Solid Forms of The New Antitrypanosomal 1-(4-Acetamide-Benzenesulfonyl)-Benzimidazole: Preparation and Physicochemical Characterization.

This study aimed to investigate the polymorphism of 1-(4-acetamide-benzenesulfonyl)-benzimidazole (PABZI), a newly developed compound with significant activity against Trypanosoma cruzi, the parasite which causes American trypanosomiasis (Chagas disease). Three different crystalline forms of PABZI [a solvent-free form (form I), three isostructural solvates (from isopropanol; acetonitrile-dichloromethane, and methanol-benzene) and a non-isostructural solvate from methanol] were isolated and characterized. The crystal structure of form I was resolved at 173 K and 300 K by single crystal X-ray diffraction. Physicochemical properties, including solubility, dissolution rate, wettability, and solid-state stability were assessed for the two most viable solid forms of PABZI, viz. form I and the isopropanol solvate (PABZI-isoOH). Form I exhibited a higher solubility and dissolution rate, and superior stability towards moisture (40 °C/75 % relative humidity) and UV-Visible light than PABZI-isoOH. Based on the solid-state stability results, form I was selected over PABZI-isoOH for further preclinical studies.

Accurate location of hydrogen atoms in hydrogen bonds of tizoxanide from the combination of experimental and theoretical models.

To obtain detailed information about the position of hydrogen atoms in hydrogen bonds, HBs, of crystalline organic molecular compounds is not an easy task. In this work we propose a combination of ssNMR experimental data with theoretical procedures to get such information. Furthermore, the combination of experimental and theoretical models provides us with well-defined grounds to analyse the strength of π-stacking interactions between layers of hydrogen bonded molecules. Two different theoretical models were considered, both approaches being quite different. The first one is a solid-state model, so that the periodicity of a crystalline system underlies calculations of the electronic energy, the electronic density and NMR parameters. The other one is a molecular model in which molecules are taken as isolated monomers, dimers and tetramers. These two models were applied to the tizoxanide, TIZ, molecular crystal though it can widely be applied to any other molecular crystal. By the application of the quantum molecular model it was possible to learn about the way the intermolecular HBs affect the position of hydrogen atoms that belong to HBs in TIZ. This molecule has two intermolecular HBs that stabilize the structure of a basic dimer, but it also has an intramolecular HB in each monomer whose position should be optimized together with the other ones. We found that by doing this it is possible to obtain reliable results of calculations of NMR spectroscopic parameters. Working with the solid-state model we found that any local variation of the TIZ crystalline structure is correlated with the variation of the values of the NMR parameters of each nucleus. The excellent agreement between experimental and calculated chemical shifts leads to the conclusion that the N10-H10 bond distance should be (1.00 ± 0.02) Å.

Preparation and characterization of polymorphs of the glucocorticoid deflazacort.

The polymorphism of new and old active pharmaceutical ingredients (APIs) is of great importance due to performance, stability and processability aspects. The objective of this study was to investigate the polymorphism of deflazacort (DEF), a glucocorticoid discovered >40 years ago, since this phenomenon has not been previously investigated for this API. Using different methods for solid form screening, it was determined for the first time that DEF is able to exist as three forms: a crystalline (DEF-1); a hydrated X-ray amorphous (DEF-t-bw) and an anhydrous amorphous phase (DEF-g) obtained from manually grinding DEF-1. The in vitro and in vivo dissolution rates (DRs) of DEF-1 and DEF-t-bw, which were measured using the rotating disk method in water at 37 °C and the pellet implantation technique in rats, respectively, indicated that DEF-t-bw exhibited slightly faster in vitro and in vivo DRs than those of the crystalline form, but the values were not significantly different. In addition, it was determined that DEF-t-bw devitrifies to DEF-1 by the effect of pressure, humidity and heat. It was concluded that DEF is glucorticoid with low tendency to exhibit different crystalline forms and that DEF-t-bw has no advantages over DEF-1 in terms of solubility, DRs and solid-state stability.

Evidence of Polymorphism on the Antitrypanosomal Naphthoquinone (4E)-2-(1H-Pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one.

The aim of this study was to characterize the solid state properties of (4E)-2-(1H-pyrazol-3-ylamino)-4-(1H-pyrazol-3-ylimino)naphthalen-1(4H)-one (BiPNQ), a compound with a significant inhibitory activity against Trypanosoma cruzi, the etiological agent of Chagas disease (American trypanosomiasis). Methods used included Differential Scanning Calorimetry (DSC), Thermogravimetry (TG), Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD), Hot Stage, and Confocal Microscopy. Two BiPNQ samples were obtained by crystallization from absolute methanol and 2-propanol-water that exhibited different thermal behaviours, PXRD patterns, and FTIR spectra, indicating the existence of an anhydrous form (BiPNQ-I) and a solvate (BIPNQ-s), which on heating desolvated leading to the anhydrous modification BiPNQ-I. It was determined that FTIR, DSC, and PXRD are useful techniques for the characterization and identification of the crystalline modifications of BiPNQ.

[Modification of solid dosage forms: survey in a hospital of the Province of Cordoba]. / Modificación de formas farmacéuticas sólidas: relevamiento en un hospital de la Provincia de Córdoba.

BACKGROUND: In the hospital setting is frequent to manipulate solid dosage forms (SDF, tablets 16 and capsules), which can affect their physicochemical and biopharmaceutical properties, the pharmacoloeffect and sometimes to cause the appearance of undesirable side effects. OBJECTIVES: To identify the medicines whose SDF is altered in a Hospital of Cordoba (Argentina), to determine how these modifications are made and to establish whether they were properly performed or not. METHODS: We retrospectively analyzed the prescriptions made between the 5th and the 11th of March of 2012 and identified impaired requesting SDF modifications. Open interviews were held with nurses and service visits to each hospital to determine how they manipulated the SDF. RESULTS: We analyzed 700 prescriptions for 113 patients, of which 61 (54%) had manipulations of the received SDF (49 for medical prescription, 7 because they had nasogastric tubes, 3 due to patient choice and 2 by nursing decision). Twenty three medicines were manipulated, but only 12 were correctly manipulated. The major changes were partition of tablets and grinding of tablets or microgranules and dispersible in water. CONCLUSION: The SDF of several medicines is altered in the analyzed hospital, many times without medical indication and scientific justification. It would be appropriate to conduct training courses and establish closer collaborations between pharmacy and nursing units in the investigated hospital.

Modificación de formas farmacéuticas sólidas: relevamiento en un hospital de la Provincia de Córdoba / [Modification of solid dosage forms: survey in a hospital of the Province of Cordoba].

BACKGROUND: In the hospital setting is frequent to manipulate solid dosage forms (SDF, tablets 16 and capsules), which can affect their physicochemical and biopharmaceutical properties, the pharmacoloeffect and sometimes to cause the appearance of undesirable side effects. OBJECTIVES: To identify the medicines whose SDF is altered in a Hospital of Cordoba (Argentina), to determine how these modifications are made and to establish whether they were properly performed or not. METHODS: We retrospectively analyzed the prescriptions made between the 5th and the 11th of March of 2012 and identified impaired requesting SDF modifications. Open interviews were held with nurses and service visits to each hospital to determine how they manipulated the SDF. RESULTS: We analyzed 700 prescriptions for 113 patients, of which 61 (54

) had manipulations of the received SDF (49 for medical prescription, 7 because they had nasogastric tubes, 3 due to patient choice and 2 by nursing decision). Twenty three medicines were manipulated, but only 12 were correctly manipulated. The major changes were partition of tablets and grinding of tablets or microgranules and dispersible in water. CONCLUSION: The SDF of several medicines is altered in the analyzed hospital, many times without medical indication and scientific justification. It would be appropriate to conduct training courses and establish closer collaborations between pharmacy and nursing units in the investigated hospital.

Modificación de formas farmacéuticas sólidas: relevamiento en un hospital de la Provincia de Córdoba. / [Modification of solid dosage forms: survey in a hospital of the Province of Cordoba].

BACKGROUND: In the hospital setting is frequent to manipulate solid dosage forms (SDF, tablets 16 and capsules), which can affect their physicochemical and biopharmaceutical properties, the pharmacoloeffect and sometimes to cause the appearance of undesirable side effects. OBJECTIVES: To identify the medicines whose SDF is altered in a Hospital of Cordoba (Argentina), to determine how these modifications are made and to establish whether they were properly performed or not. METHODS: We retrospectively analyzed the prescriptions made between the 5th and the 11th of March of 2012 and identified impaired requesting SDF modifications. Open interviews were held with nurses and service visits to each hospital to determine how they manipulated the SDF. RESULTS: We analyzed 700 prescriptions for 113 patients, of which 61 (54

) had manipulations of the received SDF (49 for medical prescription, 7 because they had nasogastric tubes, 3 due to patient choice and 2 by nursing decision). Twenty three medicines were manipulated, but only 12 were correctly manipulated. The major changes were partition of tablets and grinding of tablets or microgranules and dispersible in water. CONCLUSION: The SDF of several medicines is altered in the analyzed hospital, many times without medical indication and scientific justification. It would be appropriate to conduct training courses and establish closer collaborations between pharmacy and nursing units in the investigated hospital.

Physicochemical characterization of deflazacort: thermal analysis, crystallographic and spectroscopic study.

The solid state properties of deflazacort (1-(1beta,16alpha)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, 1) were investigated using differential scanning calorimetry (DSC), thermogravimetry (TG), single-crystal X-ray diffraction, solid and liquid nuclear magnetic resonance spectroscopy ((13)C NMR), Fourier transform infrared and Raman spectroscopy (FTIR and FT Raman). From the trends observed in the crystal structure and spectral data some conclusions can be made about hydrogen bonding, molecular conformation and crystal packing. Compound 1 crystallizes in an orthorhombic cell, space group P2(1)2(1)2(1) and the following lattice parameters: a=11.2300(5), b=12.8161(8), c=16.171(1)A, V: 2327.4(2)A(3), D(c): 1.260g/cm(3), R1=0.0479, wR2=0.1012. The crystal structure is stabilized by intra and intermolecular interactions, which provides for a very closely packed form. The NMR data indicated that 1 shows a similar conformation in solid and liquid state; while, thermal data revealed that 1 follows a monophasic pattern with a DSC melting peak at 258.4 degrees C (DeltaH 99.7Jg(-1), n=3), indicating that 1 is thermally stable as solid; but, as liquid is unstable to undergo a thermal decomposition reaction. The reactivity of 1 toward light and moisture was examined via DSC and TLC. The data indicated that 1 do not interact with water to give hydrated forms or decomposition products; however, light degrades 1.

The crystal structure and physicochemical characteristics of 2-hydroxy-N-[3(5)-pyrazolyl]-1,4-naphthoquinone-4-imine, a new antitrypanosomal compound.

This study was designed to investigate the physical characteristics and crystalline structure of 2-hydroxy-N-[3(5)-pyrazolyl]-1,4-naphthoquinone-4-imine (PNQ), a new active compound against Trypanosoma cruzi, the causative agent of American trypanosomiasis. Methods used included differential scanning calorimetry, thermogravimetry, hot stage microscopy, polarized light microscopy (PLM), Fourier-transform infrared (FTIR) spectroscopy, and high-resolution X-ray powder diffraction (HR-XRPD). According to PLM and HR-XRPD data, PNQ crystallized as red oolitic crystals (absolute methanol) or prisms (dimethyl sulfoxide [DMSO]-water) with the same internal structure. The findings obtained with HR-XRPD data (applying molecular location methods) showed a monoclinic unit cell [a = 18.4437(1) A, b = 3.9968(2) A, c = 14.5304(1) A, alpha = 90 degrees , beta = 102.71(6) degrees , gamma = 90 degrees , V = 1044.9(1) A(3), Z = 4, space group P2(1)/c], and a crystal structure (excluding H-positions) described by parallel layers in the direction of the b-axis, with molecules held by homochemical (phenyl-phenyl and pyrazole-pyrazole) van der Waals interactions. In addition, FTIR spectra displayed the NH-pyrazole stretch overlapped with the OH absorption at 3222 cm(-1), typical of -NH and -OH groups associated through H-bondings; and a carbonyl stretching absorption at 1694 cm(-1), indicating a nonextensively H-bonded quinonic C=O, which was in accordance with the solved crystal structure of PNQ. The existence of such cohesive forces shed light on the thermoanalytical data, which revealed that PNQ is a stable solid, unaffected by oxygen that decomposed without melting above 260 degrees C.

Synthesis and biological evaluation of pyrazolylnaphthoquinones as new potential antiprotozoal and cytotoxic agents.

The importance of American trypanosomiasis (Chagas' disease) in human pathology is widely known. The prognosis of this disease is poor and the choice of effective medicines limited, thus study of new drugs is absolutely necessary. In this work, the activities of three new pyrazolylnaphthoquinones, heterocyclic naphthoquinones bearing 3-aminopyrazole rings, were evaluated on Trypanosoma cruzi, the etiological agent of Chagas' disease. These activities were compared with those of three 5-aminoisoxazole analogues. In addition, since these compounds belong to a family of antiprotozoal and cytotoxic/antitumor agents, the activities of all six against Plasmodium falciparum, Trypanosoma brucei rhodesiense, and murine L-6 cells were also investigated. In the biological tests, five of the compounds showed significant in vitro trypanocidal activities against T. cruzi, with activities similar to that of benznidazole. Two of the 5-aminoisoxazole analogues also showed good activities, in one case highly selective, against the K1 and NF54 strains of P. falciparum (IC(50)<0.12 microg mL(-1)). Three of the compounds were cytotoxic to murine L-6 cells (IC(50)=0.21-0.50 microg mL(-1)). The results suggested that the three pyrazolylnaphthoquinones and one of the 5-aminoisoxazole analogues could be starting points for lead optimization programs against T. cruzi and P. falciparum, respectively.