Crystal habit modification of the drug diflunisal that normally grows into extremely thin, long needles has been achieved by breaking the stacking effect with the help of co-formers. Eight new co-crystals are reported, along with three crystal structures. In all cases, ortho F disorder, often a feature in diflunisal structures was absent due to the presence of CH…F interactions. Co-milling diflunisal with oxalic acid produced 1:1 and 2:1 co-crystals. In contrast, in solution crystallisation oxalic acid played the role of an additive resulting in the crystallisation of diflunisal form I rather than form III. To rationalize co-crystal formation a statistical analysis of the CCDC data base for aromatic o-hydroxy carboxylic acids was carried out. All co-crystals of o-hydroxy carboxylic acids with the COOH dimer motif have an electron-withdrawing group on one of the acids. COOH…Nar motifs are formed preferentially over carboxylic homo-dimers in the presence of an Nar co-former. AbstractCrystal habit modification of the drug diflunisal that normally grows into extremely thin, long needles has been achieved by breaking the stacking effect with the help of co-formers. Eight new co-crystals are reported, along with three crystal structures. In all cases, ortho F disorder, often a feature in diflunisal structures was absent due to the presence of CH…F interactions. Co-milling diflunisal with oxalic acid produced 1:1 and 2:1 co-crystals. In contrast, in solution crystallisation oxalic acid played the role of an additive resulting in the crystallisation of diflunisal form I rather than form III. To rationalize co-crystal formation a statistical analysis of the CCDC data base for aromatic o-hydroxy carboxylic acids was carried out. All co-crystals of o-hydroxy carboxylic acids with the COOH dimer motif have an electron-withdrawing group on one of the acids. COOH…Nar motifs are formed preferentially over carboxylic homo-dimers in the presence of an Nar co-former.

Needle crystals can cause filtering and handling problems in industrial settings, and the factors leading to a needle crystal morphology have been investigated. The crystal growth of the amide and methyl, ethyl, isopropyl, and t-butyl esters of diflunisal have been examined, and needle growth has been observed for all except the t-butyl ester. Their crystal structures show that the t-butyl ester is the only structure that does not contain molecular stacking. A second polymorph of a persistent needle forming phenylsulfonamide with a block like habit has been isolated. The structure analysis has been extended to known needle forming systems from the literature. The intermolecular interactions in needle forming structures have been analyzed using the PIXEL program, and the properties driving needle crystal growth were found to include a 1D motif with interaction energy greater than −30 kJ/mol, at least 50% vdW contact between the motif neighbors, and a filled unit cell which is a monolayer. Crystal structures are classified into persistent and controllable needle formers. Needle growth in the latter class can be controlled by choice of solvent. The factors shown here to be drivers of needle growth will help in the design of processes for the production of less problematic crystal products.

No abstract

We demonstrate the first examples of the transformation of gel-forming crystal needles into easily processable more equant crystals by accelerated Ostwald ripening without detectable crystal attrition. Using high solution shearing to accelerate mass transfer diflunisal and isonicotinohydrazide gels are transformed into easily filterable crystals. High-shear-ultra-low-attrition agitation conditions are generated by spinning with rapid reversal of the spinning direction every three seconds. high attrition agitation spinning without agitation

Understanding phase transitions in pharmaceutical materials is of vital importance for drug manufacturing, processing and storage. In this paper we have carried out comprehensive high-resolution spectroscopic studies on the polymorphs of the non-steroidal anti-inflammatory drug diflunisal that has four known polymorphs, forms I-IV (FI-FIV), three of which have known crystal structures. Phase transformations during milling, heating, melt-quenching and exposure to high relative humidity were investigated using Raman and terahertz spectroscopy in combination with differential scanning calorimetry and X-ray powder diffraction. The observed phase transformations indicate the stability order FIII>FI>FII, FIV. Furthermore, crystallization experiments from the gas phase and from solution by fast evaporation of different solvents were carried out. Fast evaporation of an ethanolic solution below 70°C was identified as a reliable and convenient method to obtain the somewhat elusive FII in bulk quantities.