Room-Temperature Ferroelectricity in an Organic Cocrystal.

Ferroelectric materials exhibit switchable remanent polarization due to reversible symmetry breaking under an applied electric field. Previous research has leveraged temperature-induced neutral-ionic transitions in charge-transfer (CT) cocrystals to access ferroelectrics that operate through displacement of molecules under an applied field. However, displacive ferroelectric behavior is rare in organic CT cocrystals and achieving a Curie temperature (TC ) above ambient has been elusive. Here a cocrystal between acenaphthene and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane is presented that shows switchable remanent polarization at room temperature (TC =68 °C). Raman spectroscopy, X-ray diffraction, and solid-state NMR spectroscopy indicate the ferroelectric behavior is facilitated by acenaphthene (AN) rotation, deviating from conventional design strategies for CT ferroelectrics. These findings highlight the relevance of non-CT interactions in the design of displacive ferroelectric cocrystals.

Polymorphism in phenobarbital: discovery of a new polymorph and crystal structure of elusive form V.

This report highlights the discovery of a new polymorph of the anticonvulsant drug phenobarbital (PB) using polymer-induced heteronucleation (PIHn) and unravelling the crystal structure of the elusive form V. Both forms are characterized by structural, thermal and VT-Raman spectroscopy methods to elucidate phase transformation behavior and shed light on stability relationships.

Andrographolide: solving chemical instability and poor solubility by means of cocrystals.

The bioactive agent andrographolide was screened with pharmaceutically acceptable coformers to discover a novel solid form that will solve the chemical instability and poor solubility problems of this herbal medicine. Liquid-assisted grinding of andrographolide with GRAS (generally regarded as safe) coformers in a fixed stoichiometry resulted in cocrystals with vanillin (1:1), vanillic acid (1:1), salicylic acid (1:1), resorcinol (1:1), and guaiacol (1:1). All the crystalline products were characterized by thermal, spectroscopic, and diffraction methods. Interestingly, even though the cocrystals are isostructural, their physicochemical properties are quite different. The andrographolide-salicylic acid cocrystal completely inhibited the chemical transformation of andrographolide to its inactive sulfate metabolite, and moreover, the cocrystal exhibited a dissolution rate that was three times faster and a drug release that was two times higher than pure andrographolide.

Fast dissolving eutectic compositions of curcumin.

The bioactive herbal ingredient curcumin was screened with pharmaceutically acceptable coformers to discover solid-state forms of high solubility. Mechano-chemical grinding of curcumin with cocrystal formers in a fixed stoichiometry ratio resulted in binary eutectic compositions of curcumin-coformer with nicotinamide (1:2), ferulic acid (1:1), hydroquinone (1:1), p-hydroxybenzoic acid (1:1), and l-tartaric acid (1:1). The eutectic nature of the product crystalline solids was established by differential scanning calorimetry, and the absence of hydrogen-bonded crystalline phases such as cocrystals/salts was ascertained by powder X-ray diffraction, IR-Raman, and solid-state NMR spectroscopy. The best case of CUR-NAM eutectic exhibits 10-fold faster IDR and 6-times higher AUC compared to crystalline curcumin.

Novel furosemide cocrystals and selection of high solubility drug forms.

Furosemide was screened in cocrystallization experiments with pharmaceutically acceptable coformer molecules to discover cocrystals of improved physicochemical properties, that is high solubility and good stability. Eight novel equimolar cocrystals of furosemide were obtained by liquid-assisted grinding with (i) caffeine, (ii) urea, (iii) p-aminobenzoic acid, (iv) acetamide, (v) nicotinamide, (vi) isonicotinamide, (vii) adenine, and (viii) cytosine. The product crystalline phases were characterized by powder x-ray diffraction, differential scanning calorimetry, infrared, Raman, near IR, and (13) C solid-state NMR spectroscopy. Furosemide-caffeine was characterized as a neutral cocrystal and furosemide-cytosine an ionic salt by single crystal x-ray diffraction. The stability of furosemide-caffeine, furosemide-adenine, and furosemide-cytosine was comparable to the reference drug in 10% ethanol-water slurry; there was no evidence of dissociation of the cocrystal to furosemide for up to 48 h. The other five cocrystals transformed to furosemide within 24 h. The solubility order for the stable forms is furosemide-cytosine > furosemide-adenine > furosemide-caffeine, and their solubilities are approximately 11-, 7-, and 6-fold higher than furosemide. The dissolution rates of furosemide cocrystals were about two times faster than the pure drug. Three novel furosemide compounds of higher solubility and good phase stability were identified in a solid form screen.

Fluoroquinolone salts with carboxylic acids.

The crystallization of fluoroquinolone antibiotics norfloxacin and ciprofloxacin with carboxylic acids gave six new salts that were characterized by infrared spectroscopy, differential scanning calorimetry, X-ray powder diffraction, and single crystal X-ray diffraction. Five of these salts are hydrates with different levels of water content. The molecular composition, stoichiometry, and proton transfer state in these salts are confirmed from the crystal structure. The effect of carboxylate counterion, such as oxalate, tartarate, benzoate, malonate, and citrate, and hydration state on the solubility and dissolution profile of drug salts are reported in pure water (pH 6.4), 0.1 N HCl (pH 1.2), and phosphate buffer solution (pH 6.8). These salts are more soluble and exhibit faster dissolution in pure water and phosphate buffer medium than the reference drugs, but the order is reversed in acidic medium. These salts are chemically stable to the dissolution measurement conditions, whereas the reference drug norfloxacin undergoes phase transformation to norfloxacin hydrate at the end of the experiment.

New polymorphs of curcumin.

Two new crystalline polymorphs and an amorphous phase of the active curcuminoid ingredient in turmeric are reported. Curcumin polymorph 2 has higher dissolution rate and better solubility than the known polymorph 1.