Reversible De-/Rehydration Process in Paroxetine Hydrobromide

Paroxetine (PRX) is an antidepressant widely used in depression treatment for decades. The anhydrous and hemidrate chloride forms have been used in pharmaceutical formulations. During their developing a discussion associated with its physical forms and the complex hydration/dehydration behavior involving these phases were established. To improve our understanding of this issue we investigate the crystal structure of paroxetine bromide hemidrate, (PRX+.Br-).H2O, as a model for understanding the stability anhydrous/hemihydrate paroxetine arrangements and the nature of the intermolecular interaction of water within the crystal lattice by single crystal X-ray diffraction experiments. A combination of complementary characterization techniques were also used including Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), Hot Stage microscopy and solubility measurements. As expected the paroxetine bromide hemidrate, (PRX+.Br-).H2O, is isostructural with the paroxetine chloride hemidrate, (PRX+.Cl-).H2O. As in that case, the crystal packing of (PRX+.Br-).H2O is stabilized by strong NH2+...O and NH2+...Br hydrogen bonds which forms infinite channels along the b axis. The water and bromide anions are located along these channels. The DSC/TGA analysis for (PRX+.Br-).H2O show an endothermic desolvation process with an onset temperature of 77.09 °C, that is not present in the paroxetine chloride hemidrate DSC curve. This process leaves to a paroxetine anhydrous bromide crystal structure that is isomorphic to the anhydrous chloride one. However, this structure is spontaneously rehydrated at ambient atmosphere. This rehydration phenomenon probe the stability of paroxetine hemihydrate arrangement, since (PRX+.Br-) is slightly more soluble that its hydrate form. As opposed to chloride hemidrate, the rehydration of paroxetine bromide only involves a rearrangement of the water molecule within the cavities.

Molecular architectures of new inorganic lamivudine salts, an anti-HIV drug.

One of the currently goals of the crystal engineering is the improvement of pharmaceutical properties of Active Pharmaceutical Ingredients. Herein is discussed the design of new solid forms of the Lamivudine (3TC), one of the most used and marketed anti-HIV drug. The crystalline forms herein presented correspond to inorganic acid salts: Lamivudine hydrobromide (3TCH⁺-Br^-), hydrogen difluoride (3TCH⁺-F^-HF) and nitrate (3TCH⁺-NO₃^-). These new salts crystallized in non-centrossymetric space group P2₁. The halogenated salts (3TCH⁺-Br^- and 3TCH⁺-F^-HF) exhibited isostructural supramolecular assemblies, similar to the anhydrous salt of lamivudine hydrochloride (3TCH⁺-Cl^-) reported by our research group, and whose equilibrium solubility showed an increase when compared with 3TC pharmaceutical form. [1,2] The main feature of the salt crystalline assemblies is related to the supramolecular ordering of the 3TCH⁺ cationic units, by observing the formation of vacancies between them generated in the [100] direction due to the helical symmetry, so, the anions are localized into the interstices of these vacancies, stabilizing the crystalline assemblies. Meanwhile, the 3TCH⁺NO₃^- salt showed a different conformational and supramolecular behavior from that observed in the halogenated ones. Here is observed the formation of helical strands along the b axis, which will be engaging by translational symmetry in the horizontal direction in the [10-1] plane. Therefore, they form zigzag molecular planes which will subsequently be architected in parallel with the [10-1] direction. In addition, it was used for this study X-ray powder diffraction (XRDP), vibrational analysis: Infrared (IR) and Raman spectroscopy, and thermal analysis: differential scanning calorimetry (DSC), thermogravimetry (TG) and hot-stage microscopy. Comparison of the structural properties of these salts with some forms already reported (e.g. 3TCH⁺-Cl^-) allows to infer some possible pharmaceutical properties.

Crystallochemical aspects of two microlite-group new mineral species

Fluorcalciomicrolite, Ca₁.₅Ta₂O₆F, and hydroxycalciomicrolite, Ca₁.₅Ta₂O₆(OH), are new microlite-group [1] minerals found in the Volta Grande pegmatite, Nazareno, Minas Gerais, Brazil. Both occur as octahedral and rhombododecahedral crystals. The crystals are colourless, yellow and translucent, with vitreous to resinous luster. The densities calculated for fluorcalciomicrolite [2] and hydroxycalciomicrolite are 6.160 and 6.176 g/cm³, respectively. The empirical formulae obtained from electron microprobe analysis are (Ca₁.₀₇Na₀.₈₁□₀.₁₂)Σ₂ (Ta₁.₈₄Nb₀.₁₄Sn₀.₀₂)Σ₂[O₅.₉₃(OH)₀.₀₇]Σ₆.₀₀[F₀.₇₉(OH)₀.₂₁] for fluorcalciomicrolite and (Ca₁.₄₈Na₀.₀₆Mn₀.₀₁)Σ₁.₅₅(Ta₁.₈₈Nb₀.₁₁Sn₀.₀₁)Σ₂O₆[(OH)₀.₇₆F₀.₂₀O₀.₀₄] for hydroxycalmicrolite. Fluorcalciomicrolite is cubic, space group Fd-3m, a = 10.4191(6) Å, V = 1131.07(11) ų, and Z = 8. Hydroxycalciomicrolite is also cubic; however, the presence of P-lattice is confirmed by the large number of weak reflections observed by X-ray diffraction. As a result, the space group is P4₃32 and unit-cell parameters are a = 10.4211(8) Å, and V = 1131.72(15) ų.

Structural study of new cytotoxic heteroleptic Copper (II) complexes

The widespread success of Cisplatin in the treatment of several neoplasias has arisen the interest in coordination compounds as drugs for the treatment of cancer. In the search for new compounds with antitumor activity, copper coordination complexes are being studied by our group. This work presents the synthesis and structural characterization of four new copper complexes with general stoichiometry [Cu(L-dipeptide)(phen)]·nH2O and their cytotoxicity against tumor cell lines. Single crystal X-ray diffraction experiments show that the copper ion is situated in a distorted squared pyramidal environment. The phen ligand is perpendicular to the plane defined by the coordinated dipeptide, therefore exposed and potentially available for interaction with biological molecules, e.g. DNA. The availability of the phen ligand and the physico-chemical properties of the complexes are modulated by the dipeptide. Complementary techniques (elemental analysis, infrared and UV-vis spectroscopies) were used to further characterize the complexes in solid state and aqueous solution, confirming that the coordination is maintained in solution. Lipophilicity and DNA binding constants were also measured, being able to discriminate between the behavior of even the complexes containing the ala-phe and phe-ala dipeptide. All the complexes induce cell death in the cell lines of human cervical adenocarcinoma, human metastatic breast adenocarcinoma and human lung epithelial carcinoma. Among the six complexes studied, [Cu(ala-phe)(phen)] presents the lowest half maximal inhibitory concentration (IC50) values. In an attempt to increase the activity, studies are presently being carried out using 2,9-dimethyl-10-phenanthroline. X-ray diffraction studies on the latter show slight deviations in the coordination geometries and different results are expected in their biological activities. Acknoledgements: CSIC, CAPES-UdelaR, PEDECIBA.

The crystal structure of the C-terminal domain of the Ebola virus nucleoprotein

Ebola virus (EBOV) and Marburg virus are members of the family Filoviridae. Both are highly pathogenic and cause hemorrhagic fever, lethal in 90% of infected people. There is fear that the viruses can be used as bioterrorism agents. There are no approved vaccines, and intense effort is underway to discover drugs targeting these viruses. The EBOV genome encodes seven proteins, two of which have no known structures: RNA polymerase (L) and nucleoprotein (NP). NP is essential for packaging viral genomic RNA into the nucleocapsid. Other viruses also contain nucleoproteins, but only the Ebola and Marburg NP proteins contain two distinct domains. The C-terminal domain (Ct; ~100 residues) has no homologues; it acts as a hub for protein-protein interactions important for the assembly of the nucleocapsid and for the interaction with the VP40 matrix protein, embedded in the viral membrane. We obtained three distinct crystal forms of the Ct domain of NP from EBOV, and solved the structures using anomalous scattering from Se, and Molecular Replacement. High-quality NMR data were also collected. The models were refined at 1.6-2.0 Å resolution to R factors ~20%. The protein has a novel fold, with topology distantly related to the β-grasp fold. In spite of its small size, the Ct domain shows high melting temperature of ~60°C. Our efforts focus on the identification of how the C-terminal domain of NP binds to its partners. As part of an effort towards anti-filovirus drug discovery, proteins NP, VP24, VP35 and VP40 are being targeted for small molecule inhibition using a yeast-based phenotypic assay. Each protein, when expressed in budding yeast, produces a slow-growth phenotype. Chemical suppressors of the slow-growth phenotype will be identified and used in viral growth assays to confirm their antiviral activity. The structure of NP will be used to complement small molecule screening methods.