Hovione Scientia Limited

Hovione Inter Limited

Hovione International Limited

Hovione Inter Ag

Luis Sobral

Rafael Antunes

Nuno Torres Lourenço

William Heggie

Marcio Temtem

Maria Santos

Joana Fernandes

Margarida Espadinha

Peter Villax

Filipe Gaspar

Constanca Cacela

Jose Rafael Antunes

Dionisio Martin

Constança Cacela

Márcio Temtem

Eunice Costa

Emilia Leitäo

Bruna Nunes

Emilia Leitao

Alexandre Carvalho

Livia Santana De Arruda

Margarida Figueiredo

Ana Paula Filipe

Nuno Torres LOURENÇO

Temtem Marcio

Jose Refael Antunes

Emilia Leitão

The present invention relates to an amorphous form of vilanterol trifenatate, processes for its preparation and its use in pharmaceutical formulations for the treatment of respiratory diseases, particularly for the treatment of asthma and chronic obstructive pulmonary disease. In particular, the invention relates to an amorphous form of vilanterol trifenatate, characterized by the X-ray powder diffraction (XRPD) pattern, obtained using copper K-alpha1 radiation.

Amorphous form of vilanterol trifenatate and processes for the preparation thereof

The present invention discloses processes comprising a) reacting ethyl isonipecotate with 1-bromo-2-chloroethane in the presence of an organic base in a solvent to form ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) or a salt thereof. Process step a) may be included in a process for preparing umeclidinium bromide that comprises further process steps: b) reacting ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) or a salt thereof with lithium diisopropylamide in a solvent to form ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III); c) reacting ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (III) with phenyl lithium in a solvent to form 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV); and d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV) with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide. A process comprising d) reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol with ((2-bromoethoxy)methyl) benzene in a solvent to form 4-[hydroxyl(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2]octane bromide (I), umeclidinium bromide, wherein the solvent is selected from cyclic ethers such as tetrahydrofuran, aromatic solvents, such as toluene, ketones such as acetone and protic solvents such as water or combinations thereof, optionally wherein the solvent is water is also disclosed. Umeclidinium bromide obtainable from the disclosed processes, ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (II) and pharmaceutical compositions are also disclosed.

Process for the preparation of umeclidinium bromide

The present invention relates to new crystalline forms of vilanterol trifenatate, processes for their preparation, and their use in a pharmaceutical composition for the treatment of respiratory diseases, particularly for the treatment of asthma and chronic obstructive pulmonary disease. In particular, the present invention relates to a crystalline form of vilanterol trifenatate characterised in that the form has an XRPD pattern as defined herein having characteristic diffraction angles (2-theta or 20 (&#xb0;)) falling within or at each end of one or more of the following ranges: (a) 3 to 5&#xb0;, such as 3.8 to 4.4&#xb0;; and/or (b) 7 to 9.9&#xb0;, such as 7 to 8.5&#xb0;; and/or (c) 12 to 13.3&#xb0;, such as 12 to 13.3'; and/or (d) 16.4 to 17.3&#xb0;, such as 16.4 to 17.3&#x2032;; and/or (e) 26.8 to 28.3&#xb0;, such as 26.8 to 28.3&#xb0;.

Crystalline forms of vilanterol trifenatate and processes for their preparation

A tetracycline salt comprising a tetracycline and an organic acid wherein the organic acid is oxalic acid or maleic acid is provided. The tetracycline is preferably doxycycline, minocycline, sancycline, lymecycline, tetracycline or demeclocycline, and preferred salts include oxycycline maleate, minocycline oxalate, tetracycline oxalate, demeclocycline maleate, demeclocycline oxalate, sancycline maleate, lymecycline maleate, or lymecycline oxalate. A pharmaceutical formulation comprising a tetracycline salt according to the invention is also provided, as is a medical device having coated thereon a salt or pharmaceutical formulation according to the invention. A salt of the invention, or a formulation of the invention are also provided for use as medicaments, particularly for use in the treatment or prevention of an inflammation and/or an infection. There is also provided a method of preparing a tetracycline salt, which method comprises reacting a tetracycline base with an excess of an organic acid in a solvent.

Salts of tetracyclines

A new scalable process to control the particle size and the particle size distribution, comprising 5 steps: (i) suspension preparation in a mixture of solvents in which the API and/or excipient is partially soluble in one of the solvents; (ii) particle size reduction of the suspension; (iii) aging; (iv) stopping the aging by solvent removal; and (v) optionally, a step of isolating the processed ingredients in the form of powder.

Assisted particle size reduction process

A process for preparing compounds of formula [II] by esterification of the C-17 hydroxyl group of 6&#x3b1;,9&#x3b1;-difluoro-11&#x3b2;,17&#x3b1;-dihydroxy-16&#x3b1;-methyl-3-oxoandrosta-1,4-diene-17&#x3b2;-carbothioic acid, the compound of formula [I] comprises treating compound [I] with a slight excess of an acyl chloride of general formula R&#x2014;COCl, where R represents &#x2014;CH2CH3, &#x2014;CH2CH2CH3 or &#x2014;CH(CH3)2, in an inert solvent, in the presence of a tertiary amine.  Preferably the process is carried out using pyridine in the presence of acetone at a temperature of from 5&#xb0; C. to &#x2212;20&#xb0; C.

Process for the esterification of a carbothioic acid

The present invention relates to a novel process for the preparation of tiotropium bromide there is provided a process for preparing tiotropium bromide comprising (i) reacting scopine oxalate with diethylamine in an inert solvent to form scopine; (ii) reacting scopine and methyl di-(2-dithienyl)glycolate (MDTG) in the presence of an inorganic base, and in an inert solvent to form N-demethyltiotropium; (iii) reacting N-demethyltiotropium with bromomethane in an inert solvent to form tiotropium bromide; (iv) crystallizing tiotropium bromide in a mixture of methanol and acetone, and optionally thereafter, (v) micronizing the tiotropium bromide so formed.

Process for preparing tiotropium bromide

A process for obtaining 21-disodium phosphate pregnane derivative compounds of formula (I), wherein X&#x2550;R&#x2550;H or X&#x2550;F and R=&#x3b1;-CHor X&#x2550;F and R=&#x3b2;-CH: comprises spray drying a solution comprising compound of formula (I). 

Process for obtaining steroidal phosphate compounds

A process for the purification of roxithromycin, an antibiotic for therapeutic purposes, in which the purification is carried out by the dissolution or suspension of the product in methanol followed by cooling. Purification may also be obtained by addition of a non-solvent and/or by concentration of the mixture, thus obtaining a purified product.

Process for the purification of roxithromycin

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Loures, Portugal

Luis Sobral