Isoenergetic Polymorphism: The Puzzle of Tolazamide as a Case Study.

In the present case study of tolazamide we illustrate how many seemingly contradictory results that have been obtained from experimental observations and theoretical calculations can finally start forming a consistent picture: a "puzzle put together". For many years, tolazamide was considered to have no polymorphs. This made this drug substance unique among the large family of sulfonylureas, which was known to be significantly more prone to polymorphism than many other organic compounds. The present work employs a broad and in-depth analysis that includes the use of optical microscopy, single-crystal and powder X-ray diffraction, IR and Raman spectroscopies, DSC, semiempirical PIXEL calculations and DFT of three polymorphs of tolazamide. This case study shows how the polymorphs of a molecular crystal can be overlooked even if discovered serendipitously on one of numerous crystallizations, and how very different molecular packings can be practically isoenergetic but still crystallize quite selectively and transform one into another irreversibly upon heating.

Advances in elucidating mechanochemical complexities via implementation of a simple organic system.

Mechanochemistry is becoming increasingly popular amongst both the academic and industrial communities as an alternative method for inducing physical and chemical reactions. Despite its rapidly expanding application, little is understood of its mechanisms, greatly limiting its capacity. In the present work the application of specialty devices allowed submission of the simple organic system, α-glycine + ß-malonic acid, to isolated shearing and impact treatment. In doing so, unique products were observed to result from each of these major mechanical actions; shear inducing formation of the known salt, glycinium semi-malonate (GSM), and impact yielding formation of a novel phase. Correlation of these isolated treatments with a more common ball mill indicated two unique regions within the milling jar, each characterised by varying ratios of shear and impact, leading to different products being observed. It is widely accepted that, particularly when considering organic systems, mechanical treatment often acts by inducing increases in local temperature, leading to volatilisation or melting. A combination of DSC and TGA were used to investigate the role of temperature on the system in question. Invariably, heating induced formation of GSM, with evidence supporting a eutectic melt, rather than a gas-phase reaction. Shear heating alone is unable to describe formation of the novel phase obtained through impact treatment. By considering the formation and character of mechanically produced tablets, a model is described that may account for formation of this novel phase. This system and methodology for mechanochemical study offers intriguing opportunities for continued study of this widely used and exciting field.

Low-temperature phase transition in glycine-glutaric acid co-crystals studied by single-crystal X-ray diffraction, Raman spectroscopy and differential scanning calorimetry.

The occurrence of a first-order reversible phase transition in glycine-glutaric acid co-crystals at 220-230 K has been confirmed by three different techniques - single-crystal X-ray diffraction, polarized Raman spectroscopy and differential scanning calorimetry. The most interesting feature of this phase transition is that every second glutaric acid molecule changes its conformation, and this fact results in the space-group symmetry change from P2(1)/c to P1. The topology of the hydrogen-bonded motifs remains almost the same and hydrogen bonds do not switch to other atoms, although the hydrogen bond lengths do change and some of the bonds become inequivalent.

Solid-state transformations in the ß-form of chlorpropamide on cooling to 100 K.

A single-crystal X-ray diffraction study of the effect of cooling down to 100 K on the ß-form of chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, has revealed reversible phase transitions at ∼257 K and between 150 and 125 K: ß (Pbcn, Z' = 1) ⇔ ß(II) (P2/c, Z' = 2) ⇔ ß(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 ∼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.

An extended phase transition in crystalline L-cysteine near 70 K.

An anomaly of heat capacity near 70 K was registered in the crystalline L-cysteine (orthorhombic polymorph) by adiabatic calorimetry as a small, 3-5% height, diffuse "jump", or a wide "hump" accompanied by the substantial increase in the thermal relaxation time. The Cp(T) dependence is characteristic for a transformation extended over a wide temperature range and sensitive to the thermal prehistory of the sample, that can be interpreted as nonsimultaneous changes in the dynamics and the orientation of the numerous thiol groups in the structure. The measurements of the cell parameters and cell volume on cooling suggest that a discontinuity in their values over the transition point exists.