David B. Sheen

Crystallization of paracetamol from solution in the presence and absence of impurity.

The bulk crystallization of paracetamol has been examined under controlled conditions in the presence and absence of the additive p-acetoxyacetanilide (PAA), as a function of both supersaturation and additive levels. The induction time to nucleation was found to increase with increase in PAA concentration in solution. The product micro-crystals were characterized for shape and strain/defect content using electron and optical microscopy and X-ray Laue diffraction techniques, respectively. A change in crystal habit of the pure crystals from columnar (dominant [110]) to plate-like (dominant [001]) was observed to occur with an increase in supersaturation level, whilst the addition of PAA invariably led to the development of columnar crystals with an aspect ratio that varied with impurity level and supersaturation. HPLC showed the PAA to be incorporated into the crystals with an average segregation coefficient of 14-18% depending on the supersaturation. The ready incorporation of PAA is attributed to the molecular similarity of this molecule to that of the host material. The incorporation is shown to cause a significant increase in the mosaic spread, implying the development of a significant strain/defect content in the crystals. The influence of the impurity on the time to nucleation is probably due to its effect in blocking the development of the critical nucleus. The potential implications of such variations in morphology and strain content in the design of the physical and chemical properties of the resulting particulates are discussed.

Dissolution kinetics of paracetamol single crystals.

The dissolution anisotropy of paracetamol crystals grown in the presence and absence of the molecularly similar additive, p-acetoxyacetanilide (PAA) was studied under controlled conditions using a single crystal dissolution method in undersaturated aqueous solutions. Linear dissolution rates were determined for all the major habit faces by measuring their movement (regression) with time in a flow cell using a microscope. The rates of dissolution of particular faces of the pure material were distinctly different in crystals of different morphology grown at different supersaturations. The dissolution rates of [001] and [110] faces of crystals grown in the presence of PAA (6.02% w/w in solution) are higher than those of pure paracetamol. The results correlate with the distribution of strain in the crystal and support the concept that integral strain increases the solubility and hence the dissolution rate of the material. The mechanism of the dissolution process at the [001], [201;] and [110] faces was defined using optical microscopy and X-ray topography. At all undersaturations above 1% the dissolution studies yielded well developed, structurally oriented, etch pits on both [001] and [201;] faces while on the [110] face rough shallow etch pits were observed. On all three faces, this etch-pitting was considerably more widespread than the dislocation content of the sector and probably reflects a 2-dimensional nucleation process rather than a dislocation controlled mechanism.

Morphological evaluation of the γ-polymorph of indomethacin

Abstract A study has been made of the polymorphic nature of crystals of the pharmaceutical indomethacin grown from a wide range of solvents and from the melt. In most solvents, growth at high supersaturations yielded either a 1:0.5 solvated form (approximately) or the α-polymorph. At low supersaturations the γ-polymorph was commonly produced. Solutions in MeOH and t BuOH yielded a 1:1 solvate. The morphology of the γ-form showed no variation with solvent type but changed with supersaturation in a manner consistent with a differential variation in growth rates of the faces. This lack of solvent influence was confirmed by the fact that a similar morphology resulted on growth from the melt. Morphology predictions were carried out for the γ-polymorph and these show good agreement with experimental observations.

Microhardness and Dislocation Identification Studies on Paracetamol Single Crystals

AbstractPurpose. To study the mechanical behaviour of paracetamol single crystals. Methods. Microhardness indentation techniques were used to study the hardness anisotropy of paracetamol. Solvent etching technique was used to define the range of plastic deformation and the orientation of the dislocation lines. The orientation dependence of Knoop hardness on the {001}, {110} and {20

Crystal morphology of ibuprofen predicted from single-crystal pulsed neutron diffraction data

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Cephalexin: a channel hydrate

} surfaces was compared with calculated values of the Effective Resolved Shear Stress (ERSS) for plastic deformation by specific dislocation types. Results. The principal habit faces of single crystals using both Vickers and Knoop indenters showed a range of hardness from 235 to 456 MPa depending on the type of indenter used and its orientation on the surface. Solvent etching of the plastically deformed region of the crystal around the Vickers/Knoop indentations confirmed that the slip plane was (010). ERSS analysis suggested that the deformation occurred by the slip of dislocations of the types (010)[001] and (010)[100]. Crystals doped with 0.08–0.8 w/w% p–acetoxyacetanilide showed hardness values similar to the pure material. Conclusions. The low number of distinct dislocation slip systems (two) is characteristic of a brittle material and is consistent with the observation that paracetamol will tolerate only deformations of 1 part in 106 before fracture.

Two New Structures of 5-Nitrouracil

AbstractPurpose. To study the fracture behavior of the major habit faces of paracetamol single crystals using microindentation techniques and to correlate this with crystal structure and molecular packing. Methods. Vickers microindentation techniques were used to measure the hardness and crack lengths. The development of all the major radial cracks was analyzed using the Laugier relationship and fracture toughness values evaluated. Results. Paracetamol single crystals showed severe cracking and fracture around all Vickers indentations with a limited zone of plastic deformation close to the indent. This is consistent with the material being a highly brittle solid that deforms principally by elastic deformation to fracture rather than by plastic flow. Fracture was associated predominantly with the (010) cleavage plane, but was also observed parallel to other lattice planes including (110), (210) and (100). The cleavage plane (010) had the lowest fracture toughness value, Kc = 0.041MPa m1/2, while the greatest value, Kc = 0.105MPa m1/2; was obtained for the (210) plane. Conclusions. Paracetamol crystals showed severe cracking and fracture because of the highly brittle nature of the material. The fracture behavior could be explained on the basis of the molecular packing arrangement and the calculated attachment energies across the fracture planes.

Chromatographic, spectroscopic, topographic, and X-ray crystallographic studies of the solid solution formed by racemic 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (3-carboxy-proxyl)

Low-temperature single-crystal pulsed neutron diffraction is used to determine accurate positions and thermal parameters for all 33 atoms of the ibuprofen molecule, and the data used to predict the crystal morphology.