Two crystal forms of a hydrated 2:1 b-cyclodextrin× fluconazole complex: Single crystal x-ray structures, dehydration profiles, and conditions for their individual isolation

Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between β-cyclodextrin (β-CD) and the antifungal API fluconazole (FLU) as well as temperature–concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin×API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ

Synthesis, crystal structure, structural phase transition and dielectric properties of new organic-inorganic hybrid compound: (C6H5CH2N(C2H5)3)CdCl3

Single crystal of new organic-inorganic hybrid compound, (C6H5CH2N(C2H5)3)CdCl3, was successfully synthesis by slow evaporation method at room temperature and characterized by divers techniques such as single X-ray diffraction, Infrared and Raman spectroscopy, Thermal analysis (TGA and DSC), Variable temperature X-ray powder diffraction (VT‒XRPD) and dielectric properties. The results of single X-ray studies demonstrated that the title compound crystallizes in the monoclinic system with the space group P21/n. The atomic arrangement of the crystal structure can be described as 1D polymeric inorganic chain CdCl5 along the a-axis between which the organic groups are located. It consists on isolated square-pyramidal [CdCl5]3− anions and triethylbenzylammonuim (C6H5CH2N(C2H5)3)+ cations, which are interconnected via C−H…Cl weak hydrogen bonds forming 3D network. Investigation of RT‒XRPD was carried out to identify the purity of the bulk material. Hirshfeld surface and fingerprint plots reveal that the structure is dominated by H…H and H…Cl/Cl…H contacts. It is found that the (C6H5CH2N(C2H5)3)CdCl3 material displays a irreversible structural phase transition at T = 413 K. This latter was confirmed by means of variable temperature X- ray powder diffraction and dielectric permittivity (ε′andε′)

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. Patients and methods: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 μg/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. Results: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. Conclusions: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosup-pression should be accepted in order to obtain a high anti-tumor activity of this regimen and a potential improvement in surviva

Mechanochemical Preparation of Dipyridyl-Naphthalenediimide Cocrystals: Relative Role of Halogen-Bond and π-πInteractions

Naphthalenediimide derivates are a class of π-conjugated molecules largely investigated in the literature and used as building blocks for metal-organic frameworks or coformers for hydrogen-bond-based cocrystals. However, their tendency to establish halogen-bond interactions remains unexplored. By using a crystalline engineering approach, we report here four new cocrystals with N,N′-di(4-pyrydyl)-naphthalene-1,4,5,8-tetracarboxidiimide and diiodo-substituted coformers, easily obtained via a mechanochemical protocol. Cocrystals were characterized via NMR, electron ionization mass spectrometry, thermogravimetric analysis, powder X-ray diffraction, and single-crystal X-ray diffraction. Crystallographic structures were then finely examined and correlated with energy framework calculations to understand the relative contribution of halogen-bond and π-πinteractions toward framework stabilization

Fungicidas aplicados em tratamento de sementes de soja e seus efeitos sobre a nodulação e a fixação biológica do nitrogênio

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