Clathrate Hydrates of Organic Solvents as Auxiliary Intermediates in Pharmaceutical Research and Development: Improving Dissolution Behaviour of a New Anti-Tuberculosis Drug, Perchlozon.

There is an urgent need for new drugs to overcome the challenge of the ever-growing drug resistance towards tuberculosis. A new, highly efficient anti-tuberculosis drug, Perchlozone (thioureidoiminomethylpyridinium perchlorate, Pz), is only available in an oral dosage form, though injectable forms and inhalation solutions could be better alternatives, offering higher bioavailability. To produce such forms, nano- and micro-particles of APIs would need to be prepared as dispersions with carriers. We use this case study to illustrate the principles of selecting solvents and excipients when preparing such formulations. We justify the choice of water-THF (19.1 wt % THF) as solvent and mannitol as carrier to prepare formulations of Pz-a poorly soluble compound-that are suitable for injection or inhalation. The formulations could be prepared by conventional freeze-drying in vials, making the proposed method suitable for industrial scaling. A similar strategy for selecting the organic solvent and the excipient can be applied to other compounds with low water solubility.

Compressibility of gas hydrates.

Experimental data on the pressure dependence of unit cell parameters for the gas hydrates of ethane (cubic structure I, pressure range 0-2 GPa), xenon (cubic structure I, pressure range 0-1.5 GPa) and the double hydrate of tetrahydrofuran+xenon (cubic structure II, pressure range 0-3 GPa) are presented. Approximation of the data using the cubic Birch-Murnaghan equation, P=1.5B(0)[(V(0)/V)(7/3)-(V(0)/V)(5/3)], gave the following results: for ethane hydrate V(0)=1781 Å(3) , B(0)=11.2 GPa; for xenon hydrate V(0)=1726 Å(3) , B(0)=9.3 GPa; for the double hydrate of tetrahydrofuran+xenon V(0)=5323 Å(3) , B(0)=8.8 GPa. In the last case, the approximation was performed within the pressure range 0-1.5 GPa; it is impossible to describe the results within a broader pressure range using the cubic Birch-Murnaghan equation. At the maximum pressure of the existence of the double hydrate of tetrahydrofuran+xenon (3.1 GPa), the unit cell volume was 86% of the unit cell volume at zero pressure. Analysis of the experimental data obtained by us and data available from the literature showed that 1) the bulk modulus of gas hydrates with classical polyhedral structures, in most cases, are close to each other and 2) the bulk modulus is mainly determined by the elasticity of the hydrogen-bonded water framework. Variable filling of the cavities with guest molecules also has a substantial effect on the bulk modulus. On the basis of the obtained results, we concluded that the bulk modulus of gas hydrates with classical polyhedral structures and existing at pressures up to 1.5 GPa was equal to (9±2) GPa. In cases when data on the equations of state for the hydrates were unavailable, the indicated values may be recommended as the most probable ones.

High-pressure gas hydrates of argon: compositions and equations of state.

Volume changes corresponding to transitions between different phases of high-pressure argon gas hydrates were studied with a piston-cylinder apparatus at room temperature. Combination of these data with the data taken from the literature allowed us to obtain self-consistent set of data concerning the equations of state and compositions of the high-pressure hydrates of argon.

A new method of producing monoclinic paracetamol suitable for direct compression.

PURPOSE: To develop a technique of obtaining monoclinic polymorph of paracetamol suitable for direct compression without excipients. METHODS: Preparation of spongy monoclinic paracetamol was based on quench-cooling of paracetamol solutions in water-acetone mixtures sprayed into a vessel with liquid nitrogen followed by removal of solvents by freeze-drying. X-ray powder diffraction was used to study annealing of quench-cooled solutions in "paracetamol-acetone-water" and "acetone-water" systems and to find optimum conditions for obtaining fine particles of pure monoclinic paracetamol. Samples were characterized by electron microscopy; compression properties were measured. RESULTS: The preparation technique gave fine monoclinic paracetamol powder containing agglomerates (30-200 µm) composed of flat particles (linear sizes 1-10 µm, the thickness 60-150 nm). The spongy sample was suitable for direct compression without excipients, stable on storage, and mechanically robust. Mechanically stable tablets pressed from the spongy sample were better soluble in water than commercially available tablets of paracetamol with excipients. CONCLUSIONS: The proposed method gave spongy monoclinic paracetamol samples with improved properties. For inexpensive paracetamol, the method may not yield economic advantage. However, the same method based on freeze-drying solutions in mixed aqueous-organic solvents can be used to prepare new improved forms of other molecular solids for pharmaceutical applications.

Phase diagram and high-pressure boundary of hydrate formation in the carbon dioxide-water system.

Experimental investigation of the phase diagram of the system carbon dioxide-water at pressures up to 2.7 GPa has been carried out in order to explain earlier controversial results on the decomposition curves of the hydrates formed in this system. According to X-ray diffraction data, solid and/or liquid phases of water and CO2 coexist in the system at room temperature within the pressure range from 0.8 to 2.6 GPa; no clathrate hydrates are observed. The results of neutron diffraction experiments involving the samples with different CO2/H2O molar ratios, and the data on the phase diagram of the system carbon dioxide-water show that CO2 hydrate of cubic structure I is the only clathrate phase present in this system under studied P-T conditions. We suppose that in the cubic structure I hydrate of CO2 multiple occupation of the large hydrate cavities with CO2 molecules takes place. At pressure of about 0.8 GPa this hydrate decomposes into components indicating the presence of the upper pressure boundary of the existence of clathrate hydrates in the system.

First determination of volume changes and enthalpies of the high-pressure decomposition reaction of the structure H methane hydrate to the cubic structure I methane hydrate and fluid methane.

Pressure-temperature (P-T) conditions of the decomposition reaction of the structure H high-pressure methane hydrate to the cubic structure I methane hydrate and fluid methane were studied with a piston-cylinder apparatus at room temperature. For the first time, volume changes accompanying this reaction were determined. With the use of the Clausius-Clapeyron equation the enthalpies of the decomposition reaction of the structure H high-pressure methane hydrate to the cubic structure I methane hydrate and fluid methane have been calculated.

Phase diagram and high-pressure boundary of hydrate formation in the ethane-water system.

Dissociation temperatures of gas hydrate formed in the ethane-water system were studied at pressures up to 1500 MPa. In situ neutron diffraction analysis and X-ray diffraction analysis in a diamond anvil cell showed that the gas hydrate formed in the ethane-water system at 340, 700, and 1840 MPa and room temperature belongs to the cubic structure I (CS-I). Raman spectra of C-C vibrations of ethane molecules in the hydrate phase, as well as the spectra of solid and liquid ethane under high-pressure conditions were studied at pressures up to 6900 MPa. Within 170-3600 MPa Raman shift of the C-C vibration mode of ethane in the hydrate phase did not show any discontinuities, which could be evidence of possible phase transformations. The upper pressure boundary of high-pressure hydrate existence was discovered at the pressure of 3600 MPa. This boundary corresponds to decomposition of the hydrate to solid ethane and ice VII. The type of phase diagram of ethane-water system was proposed in the pressure range of hydrate formation (0-3600 MPa).

Gas hydrates of argon and methane synthesized at high pressures: composition, thermal expansion, and self-preservation.

For the first time, the compositions of argon and methane high-pressure gas hydrates have been directly determined. The studied samples of the gas hydrates were prepared under high-pressure conditions and quenched at 77 K. The composition of the argon hydrate (structure H, stable at 460-770 MPa) was found to be Ar.(3.27 +/- 0.17)H(2)O. This result shows a good agreement with the refinement of the argon hydrate structure using neutron powder diffraction data and helps to rationalize the evolution of hydrate structures in the Ar-H(2)O system at high pressures. The quenched argon hydrate was found to dissociate in two steps. The first step (170-190 K) corresponds to a partial dissociation of the hydrate and the self-preservation of a residual part of the hydrate with an ice cover. Presumably, significant amounts of ice Ic form at this stage. The second step (210-230 K) corresponds to the dissociation of the residual part of the hydrate. The composition of the methane hydrate (cubic structure I, stable up to 620 MPa) was found to be CH(4).5.76H(2)O. Temperature dependence of the unit cell parameters for both hydrates has been also studied. Calculated from these results, the thermal expansivities for the structure H argon hydrate are alpha(a) = 76.6 K(-1) and alpha(c) = 77.4 K(-1) (in the 100-250 K temperature range) and for the cubic structure I methane hydrate are alpha(a) = 32.2 K(-1), alpha(a) = 53.0 K(-1), and alpha(a) = 73.5 K(-1) at 100, 150, and 200 K, respectively.