EP2526089A2 - A method of industrial production of an amorphous form of atorvastatin with a high specific surface area and its use in a dosage form - Google Patents

A method of industrial production of an amorphous form of atorvastatin with a high specific surface area and its use in a dosage form

Info

Publication number
EP2526089A2
EP2526089A2 EP11707780A EP11707780A EP2526089A2 EP 2526089 A2 EP2526089 A2 EP 2526089A2 EP 11707780 A EP11707780 A EP 11707780A EP 11707780 A EP11707780 A EP 11707780A EP 2526089 A2 EP2526089 A2 EP 2526089A2
Authority
EP
European Patent Office
Prior art keywords
atorvastatin
solvent
specific surface
surface area
amorphous
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.)
Withdrawn
Application number
EP11707780A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jan Stach
Martin Holan
Jaroslav Havlicek
Stanislav Simek
Jan Linek
Hana Brusova
Stanislav Radl
Michaela Dubovska
Alena Prokopova
Jaroslav Riha
Pavel Sebek
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.)
Zentiva KS
Original Assignee
Zentiva KS
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
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP2526089A2 publication Critical patent/EP2526089A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention deals with an amorphous form of the hemicalcium salt of (3R,5R) 7-[3- phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropylpyrrol-l-yl]-3,5- dihydroxyheptanoic acid (atorvastatin of formula I) with a high specific surface area, based on controlled precipitation, and its use in a medicament dosage form.
  • Atorvastatin of formula I is an important representative of hypolipidemic and hypocholesteric drugs and is the object of a number of patents.
  • amorphous atorvastatin is spray drying of a solution of atorvastatin in a suitable solvent using an inert carrier gas, e.g. nitrogen, described in CZ patent application No. 2005-94.
  • an inert carrier gas e.g. nitrogen
  • amorphous atorvastatin is also obtained in accordance with applications of Lek (WO 01/42209 Al), Ranbaxy (WO 00/71116 Al), Biocon (WO 02/057228 Al), Cadila (WO 02/08367 Al ; WO 02/08368 Al) and Morepen (WO 03/018547 A2).
  • Lek WO 01/42209 Al
  • Ranbaxy WO 00/71116 Al
  • Biocon WO 02/057228 Al
  • Cadila WO 02/08367 Al ; WO 02/08368 Al
  • Morepen WO 03/018547 A2
  • the opposite possibility is also mentioned when into a solvent in which atorvastatin does not dissolve at all or in a limited way only (anti-solvent) a solution of atorvastatin in a suitable solvent is added dropwise (WO 02/057228 Al, CZ 2002-413).
  • a concentrated solution of atorvastatin in a suitable solvent is not obtained by dissolution of crystalline or semi-crystalline atorvastatin, but is obtained directly in the last reaction stage of atorvastatin production (CZ 2002-413, WO 03/018547 A2).
  • This invention describes a new, improved method of production of an amorphous form of the hemicalcium salt of (3R,5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5- isopropylpyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (atorvastatin I) with a high specific surface area suitable for industrial use, which would not exhibit the above mentioned disadvantages, and its use in a dosage form.
  • the invention consists in an amorphous calcium salt of (3R,5R) 7-[3-phenyl-4- phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropylpyrrol-l-yl]-3,5-dihydroxyheptanoic acid, known under the non-proprietary name atorvastatin, of formula I with a high specific surface area.
  • Another aspect of the invention provides a pharmaceutical composition containing amorphous atorvastatin of formula I with a high specific surface area as characterized above.
  • the composition with thus defined active substance allows a release rate of atorvastatin of formula I higher than 75% by weight in 15 minutes. In a preferable formulation more than 85% by weight in 15 minutes can be achieved.
  • An important aspect of the invention also provides a new production method of this amorphous form of the hemicalcium salt of (3i?,5i?)7-[3-phenyl-4-phenylcarbamoyl-2-(4- fluorophenyl)-5-isopropylpyrrol-l-yl]-3,5-dihydroxyheptanoic acid with a high specific surface area, suitable for industrial use, based on precipitation and optimized isolation.
  • This entire procedure consists in:
  • Suitable solvents are those where the solubility of the atorvastatin calcium salt is equal to or higher than 5 g in 1 1.
  • Suitable solvents for obtaining an atorvastatin solution include especially esters of carboxylic acids, ethers, including cyclic ethers, alcohols, nitriles, chlorinated solvents, ketones.
  • Especially suitable solvents include esters of the RCOOR 1 type wherein R is an alkyl, e.g. methyl or ethyl, or hydrogen and R 1 is an alkyl, e.g. methyl, ethyl or isopropyl.
  • R is an alkyl, e.g. methyl or ethyl, or hydrogen and R 1 is an alkyl, e.g. methyl, ethyl or isopropyl.
  • ethers tetrahydrofuran, tert-butyl methyl ether or dioxane are the most suitable ones.
  • the most suitable alcohols are methanol, ethanol, isopropyl alcohol, n-butanol.
  • Out of nitriles acetonitrile is the most suitable one.
  • the most convenient ketones are acetone, ethyl methyl ketone, methyl isobutyl ketone.
  • Suitable anti-solvents include those where the solubility of atorvastatin is lower than 1 g per litre.
  • Alkanes, especially pentane, hexane and its isomers, or heptane are especially suitable ones.
  • Suitable ethers include diethyl ether, diisopropyl ether or their mixtures.
  • the overall specific surface area S g of the product is in the range of 40 to 67 m 2 /g and its dissolution characteristics are much more favourable than those of the amorphous product isolated under the previously described conditions.
  • Measurement of the specific surface area of the amorphous product depending on the drying of residual solvents and on the composition of the solution used for precipitation has revealed surprising correlation with the content of residual solvents in the filter cake before drying of the final product. At the same time it has turned out that a higher specific surface area facilitates the drying since the proportion of glass particles that close solvents in their structure decreases.
  • the solvent/anti-solvent ratio in the filter cake is reduced below 5% by washing with the anti-solvent.
  • composition A3 The total specific surface area was determined from the measured data of nitrogen physisorption at three different partial pressures in the area of validity of the BET equation and at the temperature of 77 K.
  • composition A3 A pharmaceutical composition containing atorvastatin of formula I with a high specific surface area as described above significantly differs in its characteristics from known pharmaceutical compositions with amorphous atorvastatin. This difference is demonstrated in example 5.
  • Compositions Al and A2 characterize extreme values of the specific surface area of atorvastatin prepared according to the prior art, in particular CZ 2003-987. It turns out that the release rate significantly differs from one lot to another, which may even render this particular composition unusable. Using the active substance in accordance with the invention (composition A3) reproducible high values of release rate of the active substance are achieved.
  • a tablet containing the calcium salt of atorvastatin of formula I it is desirable for a tablet containing the calcium salt of atorvastatin of formula I to quickly disintegrate and release the active substance in a fast manner.
  • Fillers from the group of substances such as pre-gelatinized starch, microcrystalline cellulose, cellulose, mannitol, sorbitol, xylitol, anhydrous lactose, lactose monohydrate, calcium phosphate, hydrogen or dihydrogen calcium phosphate and the like can be used. Out of this group a mixture of lactose monohydrate and microcrystalline cellulose is preferred.
  • the basic constituent can include an organic or inorganic base, such as sodium or potassium hydroxide, meglumine, arginine, calcium, magnesium, sodium or potassium hydroxide, oxide, carbonate or hydrogen carbonate, and the like.
  • an organic or inorganic base such as sodium or potassium hydroxide, meglumine, arginine, calcium, magnesium, sodium or potassium hydroxide, oxide, carbonate or hydrogen carbonate, and the like.
  • Meglumine or magnesium oxide can conveniently be used.
  • Substances from the group of polyvinylpyrrolidones can be used as binders, for example various types of povidones, povidone 25, povidone 30, or povidone 90; copolymers of vinylpyrrolidones with other vinyl derivatives, such as povidone VA 64; microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxyl propyl cellulose, methyl cellulose or pre- gelatinized starch. Out of this group of substances the use of hydroxypropyl cellulose is preferred.
  • disintegrants from the group of substances such as maize starch, pre- gelatinized starch, low substituted hydroxypropyl methyl cellulose, microcrystalline cellulose, are used, as well as substances from the group of super disintegrants such as the sodium salt of crosscarmellose, sodium salt of carboxymethyl starch of type A, B or C, or crosspovidone.
  • a mixture of low substituted hydroxypropyl cellulose and sodium salt of crosscarmellose is preferred.
  • colloidal silicon oxide For improvement of flow characteristics substances from the group of substances such as colloidal silicon oxide, talc, and the like are used. Colloidal silicon oxide is conveniently used. A substance such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate, talc, Cutina, and the like can be used as the lubricant. Out of this group of substances magnesium stearate is mainly preferred.
  • Atorvastatin calcium salt of formula I is in the amorphous form in the tablets.
  • Atorvastatin in the form of the calcium salt of formula I is dissolved in anhydrous ethanol and, in a granulation vessel, mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose, and optionally with a portion of crosscarmellose, or with magnesium oxide or calcium carbonate.
  • This mixture is granulated with an aqueous or aqueous-alcoholic solution of meglumine, or only with water or a water/ethanol mixture.
  • the resulting granulate is dried by fluidization or on metal sheets.
  • the dried granulate is sieved to a suitable size of granules, which are subsequently additionally mixed with extragranular excipients such as magnesium stearate and colloidal silicon oxide, or a portion of crosscarmellose.
  • b/ Granulation by kneading - Atorvastatin in the form of the calcium salt of formula I is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose, and optionally with a portion of crosscarmellose, or with magnesium oxide or calcium carbonate.
  • This mixture is granulated with an aqueous or aqueous-alcoholic solution of meglumine, or only with water or a water/ethanol mixture.
  • the resulting granulate is dried by fluidization or on metal sheets.
  • the dried granulate is sieved to a suitable size of granules, which are subsequently additionally mixed with extragranular excipients such as magnesium stearate and colloidal silicon oxide, or a portion of crosscarmellose.
  • extragranular excipients such as magnesium stearate and colloidal silicon oxide, or a portion of crosscarmellose.
  • c/ Dry granulation - Atorvastatin in the form of the calcium salt of formula I is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose, and optionally with a portion of crosscarmellose, or with magnesium oxide, or meglumine.
  • the resulting mixture is compacted in a suitable compactor or compressed in a tabletting press with the use of large dies.
  • the resulting compactates are sieved to a suitable size of granules, which are subsequently additionally mixed with extragranular excipients such as magnesium stearate and colloidal silicon oxide, or a portion of crosscarmellose.
  • extragranular excipients such as magnesium stearate and colloidal silicon oxide, or a portion of crosscarmellose.
  • d/ Direct blending - Atorvastatin in the form of the calcium salt of formula I is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose, and optionally with a portion of crosscarmellose, or with magnesium oxide, or meglumine.
  • the resulting mixture is additionally mixed with extragranular excipients such as magnesium stearate and colloidal silicon oxide, or a portion of crosscarmellose.
  • the tablet substance prepared in one of the above mentioned manners is compressed to form tablets, which are coated with a layer of a film-forming substance containing plasticizers, pigments and other fillers.
  • the coated tablets are preferably adjusted in Al/Al blister packs, optionally under inert atmosphere.
  • EtOH 1 : 4.5 (wt./wt.) at a common laboratory temperature (20 to 25 °C).
  • the solutions were monitored in terms of stability for 90 to 120 min. No changes of the amorphous state of the API were registered.
  • Atorvastatin (0.3 kg) dissolved in ethyl acetate (1 1) was precipitated into pentane (7 1) with a nozzle under pressure of nitrogen, the product was isolated on a nutsch filter and washed with pentane (4 x 2.5 1). The weight ratio of ethyl acetate/pentane was 4.4%. After drying at 60 °C in vacuo 276 g of the product with the specific surface area of 54,9 m 2 /g was obtained.
  • Atorvastatin (1000 g) in crystalline modification I was dissolved in tetrahydrofuran (2.5 1). After dissolution the solution was filtered and concentrated to the volume of 1.5 1 and ethyl acetate (2 1) was added. After concentration and addition of ethyl acetate in such a way to make the content of tetrahydrofuran 3% wt. the solution was injected under the surface of the stirred anti-solvent - pentane (30 1) with a nozzle under slight overpressure. The separated product was aspirated, washed with pentane (5 x 5 1; weight ratio of ethyl acetate/pentane 3.5%) and dried in vacuo at the temperature of 25 °C for 7 days. 965 g of amorphous atorvastatin of formula I with the specific surface area of 59.6 m 2 /g was obtained.
  • the aqueous phase containing the sodium salt of atorvastatin was extracted with ethyl acetate (4 1 and 4 x 2 1).
  • the ethyl acetate extract was shaken with a solution of calcium acetate in deminerahsed water (100 g of acetate in 500 ml of water) 3 times. It was washed with deminerahsed water (2 x 500 ml) and dried with CaS0 4 (1 kg) after thorough separation of water. After 1 h of drying it was filtered, the desiccant was washed with 1 1 of ethyl acetate and the extract was concentrated to the volume of ca. 1600 ml.
  • the ethyl acetate extract - was shaken with a solution of calcium acetate in deminerahsed water (1.6 kg of acetate in 6.5 1 of water) 3 times. It was washed with deminerahsed water (3 x 5 1). After filtration the solution was concentrated to the final volume of 26 1 (water content 0.2% wt., tetrahydrofuran content 2.7% wt.) and then injected into stirred pentane (170 1) under pressure of nitrogen by means of a nozzle.
  • Example 5 In order to monitor the influence of the specific surface area of the active substance used in the formulation on the rate of dissolution from the dosage form and on the dissolution kinetics itself the method of preparing the tablet substance by direct blending has been selected.
  • the compositions of various formulations are summarized in the table below. All the percentages mentioned below are weight percentages.
  • composition %/tbl. %/tbl. %/tbl.
  • the release rate of the active substance was monitored in a dissolution device by the paddle method in the dissolution media of a 0.01 M HC1 solution at pH 2.0. Under these conditions the following amounts of the active ingredient in % wt. were released from various formulations:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
EP11707780A 2010-01-19 2011-01-12 A method of industrial production of an amorphous form of atorvastatin with a high specific surface area and its use in a dosage form Withdrawn EP2526089A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20100039A CZ201039A3 (cs) 2010-01-19 2010-01-19 Zpusob prumyslové výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) s vysokým specifickým povrchem a jeho použití v lékové forme
PCT/CZ2011/000003 WO2011088806A2 (en) 2010-01-19 2011-01-12 A method of industrial production of an amorphous form of atorvastatin with a high specific surface area and its use in a dosage form

Publications (1)

Publication Number Publication Date
EP2526089A2 true EP2526089A2 (en) 2012-11-28

Family

ID=43902821

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11707780A Withdrawn EP2526089A2 (en) 2010-01-19 2011-01-12 A method of industrial production of an amorphous form of atorvastatin with a high specific surface area and its use in a dosage form

Country Status (3)

Country Link
EP (1) EP2526089A2 (cs)
CZ (1) CZ201039A3 (cs)
WO (1) WO2011088806A2 (cs)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101858913B1 (ko) 2013-02-21 2018-05-16 화이자 인코포레이티드 고체 형태의 선택적인 cdk4/6 억제제

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4681893A (en) 1986-05-30 1987-07-21 Warner-Lambert Company Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
HRP960313B1 (en) 1995-07-17 2002-08-31 Warner Lambert Co Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1)
IL128862A (en) 1995-07-17 2007-12-03 Warner Lambert Co [R - (R * R *)] - 2 - (4 - fluorophenyl) - ß, d - dihydroxy - 5 - (1 - methyl - ethyl) 3 - phenyl - 4 - [(phenamino) carbonyl)] - 1H - Pyrol - 1 - Patenoic acid Hydrogen salt Hydrogen crystalline (Atorostatin) Crystalline hydrate
HRP960312B1 (en) 1995-07-17 2001-10-31 Warner Lambert Co NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS /R-(R*, R*)/-2-(4-FLUOROPHENYL)-"beta", "delta"-DIHYDROXY-5-PHENYL-4-/(PHENYLAMINO)CARBONYL/-1H-PYRROLE -1-HEPTANOIC ACID CALCIUM SALT (2 : 1)
IN191236B (cs) 1999-05-25 2003-10-11 Ranbaxy Lab Ltd
HU226640B1 (en) 1999-10-18 2009-05-28 Egis Gyogyszergyar Nyilvanosan Process for producing amorphous atorvastatin calcium salt
HUP0203257A3 (en) 1999-11-17 2003-05-28 Teva Pharma Polymorphic forms of atorvastatin calcium, process for their preparations and pharmaceutical compositions containing them
SI20425A (sl) 1999-12-10 2001-06-30 LEK tovarna farmacevtskih in kemi�nih izdelkov d.d. Priprava amorfnega atorvastatina
EP1301581A1 (en) 2000-07-21 2003-04-16 Cargill, Incorporated Method for removing contaminants from vegetable oil and lecithin
JP2002038174A (ja) 2000-07-24 2002-02-06 Nippon Mitsubishi Oil Corp 冷凍機油組成物
WO2002057228A1 (en) 2001-01-17 2002-07-25 Biocon India Limited Atorvastatin calcium
EP3009423A3 (en) 2001-06-29 2016-12-28 Warner-Lambert Company LLC Crystalline forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin)
US7563911B2 (en) 2001-08-31 2009-07-21 Morepen Laboratories Ltd. Process for the preparation of amorphous atorvastin calcium salt (2:1)
CZ296967B6 (cs) 2002-02-01 2006-08-16 Zentiva, A.S. Zpusob výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu)
CZ2003987A3 (cs) * 2003-04-08 2004-11-10 Zentiva A. S. Způsob výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbanioyl-2-(4- fluorfenyl)-5-isopropylpyrrol-l-yl]-3,5- dihydroxyheptanové kyseliny (atorvastatinu) vhodný pro průmyslovou výrobu a zařízení k jeho provádění
US20090124817A1 (en) * 2007-11-09 2009-05-14 The Industry & Academic Cooperation In Chungnam National University Process for Preparing Amorphous Atorvastatin Calcium Nanoparticles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011088806A2 *

Also Published As

Publication number Publication date
WO2011088806A2 (en) 2011-07-28
WO2011088806A3 (en) 2011-09-22
CZ201039A3 (cs) 2011-07-27

Similar Documents

Publication Publication Date Title
JP2585495B2 (ja) 医薬品
JP4084309B2 (ja) 単一の結晶形を含有する固形製剤
RU2744432C2 (ru) Фармацевтическая композиция, включающая ингибитор янус-киназы или его фармацевтически приемлемую соль
JP2025085845A (ja) ブルトン型チロシンキナーゼ阻害剤を含む経口固体錠剤及びその調製方法
EP2988733B1 (en) Pharmaceutical composition containing crystalline macitentan
WO2008065097A2 (en) Stabilized solid pharmaceutical composition of candesartan cilexetil
EP2732810A1 (en) Spherical particles of clopidogrel bisulfate, pharmaceutical composition including same, and method for manufacturing same
EA036131B1 (ru) Способ получения аморфного летермовира
JP6215940B2 (ja) ８−［（３ｒ）−３−アミノ−１−ピペリジニル］−７−（２−ブチン−１−イル）−３，７−ジヒドロ−３−メチル−１−［（４−メチル−２−キナゾリニル）メチル］−１ｈ−プリン−２，６−ジオンまたはその医薬的に許容され得る塩を含む安定な医薬組成物
KR100988233B1 (ko) 클로피도그렐 1,5-나프탈렌 다이술폰산 염 또는 이의수화물의 약학 조성물 및 제제
EA035390B1 (ru) Совместный осадок тадалафила с фармацевтически приемлемыми эксципиентами, содержащая его фармацевтическая композиция и способ их получения
WO2009084023A2 (en) Amorphous ramelteon and process for the preparation thereof
EA012220B1 (ru) Твёрдая фармацевтическая композиция, содержащая донепезила гидрохлорид
HUP0402006A2 (hu) Eljárás ibuprofen kristályok képzésére és ezek alkalmazása gyógyszerkészítmények előállítására
WO2011088806A2 (en) A method of industrial production of an amorphous form of atorvastatin with a high specific surface area and its use in a dosage form
KR20030085059A (ko) 결정성 이속사졸 유도체 및 그의 약학 제제
US20080014263A1 (en) Amorphous eprosartan mesylate and process for the preparation thereof
US10961235B2 (en) Crystalline form of masitinib
JP2012180280A (ja) 貯蔵安定性が改善された固形製剤
JP3503222B2 (ja) ニコランジルの安定化錠剤の製造方法
EP2945948B1 (en) Crystalline form ii of anagrelide hydrochloride monohydrate
JP6007096B2 (ja) 安定化カンデサルタンシレキセチル含有物の製造方法
WO2014140159A1 (en) Dosage form comprising crizotinib
US20090124817A1 (en) Process for Preparing Amorphous Atorvastatin Calcium Nanoparticles
CN112057427A (zh) 一种含有布鲁顿氏酪氨酸激酶抑制剂的口服固体片剂及其制备方法

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: 20120716

AK Designated contracting states

Kind code of ref document: A2

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

AX Request for extension of the european patent

Extension state: BA ME

17Q First examination report despatched

Effective date: 20130813

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

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20140506