EP2493867A1 - Procédé de fabrication d'une forme cristalline a de linézolide - Google Patents

Procédé de fabrication d'une forme cristalline a de linézolide

Info

Publication number
EP2493867A1
EP2493867A1 EP10773295A EP10773295A EP2493867A1 EP 2493867 A1 EP2493867 A1 EP 2493867A1 EP 10773295 A EP10773295 A EP 10773295A EP 10773295 A EP10773295 A EP 10773295A EP 2493867 A1 EP2493867 A1 EP 2493867A1
Authority
EP
European Patent Office
Prior art keywords
linezolid
process according
antisolvent
solution
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP10773295A
Other languages
German (de)
English (en)
Inventor
Raymond Jozef Hubertus Westheim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2009/007919 external-priority patent/WO2011050826A1/fr
Application filed by Synthon BV filed Critical Synthon BV
Priority to EP10773295A priority Critical patent/EP2493867A1/fr
Publication of EP2493867A1 publication Critical patent/EP2493867A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2

Definitions

  • the present invention relates to an improved process for making the compound linezolid, especially in its specific crystalline form called Form A.
  • Linezolid is a pharmaceutically active compound useful as an antibacterial agent, e.g. for the treatment of diabetic food infections caused by Gram-positive bacteria. It is represented by the formula (I).
  • the marketed pharmaceutical compositions are a sterile isotonic solution for an i.v. infusion, a tablet for oral administration and an aqueous suspension for oral administration. They are marketed, i.e., under brand name ZYVOX by Pfizer.
  • the molecule of linezolid has one asymmetric carbon in the molecule allowing for 2 enantiomers; the marketed compound is the (S)-enantiomer.
  • linezolid is present as a free base.
  • the Form III was obtained in the original WO 2005/035530, e.g., by heating linezolid at
  • the WO 2009/063505 obtained the crystalline linezolid (which corresponds to the Form III by evaluating of the disclosed XRPD pattern) by crystallization from various polar aprotic organic solvents, preferably from dioxane/di-isopropyl ether mixture, or by a rapid
  • WO 2005/035530 appeared to be identical with the product of WO 95/07271 (Form I) during prosecution.
  • Form A solid state form of linezolid resulting from the processes described in the present application is denoted Form A throughout the specification and is defined by its X-ray powder diffraction (XRPD) data. In respect to the prior art, it can either correspond to previously denoted Form I or to Form III.
  • the present invention relates to the discovery of a new process for making the crystalline linezolid, in particular the Form A of linezolid, as defined hereinafter, which process is useful in a reliable production on an industrial scale.
  • the process is characterized by a rapid and controlled precipitation of the solid linezolid from a solution thereof in an organic solvent by means of an antisolvent kept at a preselected temperature.
  • a process for crystallizing linezolid, especially in the crystalline Form A comprising a step of dissolving linezolid in an organic solvent to obtain a solution followed by a step of adding the obtained solution into an antisolvent kept at a pre-selected temperature and, optionally, seeded with crystals of the desired crystalline form of linezolid, especially linezolid Form A.
  • the formed linezolid Form A is substantially free from other solid state forms of linezolid, particularly from the Form II and/or from hydrated forms.
  • the organic solvent is selected from an aliphatic alcohol, a cyclic ether or an aliphatic ester and mixtures thereof.
  • the organic solvents are essentially anhydrous.
  • the antisolvent is a] an aliphatic hydrocarbon, which preferably is a hexane such as n-hexane, a heptane such as n-heptane, a cyclohexane and/or petroleum ether; b] an aliphatic ether, which preferably is methyl-tert.butyl ether; and mixtures thereof.
  • the temperature of the solution is within the range from 50°C up to the reflux temperature.
  • a first preferred aspect of the process of the invention is the pre-selected temperature of the antisolvent within the range from -20°C to +25°C, preferably at a temperature lower than 0°C.
  • the pre-selected temperature of the antisolvent less than 15°C, preferably less than 10°C lower than the boiling temperature of the antisolvent and is preferably higher than 80°C.
  • the process of the present invention based on a technique in which a hot solution of linezolid in a solvent is brought into a contact with an anti-solvent (i.e. with a liquid in which the linezolid is practically insoluble) at a defined, pre-determined temperature with a defined, pre-determined speed, and optionally, in the presence of seeds of the desired crystalline form of linezolid , allows to form crystals of linezolid under reliable and well controllable conditions, which are particularly important in a large scale production.
  • an anti-solvent i.e. with a liquid in which the linezolid is practically insoluble
  • the process of the present invention is particularly useful for making the crystalline Form
  • the "Form A" of linezolid is a crystalline form of linezolid that is characterized by a XRPD powder diffraction pattern comprising , inter alia, the peaks at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees 2 theta ( ⁇ 0.2 degrees 2 theta) .
  • XRPD powder diffraction pattern comprising , inter alia, the peaks at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees 2 theta ( ⁇ 0.2 degrees 2 theta) .
  • the XRPD pattern of the Form A obtained by the process of the present invention substantially corresponds to that as disclosed for the Form III in
  • the Form A of linezolid produced by the process of the present invention has an excellent batch-to-batch uniformity in the size and shape of the formed crystals. Importantly, the process provides for crystals of a relatively small average size, which is advantageous and very suitable property for formulation into pharmaceutical compositions.
  • the linezolid Form A crystals produced by the process of the present invention are advantageously substantially free from other crystalline forms of linezolid, particularly from the Form II of linezolid, which can be otherwise very easily formed by any process of "classical crystallization".
  • the "substantially free” means that less than 10%, and advantageously less than 5% of other crystalline forms are present in the precipitated and/or isolated product comprising the Form A of linezolid.
  • the linezolid starting material useful for making the solution can be in any physical form of linezolid base including the hydrated forms, in any degree of purity.
  • the starting linezolid can also be crude linezolid that is present in the reaction mixtures obtained after the chemical synthesis of linezolid (an example is, e.g., WO 95/07271) or after liberation of linezolid base from a linezolid salt. Processes for obtaining linezolid and its isolated forms are well known in the art.
  • the solvent is an organic solvent.
  • the solvent is essentially anhydrous, i.e. it does not comprise water or may comprise only traces of water. This is because of a risk of forming linezolid hydrates, which should be limited or avoided.
  • the organic solvent is advantageously a polar organic solvent, more advantageously that of having less than 10 carbon atoms; suitable examples comprise, alone or in an admixture: an aliphatic ester, e.g. ethyl acetate, an aliphatic alcohol, e.g. methanol, ethanol, 1-propanol, isopropanol or 1-butanol, a cyclic ether, e.g. 1,4-dioxane.
  • the solution is provided by dissolving linezolid in the solvent preferably at an enhanced temperature.
  • the solution may be filtered hot to remove undesired solid particles, optionally in the presence of a surface active material, e.g. activated carbon, for to improve colour and clarity of the solution.
  • a surface active material e.g. activated carbon
  • the obtained solution is contacted with the antisolvent, which is kept at a pre-selected temperature.
  • the useful antisolvent is a liquid, in which the linezolid is essentially insoluble.
  • the antisolvent comprises an aliphatic and/or alicyclic hydrocarbon, preferably the hydrocarbon with 5 to 10 carbon atoms, or an aliphatic ether, preferably that of 4 to 10 carbon atoms.
  • the antisolvent is a hexane such as n-hexane, a heptane such as n-heptane, a cyclohexane, methyl- tert. -butyl ether and/or petroleum ether, and mixtures thereof.
  • the antisolvent is free from the traces of water.
  • the process of the present invention can be essentially performed by two techniques: a) Contacting with a cold antisolvent with seeding
  • the enhanced temperature at which the solution of linezolid in the solvent is provided, comprises any temperature within the range from 50°C up to the reflux temperature.
  • the suitable concentration of linezolid in the solvent is so selected that the solution can be kept at the chosen temperature without any danger of nucleation at said temperature.
  • concentration comprises a range of between 2- 100 ml of the solvent per 1 gram of linezolid.
  • the antisolvent Prior to any addition of the linezolid solution, the antisolvent is temperated and kept cold at a predetermined temperature below +25° C under stirring. Typically, the temperature of the antisolvent is within the range between -20°C to +25°C, preferably between -15 and 0°C.
  • the mutual ratio between the antisolvent and the solvent is from 1 : 1 to 10:1 (v/v), advantageously from 2: 1 to 7: 1 (v/v).
  • the antisolvent is seeded with seeds of the desired Form A of linezolid. These seeds may be obtained by heating linazolid (produced following US 5,688,792) at 130°C to 140°C under nitrogen atmosphere for 4 hours). This is important as no spontaneous nucleation is allowed. Typically, the relative amount of the seeds in respect to the weight of the linezolid in the solution is 1- 25 %. Seeds of other crystalline forms of linezolid, such as seeds of linezolid Form I and Form III, may be obtained using processes known in the art.
  • the rate of the addition of the solution into the antisolvent is not specifically limited and is advantageously so selected that the whole volume of the solution is poured into the stirred antisolvent in 30 minutes or less. Care is to be taken that the cooling speed is sufficient to maintain the temperature of the formed mixture at the predetermined value.
  • the actual temperature during the period of contacting the solution with the antisolvent does not exceed +5°C from the predetermined temperature. Care is also to be taken that the nucleation does not start prior to the contact of the solution with the antisolvent.
  • the pipelines and valves coming into the contact with the hot solution should be advantageously pre-heated to a suitable temperature.
  • the order of contacting the solution with the antisolvent cannot be reversed, i.e. the antisolvent may not be added to the hot solution.
  • the linezolid rather precipitates as the Form II.
  • the precipitate is formed practically immediately after contacting of both fluids.
  • the precipitate comprises small and uniform particles of the Form A of linezolid. If the above process conditions are met, the precipitate comprises the product, which is essentially free from the Form II of linezolid and/or from any hydrated form thereof.
  • the precipitated product can be isolated from the mixture by conventional techniques, e.g. filtering or centrifugation, and can be washed, preferably by a fresh antisolvent, and dried. b) contacting with a hot antisolvent, preferably without seeding
  • linezolid When linezolid is dissolved in an alcoholic solvent, particularly in a propanol or butanol solvent (e.g. in 1 -propanol or 1 -butanol) at a reflux temperature, whereby a very concentrated solution of linezolid, e.g of more than 100 mg/ml and typically of about 200-400 mg/ml, is obtained, it is advantageous that such concentrated solution is contacted with the antisolvent at a near-to-reflux temperature.
  • near-to-reflux temperature is less than 15 degrees Celsius, preferably less than 10 degrees Celsius lower than is the boiling temperature of the antisolvent.
  • the temperature both of the solvent and of the antisolvent is higher than 80°C.
  • n-heptane when used as the antisolvent, it is typically temperated to about 90°C prior to contacting with the hot linezolid solution.
  • the antisolvent is advantageously used in a volume ratio from 1 : 1 to to 10: 1
  • the rate of the addition of the solution into the antisolvent is not specifically limited and is advantageously so selected that the whole volume of the solution is poured into the stirred antisolvent in 30 minutes or less. Care is to be taken as the reaction mixture may temporarily boil during the mixing.
  • the suspension is then cooled to a temperature of 25°C or less, whereby the rate of cooling is not specifically prescribed, and is kept at this temperature preferably for a period not exceeding 3 hours.
  • the solid material is isolated from the mixture by conventional techniques, e.g. filtering or centrifugation, and can be washed, preferably by a fresh antisolvent, and dried.
  • This technique may be also modified in such a way that when linezolid is present as a solution in a solvent, which is other than the alcoholic solvent (e.g. an ethyl acetate reaction mixture after making the linezolid by a synthesis) , it is advantageous to replace the solvent by the alcoholic solvent .
  • the original reaction solvent may be distilled off and replaced by the corresponding amount of the alcohol.
  • the linezolid Form A prepared by the process of the present invention can be formulated and used in pharmaceutical compositions.
  • a suitable pharmaceutical composition may comprise the linezolid Form A and at least one pharmaceutically acceptable excipient.
  • excipients are known in the art and include carriers, diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste masking agents, sweeteners, flavorants, plasticizers, and any acceptable auxiliary substances such as absorption enhancers, penetration enhancers, surfactants, co-surfactants, and specialized oils.
  • the proper excipient(s) are selected based in part on the dosage form, the intended mode of administration, the intended release rate, and manufacturing reliability. Examples of common types of excipients include various polymers, waxes, calcium phosphates, sugars, etc.
  • Polymers include cellulose and cellulose derivatives such as HPMC, hydroxypropyl cellulose, hydroxy ethyl cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and ethylcellulose; polyvinylpyrrolidones; polyethylenoxides;
  • polyalkylene glycols such as polyethylene glycol and polypropylene glycol
  • polyacrylic acids including their copolymers and crosslinked polymers thereof, e.g., Carbopol ® (B.F.
  • Waxes include white beeswax, microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl behenate, glycerylpalmito stearate, and saturated polyglycolyzed glycerate.
  • Calcium phosphates include dibasic calcium phosphate, anhydrous dibasic calcium phosphate, and tribasic calcium phosphate.
  • Sugars include simple sugars, such as lactose, maltose, mannitol, fructose, sorbitol, saccharose, xylitol, isomaltose, and glucose, as well as complex sugars (polysaccharides), such as maltodextrin, amylodextrin, starches, and modified starches.
  • the compositions may be formulated into various types of dosage forms, for instance as solutions or suspensions for parenteral or oral administration, as tablets or capsules for oral administration, ointments or lotions for transdermal administration etc. The above lists of excipients and forms are not exhaustive.
  • the linezolid Form A prepared by the process of the present invention is useful as antibacterial agent, in treating various diseases caused by some types of bacteria, by
  • the effective amounts range from 1 mg to 500 mg, expressed as the amount of linezolid base, per day.
  • Linezolid Form II (0.5 g) is dissolved in 20 ml of ethyl acetate at reflux. The hot solution is dropwise added, through a funnel preheated to 100°C, into 100 ml of n-heptane stirred at -10°C and containing 50 mg of linezolid Form A seeds. After 20 minutes of stirring at a temperature between -10 and 0° C, the suspension is filtered. The solid is washed with n-heptane and dried on air at room temperature. Yield: 0.32 g.
  • Linezolid Form II (0.5 g) is dissolved in 20 ml of ethanol at reflux. The hot solution is dropwise added, through a funnel preheated to 100°C, into 100 ml of n-heptane stirred at -10°C and containing 50 mg of linezolid Form A seeds. After 10 minutes of stirring at a temperature between -10 and 0°C, the suspension is filtered. The solid is washed with n-heptane and dried on air at room temperature. Yield: 0.50 g.
  • Linezolid Form II (0.5 g) is dissolved in 20 ml of 2-propanol at reflux. The hot solution is dropwise added, through a funnel preheated to 100°C, into 50 ml of n-heptane stirred at -10°C and containing 50 mg of linezolid Form A seeds. After 10 minutes of stirring at a temperature between -10 and 0° C, the suspension is filtered. The solid is washed with n-heptane and dried on air at room temperature. Yield: 0.50 g.
  • Linezolid Form III (WO 2005/035530) was dissolved in 10 ml of 1-propanol at reflux. The hot solution was added slowly but at once to 10 ml of hot n-heptane, stirred at 90°C and containing approximately 25 mg of Linezolid Form A as seeds. The suspension was rapidly cooled down to 0°C using ice-water and stirred at 0°C for about 2.5 hour. The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with n-heptane and vacuum-dried over weekend at 40°C. The yield was 1.80 g (90%).
  • Linezolid Form III (WO 2005/035530) was dissolved in 5 ml of 1-butanol at reflux. The hot solution was added slowly but at once to 10 ml of hot n-heptane, stirred at 90°C (containing no seeds of Form A. As a result, a solid was formed. The suspension was rapidly cooled down to 0°C using ice-water (took about 5 minutes) and stirred at 0°C for about 1 hour. The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with n-heptane and vacuum-dried overnight at 40°C. The yield was 1.83 g (92%).
  • Linezolid Form III (WO 2005/035530) was dissolved in 250 ml of 1-butanol at reflux. The hot solution was added slowly to 500 ml of hot n-heptane, mechanically stirred at 90°C (200 rpm). The anti-solvent was not seeded prior to mixing. The suspension was cooled down to 20°C using a water bath and stirred at 20°C for 30-60 min (150 rpm). The solid was isolated by filtration over a P3 -glass filter (reduced pressure), washed with n-heptane and vacuum-dried overnight at 40°C. The yield was 97.32 g (97%).
  • the solid was isolated by filtration over a P3 -glass filter (reduced pressure), washed with n-heptane and vacuum-dried overnight at 40°C. Off-white, shiny crystals were obtained. The yield was 1.78 g (89%).
  • Step II Crystallization of linezolid Form A.
  • the solution from the Step I comprising a solution of approximately 2.0 g of crude linezolid in 130 ml of ethyl acetate was heated to reflux. At reflux, 10 ml of 1-butanol was added. Then, ethyl acetate was distilled off, leaving a concentrated yellow solution in 1-butanol with a small residual amount of ethyl acetate.
  • This hot solution was slowly added to 10 ml of n-heptane, stirred at 90°C. To the mixture, a few mg of linezolid Form A and 10 ml of hot n-heptane was added. As a result, slow crystallisation took place.
  • the mixture was rapidly cooled to 0°C and stirred at 0°C for about 10 minutes, during which more solid crystallised.
  • the solid was isolated by filtration over a P3 -glass filter (reduced pressure), washed with n-heptane and vacuum-dried overnight at 40°C. The yield was 1.65 g (about 67.5%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé de fabrication d'un linézolide cristallin, comprenant une étape de dissolution du linézolide dans un solvant organique pour obtenir une solution faisant suivre par une étape d'addition de la solution obtenue dans un antisolvant maintenu à une température présélectionnée et facultativement ensemencé par des cristaux de la forme cristalline désirée du linézolide.
EP10773295A 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide Ceased EP2493867A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10773295A EP2493867A1 (fr) 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
PCT/EP2009/007919 WO2011050826A1 (fr) 2009-10-28 2009-10-28 Procédé de fabrication d'une forme cristalline de linézolide
PCT/EP2010/001214 WO2011050865A1 (fr) 2009-10-28 2010-02-23 Procédé pour la fabrication de la forme cristalline a du linézolide
EP10773295A EP2493867A1 (fr) 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide
PCT/EP2010/066348 WO2011051384A1 (fr) 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide

Publications (1)

Publication Number Publication Date
EP2493867A1 true EP2493867A1 (fr) 2012-09-05

Family

ID=43242710

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10773295A Ceased EP2493867A1 (fr) 2009-10-28 2010-10-28 Procédé de fabrication d'une forme cristalline a de linézolide

Country Status (1)

Country Link
EP (1) EP2493867A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035530A1 (fr) 2003-10-16 2005-04-21 Symed Labs Limited Nouvelle forme cristalline du linezolid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035530A1 (fr) 2003-10-16 2005-04-21 Symed Labs Limited Nouvelle forme cristalline du linezolid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2011051384A1

Similar Documents

Publication Publication Date Title
JP2014530805A (ja) アジルサルタンの結晶形並びにその製造及び使用
WO2011051384A1 (fr) Procédé de fabrication d'une forme cristalline a de linézolide
EP3248983B1 (fr) Forme cristalline a de l'acide obéticholique et son procédé de préparation
RU2577334C2 (ru) КРИСТАЛЛИЧЕСКАЯ ФОРМА МОНОГИДРАТА ГИДРОХЛОРИДА (R)-7-ХЛОР-N-(ХИНУКЛИДИН-3-ИЛ)БЕНЗО[b]ТИОФЕН-2-КАРБОКСАМИДА
EP1919893A2 (fr) Formes polymorphes de mésylate d'imatinibe et procédés de préparation de nouvelles formes cristallines et amorphes et de forme
US20090298947A1 (en) Polymorphic and amorphous forms of lacosamide and amorphous compositions
US11174240B2 (en) Crystalline solid compound of 3-phenyl-4-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol hydrochloride
WO2006110155A1 (fr) Formes solides du linezolide et leurs procedes de preparation
AU2014225392A1 (en) Crystalline forms of D-glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3, 5-difluoropyridine-2-yl)-8-chloro-6-fluoro-1, 4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate
JP2015508090A (ja) 固体形態のダビガトランエテキシレートメシレート及びその調製方法
CN111278808B (zh) 2-(5-(4-(2-吗啉代乙氧基)苯基)吡啶-2-基)-n-苄基乙酰胺的固体形式
JP2005529933A (ja) キサンチンホスホジエステラーゼｖインヒビター多形体
JP2018537486A (ja) キノロン類似体及びその塩の結晶形
EP2032544A1 (fr) Formes cristallines du létrozole et leurs procédés de fabrication
CA2528100A1 (fr) Formes polymorphes de ziprasidone chlorhydrate et procedes pour leur elaboration
US20030004154A1 (en) New crystal forms of oxcarbazepine and processes for their preparation
JP5918856B2 (ja) （１，１−ジオキソ−４−チオモルホリニル）−［６−［［３−（４−フルオロフェニル）−５−メチル−４−イソオキサゾリル］メトキシ］−３−ピリジニル］−メタノンの固体形態
JP6785523B2 (ja) ナトリウム−グルコース共輸送体２阻害剤の結晶形
TWI399374B (zh) 新穎晶體形式及製備方法以及其醫藥組合物
WO2012119653A1 (fr) Procédé de préparation de la forme cristalline a du linézolid
EP2493867A1 (fr) Procédé de fabrication d'une forme cristalline a de linézolide
US20240239791A1 (en) Processes for the synthesis of valbenazine
KR20230004723A (ko) 프탈라지논 화합물의 결정형
WO2011029460A1 (fr) Sels non hygroscopiques de linézolide
JP2016540001A (ja) ステロイド様化合物の多形形態並びにその製造方法及びその用途

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120529

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20130408

TPAC Observations by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

REG Reference to a national code

Ref country code: DE

Ref legal event code: R003

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20150829