N. Rajesh Goud

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.

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.

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.

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.

Modulating the solubility of sulfacetamide by means of cocrystals

Sulfacetamide is a popular antibiotic prescribed for treating ocular infections. However, various physiological constraints are known to reduce its concentration at the site of action, thereby limiting its therapeutic efficacy. In this crystal engineering study, we report novel cocrystals of sulfacetamide with the objective to lower the solubility of the reference drug and improve its residence time at the site of action. Standard cocrystallization methods resulted in cocrystals with caffeine, isonicotinamide, theophylline, bipyridine and a salt with 4-aminopyridine. These crystalline forms were characterized by thermal, spectroscopic and diffraction techniques. In pH 7 phosphate buffer medium, sulfacetamide–caffeine cocrystal exhibited lower solubility (8.64 g L−1, 0.69 times) than the drug (12.5 g L−1). The dissolution of sulfacetamide–isonicotinamide and sulfacetamide–caffeine is 0.64 and 0.68 times lower, whereas sulfacetamide–theophylline is comparable to the reference drug. This study highlights a less explored application of pharmaceutical cocrystals to reduce the solubility and dissolution rate of the drug for improved therapeutic action.

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.

Synthon polymorphs of sulfacetamide–acetamide cocrystal based on N–H⋯OS and N–H⋯OC hydrogen bonding

A rare case of polymorphism in SO2–NH–CO containing molecules is reported in the 1 : 1 cocrystal of sulfacetamide (SACT) and acetamide (ACT). The R44(16) ring motif in polymorph 1 is assembled via N–H⋯OS and N–H⋯OC H-bonds whereas a similar hydrogen-bonded ring motif made of N–H⋯OC H-bonds only is present in form 2.

High solubility crystalline hydrates of Na and K furosemide salts

Novel sodium and potassium salts of the poorly soluble loop diuretic drug furosemide were prepared with the intent of improving drug solubility and bioavailability. Furo–Na salt was obtained as a trihydrate upon crystallization from aqueous NaOH solution, and furo–K salt crystallized as a monohydrate from KOH solution. Both salt hydrates were characterized by X-ray diffraction, DSC, TGA, and IR spectroscopy. An exothermic phase transition at 165 °C in the DSC heating curve of the furo–Na salt indicates the likelihood of polymorphism in its anhydrate phase. Based on solubility studies, furo–Na–trihydrate and furo–K–monohydrate in pH 7 phosphate buffer medium exhibited significantly higher aqueous solubilities of 41 mg mL−1 and 106 mg mL−1 compared to the free drug (0.01 mg mL−1). The physical stability of these fast dissolving salts under accelerated ICH conditions of 40 °C and 75% RH was modest, with furo–Na salt being stable for 2 weeks and furo–K salt for 1 week.

2-Bromo-3-hy­droxy-6-methyl­pyridine

In the title compound, C6H6BrNO, the Br atom is displaced from the pyridine ring mean plane by 0.0948 (3) Å, while the hydroxyl O atom and the methyl C atom are displaced by 0.0173 (19) and 0.015 (3) Å, respectively. In the crystal, molecules are linked via O—H⋯N hydrogen bonds, forming chains propagating along the a-axis direction. These chains are linked by C—H⋯Br hydrogen bonds, forming corrugated two-dimensional networks lying parallel to the ac plane.