The present invention provides an industrial method production of amorphous posaconazole. The present invention also relates to a method for production of the posaconazole via and novel crystalline forms of posaconazole intermediate. More particularly the present invention relates to novel crystalline forms of posaconazole intermediate and methods for production of novel crystalline forms of posaconazole intermediate represented by the following structural formula III Which is key intermediate in the production of posaconazole. The present invention also provides for the one pot process for the preparation of amorphous posaconazole using novel crystalline forms of benzyl posaconazole.

##STR00001##

A method for precipitating as particles 2,6-diamino-3,5-dinitropyrazine-1-oxide (or ANPZO) present in an acid medium, which comprises adding the acid medium to an aqueous solution and which is characterized in that the aqueous solution comprises a nitrate salt. Further disclosed is a method for synthesizing ANPZO implementing this precipitation method. The synthesis method comprises converting 2,6-diaminopyrazine-1-oxide (or DAPO) into ANPZO by nitration in an acid medium, and then precipitating as particles the ANPZO by adding the acid medium to an aqueous solution, and is characterized in that the aqueous solution comprises a nitrate salt.

A method for forming, or crystallising, clathrates hydrates of a host molecule in a liquid including water includes the following consecutive steps: cooling the liquid to a temperature no higher than the crystallisation temperature of the clathrates hydrates; and placing the cooled liquid in contact with host molecules that are capable of forming clathrates hydrates and are adsorbed on a solid support that has a large specific surface area and is made of a hydrophobic and apolar material, whereby the host molecules are desorbed from the solid support that has a large specific surface area and is made of a hydrophobic and apolar material, and react with the water of the liquid in order to provide a liquid containing clathrates hydrates and the solid support.

The present invention provides an industrial method production of amorphous posaconazole. The present invention also relates to a method for production of the posaconazole via and novel crystalline forms of posaconazole intermediate. More particularly the present invention relates to novel crystalline forms of posaconazole intermediate and methods for production of novel crystalline forms of posaconazole intermediate represented by the following structural formula III Which is key intermediate in the production of posaconazole. The present invention also provides for the one pot process for the preparation of amorphous posaconazole using novel crystalline forms of benzyl posaconazole. ##STR00001##

A method for producing high-purity terephthalic acid, comprising following steps (a) to (e):

(a) a step of obtaining a crude terephthalic acid crystal by liquid-phase oxidizing a p-phenylene compound,
(b) a step of dissolving the crude terephthalic acid crystal in water and then subjecting to catalytic hydrogenation treatment,
(c) a step of depressurizing and cooling a reaction liquid after the catalytic hydrogenation treatment in stages with two or more stages of crystallization vessels, to crystallize terephthalic acid to obtain a terephthalic acid slurry,
(d) a step of introducing the terephthalic acid slurry into an upper portion of a mother liquor replacement tower, bringing the terephthalic acid crystal into contact with an upward flow of replacement water introduced from a tower lower compartment of the mother liquor replacement tower while making the terephthalic acid crystal settled down in the tower, and withdrawing the terephthalic acid crystal as slurry with the replacement water from the tower lower compartment, and
(e) a step of subjecting the slurry withdrawn from the tower lower compartment to solid-liquid separation into water and the terephthalic acid crystal, and drying the separated terephthalic acid crystal, wherein when a throughput of the crystal subjected to the catalytic hydrogenation treatment is Q [ton/hr], and residence time in a first-stage crystallization vessel of the two or more stages of crystallization vessels is T.sub.1 [hr], and a cross-sectional area of the mother liquor replacement tower is A [m.sup.2], following conditions (1) to (3):

0.07T.sub.10.5(1)

0.3A/Q0.8(2)

0.035T.sub.1A/Q0.25(3)

are all satisfied. In the method for producing high-purity terephthalic acid, mother liquor replacement is efficiently performed, the heating load during the step of drying the purified terephthalic acid cake after the solid-liquid separation is small, and terephthalic acid that exhibits good behavior as a starting material of polyester can be produced.

Compositions and methods for the isolation of protein-nucleic acid complexes, extracellular vesicle (EV) (e.g., microvesicles) and free nucleic acids (collectively referred to as bioparticles) released by mammalian cells into body fluids or cell culture media are provided. Isolated bioparticles of the current disclosure contain biomolecules that are useful as diagnostic/prognostic biomarkers or for identification of therapeutic targets (e.g., disease or disorder-associated miRNAs, circulating tumor DNA). Isolation of biomolecules results in purification and concentration. Methods for producing biofluids without detectable bioparticles, largely depleted of bioparticles, and/or possessing a reduced concentration of bioparticles compared to a biofluid starting material (collectively termed bioparticle-depleted) are provided. Bioparticle-depleted biofluid is useful, e.g., in experimental systems where desirable to obtain a biofluid lacking or substantially depleted of endogenous bioparticles from the source material. Non-toxic bioparticle absorbing materials (e.g., exosome-reducing materials) can also be used for prophylactic, therapeutic, validation and/or experimental purposes.

A method for forming, or crystallising, clathrates hydrates of a host molecule in a liquid including water includes the following consecutive steps: cooling the liquid to a temperature no higher than the crystallisation temperature of the clathrates hydrates; and placing the cooled liquid in contact with host molecules that are capable of forming clathrates hydrates and are adsorbed on a solid support that has a large specific surface area and is made of a hydrophobic and apolar material, whereby the host molecules are desorbed from the solid support that has a large specific surface area and is made of a hydrophobic and apolar material, and react with the water of the liquid in order to provide a liquid containing clathrates hydrates and the solid support.

The present invention provides an industrial method production of amorphous posaconazole. The present invention also relates to a method for production of the posaconazole via and novel crystalline forms of posaconazole intermediate. More particularly the present invention relates to novel crystalline forms of posaconazole intermediate and methods for production of novel crystalline forms of posaconazole intermediate represented by the following structural formula III Which is key intermediate in the production of posaconazole. The present invention also provides for the one pot process for the preparation of amorphous posaconazole using novel crystalline forms of benzyl posaconazole.

##STR00001##

A method is disclosed for purifying, by direct osmosis, a first liquid including water and at least one impurity, in which the method comprises the consecutive steps of: contacting the first liquid with a first side of a semi-permeable membrane, a second aqueous liquid containing an osmotic agent being in contact with the second side of the semi-permeable membrane, whereby water is extracted by direct osmosis from the first liquid through the semi-permeable membrane and passes into the second liquid containing the osmotic agent; forming clathrates hydrates of a host molecule in the second liquid containing the osmotic agent into which the water has passed; separating the clathrates hydrates from the second liquid containing the osmotic agent; and dissociating the separated clathrates hydrates to obtain pure water and the host molecule.

The present invention provides a crystal of reduced glutathione that is stable, and is easy to process, and a method for producing the crystal. According to the present invention, a crystal of a metal salt of reduced glutathione is produced by suspending an amorphous solid of a metal salt of reduced glutathione in a hydrophobic organic solvent, and adding water to the resulting suspension to precipitate a crystal of a metal salt of reduced glutathione.