Tatiana N. Drebushchak

DSC and adiabatic calorimetry study of the polymorphs of paracetamol

Monoclinic (I) and orthorhombic (II) polymorphs of paracetamol were studied by DSC and adiabatic calorimetry in the temperature range 5 - 450 K. At all the stages of the study, the samples (single crystals and powders) were characterized using X-ray diffraction. A single crystal → polycrystal II→ I transformation was observed on heating polymorph II, after which polymorph I melted at 442 K. The previously reported fact that the two polymorphs melt at different temperatures could not be confirmed. The temperature of the II→I transformation varied from crystal to crystal. On cooling the crystals of paracetamol II from ambient temperature to 5 K, a II→ I transformation was also observed, if the cooling-heating cycles were repeated several times. Inclusions of solvent (water) into the starting crystals were shown to be important for this transformation. The values of the low-temperature heat-capacity of the I and II polymorphs of paracetamol were compared, and the thermodynamic functions calculated for the two polymorphs.

A high-pressure polymorph of chlorpropamide formed on hydrostatic compression of the α-form in saturated ethanol solution.

The crystal structure of the high-pressure polymorph (α′) of an antidiabetic drug, chlorpropamide [4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C10H13ClN2O3S], which is formed at ∼u20052.8u2005GPa from the α-polymorph (P212121) on hydrostatic compression in saturated ethanol solution, has been determined. As a result of the phase transition, the a, c and α parameters change jumpwise, whereas the changes in b parameter are continuous through the phase transition point. The high-pressure form is monoclinic (P2111) 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 β-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 β-form of chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, has revealed reversible phase transitions at ∼257 K and between 150 and 125 K: β (Pbcn, Z = 1) ⇔ β(II) (P2/c, Z = 2) ⇔ β(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.

A New Method of Producing Monoclinic Paracetamol Suitable for Direct Compression

ABSTRACTPurposeTo develop a technique of obtaining monoclinic polymorph of paracetamol suitable for direct compression without excipients.MethodsPreparation of spongy monoclinic paracetamol was based on quench-cooling of paracetamol solutions in water-acetone mixtures sprayed into a vessel with liquid nitrogen followed by removal of solvents by freeze-drying. X-ray powder diffraction was used to study annealing of quench-cooled solutions in “paracetamol-acetone-water” and “acetone-water” systems and to find optimum conditions for obtaining fine particles of pure monoclinic paracetamol. Samples were characterized by electron microscopy; compression properties were measured.ResultsThe preparation technique gave fine monoclinic paracetamol powder containing agglomerates (30–200xa0μm) composed of flat particles (linear sizes 1–10xa0μm, the thickness 60–150xa0nm). The spongy sample was suitable for direct compression without excipients, stable on storage, and mechanically robust. Mechanically stable tablets pressed from the spongy sample were better soluble in water than commercially available tablets of paracetamol with excipients.ConclusionsThe proposed method gave spongy monoclinic paracetamol samples with improved properties. For inexpensive paracetamol, the method may not yield economic advantage. However, the same method based on freeze-drying solutions in mixed aqueous-organic solvents can be used to prepare new improved forms of other molecular solids for pharmaceutical applications.

‘Hedvall effect’ in cryogrinding of molecular crystals. A case study of a polymorphic transition in chlorpropamide

The effect of grinding at ambient temperature and at 77 K (CryoMill Retsch) on the polymorphic transitions in α- and e- chlorpropamide has been compared. The result of grinding of α-chlorpropamide at room temperature could not be interpreted as a mere formation of traces of the e-polymorph. The diffraction patterns suggested the presence of small amounts of some unknown polymorph, possibly in a mixture with other polymorph(s). Possibly, mechanical treatment gave a defect nanostructured phase with alternating domains. Cryogrinding of α-chlorpropamide did not result in polymorphic transitions. In contrast, cryogrinding of the e-polymorph was much more efficient than grinding at ambient temperature: almost no changes could be observed at ambient temperature, whereas cryogrinding gave the α-form. The observed phenomena could be interpreted taking into account that at low temperatures the e-polymorph undergoes a polymorphic transition into another polymorph— the e′-form. Without grinding, the e′-form transforms back to the e-polymorph when heated back to ambient temperature. If grinding takes place in the temperature range of the e- to e′-polymorphic transition, the transformation to the α-form occurs. One phase transition, induced by low temperature, facilitates another one, induced by mechanical treatment. The reason for this interesting phenomenon is to be sought in the similarity of the crystal packing of molecules with different molecular conformations in the e- and e′-forms, and of the similarity of the molecular conformations despite different crystal packing in the e′- and α-forms.

A conformational polymorphic transition in the high-temperature ∊-form of chlorpropamide on cooling: a new ∊′-form

Structural changes in the high-temperature -polymorph of chlorpropamide, 4-chloro-N-(propylaminocarbonyl)benzenesulfonamide, C(10)H(13)ClN(2)O(3)S, on cooling down to 100 K and on reverse heating were followed by single-crystal X-ray diffraction. At temperatures below 200 K the phase transition into a new polymorph (termed the epsilon-form) has been observed for the first time. The polymorphic transition preserves the space group Pna2(1), is reversible and is accompanied by discontinuous changes in the cell volume and parameters, resulting from changes in molecular conformation. As shown by IR spectroscopy and X-ray powder diffraction, the phase transition in a powder sample is inhomogeneous throughout the bulk, and the two phases co-exist in a wide temperature range. The cell parameters and the molecular conformation in the new polymorph are close to those in the previously known alpha-polymorph, but the packing of the z-shaped molecular ribbons linked by hydrogen bonds inherits that of the epsilon-form and is different from the packing in the alpha-polymorph. A structural study of the alpha-polymorph in the same temperature range has revealed no phase transitions.

Stabilizing structures of cysteine-containing crystals with respect to variations of temperature and pressure by immobilizing amino acid side chains

In a series of recent publications, the crystals of L- and DL-cysteine were shown to undergo multiple phase transitions upon variation of temperature and pressure. All these transitions are related to rotation of the amino acid side chain. Accordingly, cysteine-containing crystal structures should be stabilized with respect to phase transitions by measures that reduce the mobility of the side chain in the crystalline environment. In the present work, we show that this can be achieved by increasing the significance of the side chain –SH group as a participant in intermolecular hydrogen bonds, either by N-acetylation, which removes the strong –NH3+ donor of cysteine and leaves a system without strong charge-assisted interactions, or by co-crystallization with an acid (oxalic acid) that converts the amino acid to a cation and itself forms a strong anion H-bond acceptor, thus boosting the importance of potential –SH donors. The crystal structures of the three compounds N-acetyl-L-cysteine, DL-cysteinium semioxalate, and bis(DL-cysteinium) oxalate have thus been studied with variation of temperature and pressure. Cooling down to 4 K and increasing pressure up to 9.5 GPa did not result in any structural phase transitions in N-acetyl-L-cysteine and bis(DL-cysteinium) oxalate. In case of DL-cysteinium semioxalate, increasing pressure caused a phase transition at a much higher pressure (∼6 GPa), compared to the ranges of pressure-induced phase transitions observed earlier for both monoclinic and orthorhombic L-cysteine (2.5–3.9 GPa and 1.1–2.5 GPa, respectively) or DL-cysteine (0.1–5 GPa). This phase transition had a large hysteresis, so that the reverse transformation on decompression was observed at ∼3.7 GPa only, and was accompanied by a change in molecular conformations, as well as by the reorganization in the N–H⋯O hydrogen bonds in the crystal structure.

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.

Glycinium semi-malonate and a glutaric acid–glycine cocrystal: new structures with short O—H...O hydrogen bonds

Glycinium semi-malonate, C(2)H(6)NO(2)(+)·C(3)H(3)O(4)(-), (I), and glutaric acid-glycine (1/1), C(2)H(5)NO(2)·C(5)H(8)O(4), (II), are new examples of two-component crystal structures containing glycine and carboxylic acids. (II) is the first example of a glycine cocrystal which cannot be classified as a salt, as glutaric acid remains completely protonated. In the structure of (I), there are chains formed exclusively by glycinium cations, or exclusively by malonate anions, and these chains are linked with each other. Two types of very short O-H...O hydrogen bonds are present in the structure of (I), one linking glycinium cations with malonate anions, and the other linking malonate anions with each other. In contrast to (I), no direct linkages between molecules of the same type can be found in (II); all the hydrogen-bonded chains are heteromolecular, with molecules of neutral glutaric acid alternating with glycine zwitterions, linked by two types of short O-H...O hydrogen bonds.

New interpretation of heat effects in polymorphic transitions

Overlapping endothermic and exothermic effects in DSC measurements of polymorphic transitions is often detected in molecular crystals and drugs. It is explained by the sequence of melting and crystallization. In this paper, we argue that this explanation is incorrect. In revealing the kinetic nature of the endo/exo thermal effect, we suggest another explanation, based on the nucleation. New interpretation does allow us to measure the energetic barrier in the nucleation of bulk sample, thus providing a tool for testing the nucleation models.