystallization to Form III at a lower concentration (0.5 mM), whereas to Form II in a higher concentration (5 mM). At an intermediate concentration (2 mM), the least stable Form II crystal was initially precipitated, but it was transformed to Form III crystal. At higher temperature, Form III crystal was converted to stable Form A crystal. In aqueous solution, Chlorpropamide crystallized to stable Form A crystal consecutively through metastable Forms II and III, according to "Ostwald's Rule of Stages". 2-Hydroxybutyl-beta-cyclodextrin inhibits the transition of Form II to Form III at higher concentrations and that of Form III to Form A at lower concentrations. The results suggest that 2-hydroxybutyl-beta-cyclodextrin is useful for selective preparation of metastable Chlorpropamide polymorphs occurring during crystallization according to the Ostwald's rule.

The polymorphic phase transformations in the chlorpropamide under pressure.[Pubmed:25393056]

J Pharm Sci. 2015 Jan;104(1):81-6.

The crystal structure and vibrational spectra of the Chlorpropamide have been studied by means of the X-ray diffraction and Raman spectroscopy at pressures up to 24.6 and 4.4 GPa, respectively. Two polymorphic phase transitions, between initial orthorhombic form-A and a monoclinic form-AI at P approximately 1.2 GPa and, in additional, to another monoclinic form-AII at P approximately 3.0 GPa, were observed. At pressures above 9.6 GPa, a transformation to the amorphous phase of Chlorpropamide was revealed. The lattice parameters, unit cell volumes, and vibration modes as functions of pressure were obtained for the different polymorphic modifications of Chlorpropamide.

A high-pressure polymorph of chlorpropamide formed on hydrostatic compression of the alpha-form in saturated ethanol solution.[Pubmed:23364463]

Acta Crystallogr B. 2013 Feb;69(Pt 1):77-85.

The crystal structure of the high-pressure polymorph (alpha') of an antidiabetic drug, Chlorpropamide [4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C(10)H(13)ClN(2)O(3)S], which is formed at ~2.8 GPa from the alpha-polymorph (P2(1)2(1)2(1)) on hydrostatic compression in saturated ethanol solution, has been determined. As a result of the phase transition, the a, c and alpha parameters change jumpwise, whereas the changes in b parameter are continuous through the phase transition point. The high-pressure form is monoclinic (P2(1)11) and has Z' equal to 2, the two independent molecules differing in their conformations. The hydrogen bonds expand slightly in the high-pressure polymorph after the transition, and this expansion is interrelated with the changes in molecular conformations enabling a denser packing. The transition is reversible, but the crystal quality deteriorates as a result of multiple compression-decompression cycles, and a pseudomerohedral twinning accompanies the transformation.

Solid-state transformations in the beta-form of chlorpropamide on cooling to 100 K.[Pubmed:21422615]

Acta Crystallogr B. 2011 Apr;67(Pt 2):163-76.

A single-crystal X-ray diffraction study of the effect of cooling down to 100 K on the beta-form of Chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, has revealed reversible phase transitions at approximately 257 K and between 150 and 125 K: beta (Pbcn, Z' = 1) <--> beta(II) (P2/c, Z' = 2) <--> beta(III) (P2/n, a' = 2a, Z' = 4); the sequence corresponds to cooling. Despite changes in the space group and number of symmetry-independent molecules, the volume per molecule changes continuously in the temperature range 100-300 K. The phase transition at approximately 257 K is accompanied by non-merohedral twinning, which is preserved on further cooling and through the second phase transition, but the original single crystal does not crack. DSC (differential scanning calorimetry) and X-ray powder diffraction investigations confirm the phase transitions. Twinning disappears on heating as the reverse transformations take place. The second phase transition is related to a change in conformation of the alkyl tail from trans to gauche in 1/4 of the molecules, regularly distributed in the space. Possible reasons for the increase in Z' upon cooling are discussed in comparison to other reported examples of processes (crystallization, phase transitions) in which organic crystals with Z' > 1 have been formed. Implications for pharmaceutical applications are discussed.