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WO2011095984A1 - Procédé de préparation d'ésoméprazole amorphe - Google Patents

Procédé de préparation d'ésoméprazole amorphe Download PDF

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Publication number
WO2011095984A1
WO2011095984A1 PCT/IN2011/000042 IN2011000042W WO2011095984A1 WO 2011095984 A1 WO2011095984 A1 WO 2011095984A1 IN 2011000042 W IN2011000042 W IN 2011000042W WO 2011095984 A1 WO2011095984 A1 WO 2011095984A1
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WIPO (PCT)
Prior art keywords
esomeprazole
amorphous
solvent
solution
acid
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
PCT/IN2011/000042
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English (en)
Inventor
Joseph Prabahar Koilpillai
Hemant Nimba Raundal
Nagan Nirmalan Kandasamy
Hiremath Veerabhadra Swamy
Milind Moreshwar Gharpure
Mubeen Ahmed Khan
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.)
Glenmark Generics Ltd
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Glenmark Generics Ltd
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
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Publication of WO2011095984A1 publication Critical patent/WO2011095984A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of esomeprazole in amorphous form by spray drying.
  • the present invention also relates to a pharmaceutical composition comprising amorphous esomeprazole and a pharmaceutically acceptable carrier.
  • Omeprazole is chemically known as 5-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl) methyl] sulfinyl]-l H-benzimidazole.
  • the S-enantiomer, "esomeprazole” is chemically known as (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)-methyl]sulfinyl ⁇ -l H-benzimidazole.
  • Esomeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and Zollinger-Ellison syndrome. Esomeprazole is marketed as LOSEC®/PRILOSEC®.
  • the magnesium salt of esomeprazole in the form of trihydrate is marketed under the brand name NEXIUM® and is represented by formula I.
  • compositions comprising the same.
  • U.S. Patent. No. 7,563,812 describes amorphous esomeprazole hydrate and process thereof.
  • U.S. PG publication No. 20060247277 describes crystalline esomeprazole Form I and II or hydrates and process thereof.
  • U.S. PG publication No. 20090082572 describes a process for preparation of amorphous esomeprazole by lyophilization.
  • the present invention relates to a process for the preparation of amorphous esomeprazole.
  • the present invention relates to a process for the preparation of esomeprazole substantially in amorphous form comprising:
  • the present invention provides amorphous esomeprazole obtained by process herein described with an X-ray diffractogram, which is substantially in accordance with Fig. 1.
  • the present invention provides amorphous esomeprazole obtained by process herein described with a differential scanning calorimetry (DSC) glass transition temperature curve, which is substantially in accordance with Fig. 2.
  • DSC differential scanning calorimetry
  • the present invention provides amorphous esomeprazole obtained by process herein described with a thermogravimetric analysis curve, which is substantially in accordance with Fig. 3.
  • the present invention provides amorphous esomeprazole having purity at least about 99.8% as determined by chiral high performance liquid chromatography (HPLC).
  • the present invention provides amorphous esomeprazole having less than about 0.15% area of (R)-isomer impurity as determined by chiral HPLC.
  • the present invention provides amorphous esomeprazole having less than about 0.1% area of (R)-isomer impurity as determined by chiral HPLC.
  • the present invention provides amorphous esomeprazole having a specific surface area from about 0.4 m 2 /g to about 1.5 m 2 /g as measured by Brunauer-Emmett-Teller (BET) method.
  • BET Brunauer-Emmett-Teller
  • the present invention provides a pharmaceutical composition comprising amorphous esomeprazole obtained by the process of present invention and at least one pharmaceutically acceptable carrier.
  • Fig. 1 is an X-ray powder diffractogram of amorphous esomeprazole obtained by the process of the present invention.
  • Fig. 2 is a glass transition temperature by Differential scanning calorimetry of amorphous esomeprazole obtained by the process of the present invention.
  • Fig. 3 is a thermogravimetric analysis curve of amorphous esomeprazole obtained by the process of the present invention. DETAILED DESCRIPTION OF THE INVENTION
  • polymorphism includes different physical forms, crystal forms, crystalline/liquid crystalline/non-crystalline (amorphous) forms. It has been observed that one or more polymorphic forms of a given drug exhibit superior bioavailability and consequently show much higher activity compared to other polymorphs. Amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. Amorphous materials do not exhibit the three dimensional long range order found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random.
  • amorphous solids offer opportunities for solubility and bioavailability enhancement since these materials are more soluble than the crystalline form of the same compound.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • amorphous solids are not crystalline and therefore do not give a definitive X-ray diffraction pattern. Amorphous materials do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point.
  • polymorphic forms of the same drug substance or active pharmaceutical ingredient can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
  • the present invention relates to a process for the preparation of amorphous esomeprazole.
  • the present invention relates to a process for the preparation of esomeprazole substantially in amorphous form comprising:
  • esomeprazole substantially in amorphous form by spray drying.
  • the solution of esomeprazole or its salt, used in the process directly described above, can be obtained by dissolving esomeprazole or a pharmaceutically acceptable salt thereof in a solvent or mixture of solvents.
  • a solvent is any liquid substance capable of dissolving esomeprazole or its pharmaceutically acceptable salt.
  • a mixture of solvents refers to a composition comprising more than one solvent and may include water.
  • the present invention provides a solution of esomeprazole in a solvent.
  • Suitable solvent may be chlorinated solvents and the like: Suitable chlorinated solvents include, but are not limited to, chloroform, carbon tetrachloride, perchloroethylene, methylene dichloride, and mixtures thereof. Preferably, methylene dichloride is used.
  • the present invention provides a process comprising obtaining the solution of esomeprazole in a solvent by dissolving the esomeprazole salt in a solvent or a mixture of solvent and water; treating with an acid; and separating the solvent containing esomeprazole.
  • the present invention provides a process comprising dissolving esomeprazole salt in a mixture of water and chlorinated solvent and treating with an acid.
  • the chlorinated solvent is methylene dichloride.
  • Suitable salts of esomeprazole include, but are not limited to, alkali or alkaline salts of esomeprazole, such as sodium, lithium, potassium, magnesium, strontium, barium, calcium or alkyl ammonium salts of esomeprazole known in the art.
  • alkali or alkaline salts of esomeprazole such as sodium, lithium, potassium, magnesium, strontium, barium, calcium or alkyl ammonium salts of esomeprazole known in the art.
  • potassium salts of esomeprazole Preferably potassium salts of esomeprazole.
  • the volume of the solvent used to solubilize esomeprazole or a salt thereof may range from about 2 volumes to about 20 volumes to the weight of the esomeprazole or a pharmaceutically acceptable salt thereof taken. Preferably, from about 5 volumes to about 10 volumes.
  • Suitable acids may be selected from the group consisting of acetic acid, formic acid, succinic acid, hydrochloric acid, sulfuric acid and aqueous mixtures thereof.
  • acetic acid is used.
  • the solution obtained is optionally filtered by using conventional filtration techniques known in the art, such as through celite or diatomaceous earth, to separate the extraneous matter present or formed in the solution.
  • the solution of esomeprazole in solvent is evaporated to provide a residue. Evaporation may be carried out by heating under reduced pressure
  • the chlorinated solvent may be removed by heating, preferably under reduced pressure.
  • the solution is heated from about 0°C to about 60°C, more preferably from about from about 20°C to about 40°C, and even more preferably from about 30°C to about 40°C.
  • the present invention provides a process comprising dissolving esomeprazole potassium in a mixture of water and methylene dichloride; treating with acetic acid; separating the methylene dichloride layer containing esomeprazole from the aqueous layer; and evaporating the methylene dichloride layer under reduced pressure to obtain a residue.
  • a suitable solvent may be added to the residue to form a solution from which the esomeprazole can be recovered substantially in amorphous form by spray drying.
  • the solvent to be added to the residue may be selected from the group consisting of C 3 -C 5 aliphatic ketones; C C 6 chlorinated hydrocarbons; Cj-C 6 aliphatic alcohols; C 3 -C 6 aliphatic esters; C 2 -C 5 aliphatic nitriles; ethers.
  • the solvent that may be used for adding to the residue may include C3-C5 aliphatic ketones such as acetone and the like; C
  • acetone is used as a solvent.
  • the solution of esomeprazole may be added dropwise or continuously to the drying chamber.
  • the speed of the addition of the solution will depend on the solvent used, the viscosity of the mixture, and the height of the chamber. These and other parameters are well known to a person skilled in the art of drying.
  • the concentration, solvent type, temperature, vacuum and feeding rate are set to combinations where the esomeprazole coming from the inlet precipitates essentially instantly. Otherwise, crystalline material can also form.
  • a solution of esomeprazole is sprayed into the spray drier at the flow rate ranging from about 10 ml/hr to about 300 ml/hr. Preferably at flow rate of about 100 ml/hr to about 200ml/hr.
  • the air inlet temperature to the spray drier used may range from about 25 °C to about 100°C. In one embodiment, the air inlet temperature is in the range from about 30 °C to about 80°C. Preferably from about 35°C to about 55°C.
  • the air outlet temperature used may range from about 30°C to about 90°C. Preferably, from about 35°C to about 50°C.
  • the esomeprazole product produced by spray-drying may be recovered by techniques commonly used in the art, such as using a cyclone or a filter.
  • a typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber.
  • atomizing means for atomizing a solvent-containing feed into the drying chamber
  • source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed
  • an outlet for the products of drying and product collection means located downstream of the drying chamber.
  • the product collection means includes a cyclone connected to the drying apparatus. In the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent ⁇ allowing the particles to be collected.
  • a filter may also be used to separate and collect the particles produced by spray drying.
  • Spray- drying may be performed in a conventional manner in the processes of the present invention (see, e.g., Remington: The Science and Practice of Pharmacy, 19th ed., vol. II, pg. 1627, 2006 herein incorporated by reference).
  • the drying gas used in the invention may be any suitable gas, although inert gases such as nitrogen, nitrogen-enriched air, and argon are preferred. Nitrogen gas is a particularly preferred drying gas for use in the process of the invention.
  • the residue obtained after removal of methylene dichloride solution containing esomeprazole is dissolved in acetone and is subjected to spray drying at a flow rate ranging from about lOOml/hr to 200ml/hr.
  • the air inlet temperature to the spray drier used may range from about 35°C to about 50°C, preferably about 40°C to 45°C and the outlet air temperature used may range from about 30°C to about 60°C, preferably, about 35°C to about 40°C to obtain esomeprazole substantially in amorphous form by spray drying.
  • the esomeprazole substantially in an amorphous form obtained by the above process may be further dried in, for example, vacuum tray dryer, rotocon vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual solvents.
  • the preferred instrument is a vacuum tray dryer.
  • the temperature for drying can range from about 25°C to about 75°C under vacuum. Preferably, from about 25°C to about 35°C, under vacuum.
  • the drying can be carried out for any desired time, preferably time periods from about 1 hour to about 10 hours frequently being sufficient.
  • the present invention provides amorphous esomeprazole having specific surface area from about 0.4 m 2 /g to about 1.5 m 2 /g as measured by BET (Brunauer-Emmett-Teller) method.
  • BET Brunauer-Emmett-Teller
  • the specific surface area of amorphous esomeprazole is in the range from about 0.5 m 2 /g to about 1.0 m 2 /g as measured by BET method.
  • Specific surface area is defined in units of square meters per gram (m 2 /g).
  • Specific surface area is defined in units of square meters per gram (m /g). It is usually measured by nitrogen absorption analysis. In this analysis, nitrogen is absorbed on the surface of the substance. The amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the BET formula. [0058]
  • the dried product optionally can be milled to get the required particle size.
  • Milling or micronization can be performed prior to drying, or after the completion of drying of the product.
  • the milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.
  • Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling can be performed prior to the drying operation. Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.
  • the esomeprazole or a salt thereof used as starting material in the process described herein above may be of indefinite morphology, or may be crude esomeprazole or a salt thereof resulting from synthetic processing steps known in the art.
  • the esomeprazole or a salt thereof used as starting material are as those described in U.S. Patent Nos. 5.714.504. 6, 124.464; and 6,369,085, which are included herein as references, in their entirety.
  • the process of the present invention provides a substantially pure amorphous form of esomeprazole having less than about 20%, more preferably less than about 10%, even more preferably less than about 5%, and most preferably less than about 1 %, of any one of crystalline forms A, B, C, E, G, I, and II of esomeprazole known in the art.
  • the present invention provides the XRPD pattern of the amorphous esomeprazole, which is substantially in accordance with Fig. 1.
  • the present invention provides amorphous esomeprazole obtained by process herein described, characterized by an X-ray diffractogram, which is substantially in accordance with Fig.1.
  • the present invention provides amorphous esomeprazole obtained by process herein described characterized by differential scanning calorimetry (DSC) glass transition temperature curve, which is substantially in accordance with Fig. 2.
  • DSC differential scanning calorimetry
  • the present invention provides amorphous esomeprazole obtained by process herein described characterized by thermogravimetric analysis curve, which is substantially in accordance with Fig. 3.
  • the present invention provides amorphous esomeprazole having a purity of at least about 99.8%, as determined by chiral high performance liquid chromatography (HPLC).
  • the present invention provides amorphous esomeprazole having less than about 0.15% area of (R)-isomer impurity as determined by chiral HPLC.
  • the present invention provides amorphous esomeprazole having less than about 0.1% area of (R)-isomer impurity, as determined by chiral HPLC.
  • the present invention provides the esomeprazole amorphous compound prepared by the process herein described, exists in a well defined and stable state, which allows easier characterization and facile handling and storage. Additionally, the compound, prepared by the process herein described, is easier to synthesize in a reproducible manner and thereby easier to handle in a full scale production.
  • the amorphous esomeprazole obtained by the process of present invention is substantially free from other polymorphic forms of esomeprazole known in the art.
  • the amorphous esomeprazole obtained by the process of present invention is easily distinguishable from any other form esomeprazole disclosed in prior art.
  • any other form is meant anhydrates, hydrates, solvates, and polymorphs or amorphous forms thereof disclosed in the prior art.
  • examples of any other forms of esomeprazole or salt of esomeprazole includes, but are not limited to, anhydrates, monohydrates, dihydrates, sesquihydrates, trihydrates, alcoholates, such as methanolates and ethanolates, and polymorphs or amorphous forms thereof.
  • the process of present invention consistently produces esomeprazole substantially in amorphous form and well suited on commercial scale.
  • the amorphous esomeprazole obtained by the process of present invention is substantially stable at about 2°C to about 8°C at relative humidity (RH) about 60%v/v for any give time period.
  • the amorphous esomeprazole obtained by the process of the present invention is characterised by differential scanning calorimetry (DSC), where the measurement uses a pproximately 1 -2mg sample accurately weighed into an aluminum DSC pan (40 ⁇ ,) with a lid and then slightly pierced the lid. The sample was placed into the Mettler Toledo DSC822 6® equipped with a nitrogen cooling unit and allowed to equilibrate at 30°C until the stable heat flow reference was seen. A purge nitrogen as dry gas at a flow rate of 50ml/minute was used to produce inert atmosphere to prevent oxidation of sample during the heating. The sample was then scanned from 30- 350°C at rate of 10°C/minute.
  • DSC differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • D % refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the said value.
  • D 50 and Dio refer, respectively, to the values for the particle size for which 50 volume percent, and 10 volume percent of the particles that have a size smaller than the said value.
  • a D50 value can be considered as being the mean particle size of a powder.
  • Amorphous esomeprazole obtained by the process of present invention has a
  • Any milling, grinding micronizing or other particle size reduction method known in the art can be used to bring the amorphous esomeprazole into any desired particle size range as set forth above.
  • amorphous esomeprazole obtained by the process described herein has a residual organic solvent content of less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; i.e., less than about 2000ppm of isopropyl alcohol, less than about lOOOppm of methanol, less than about 500ppm of dichloromethane, less than about lOOOppm of acetone and acetic acid, toluene at below the detection limit.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the amorphous esomeprazole obtained by the process of present invention, as an active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients.
  • Said pharmaceutical composition comprising the amorphous esomeprazole is useful in the manufacture of a medicament for use in the treatment of a gastric-acid related condition and a method of treating a gastric-acid related condition which method comprises administering to a subject suffering from said condition a therapeutically effective amount.
  • compositions of the invention include compositions suitable for per oral or parental administration.
  • the most preferred route is the oral route.
  • the compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the art of pharmacy.
  • the dose, and dose frequency may also vary according to the age, body weight, and response of the individual patient. Special requirements may be needed for patients having Zollinger-Ellison syndrome, such as a need for higher doses than the average patient. Children and patients with liver diseases generally will benefit from doses that are somewhat lower than the average. Thus, in some conditions it may be necessary to use doses outside the ranges stated below, for example long term treatments may request lower dosage. Such higher and lower doses are within the scope of the present invention. Such daily doses may vary between 5mg to 300mg. Dosage forms include capsules, tablets, dispersions, suspensions and the like.
  • Esomeprazole potassium (100 gm) was dissolved in demineralized (DM) water
  • Potassium salt of esomeprazole (5 gm) was dissolved in water (250ml) at about room temperature and treated with ammonium chloride solution (5 %). The aqueous layer was further treated with methylene dichloride. The organic layer was separated off and evaporated under vacuum at about 30°C to about 40°C. The residue was dissolved in acetone (50ml) and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm 2 nitrogen pressure. Further the input temperature was maintained at about 40-45°C and the outlet temperature was maintained at about 30-35°C. The solid was collected from the spray drier and dried at about 30-35°C under vacuum to afford Esomeprazole base (3.3 g) in amorphous form.
  • Solubility Soluble in Complies Complies Complies Complies methanol and
  • BDL Below detection limit ; NMT: Not more than ; NLT: Not less than.
  • Impurity A 5-Methoxy-2- ⁇ [(4-methoxy-3,5-dimethylpyridin-2-yl) methyl] sulfo nyl ⁇ -lH- benzimidazole
  • Impurity B 5-Methoxy-2- ⁇ [(4-nitro-3,5-dimethylpyridin-2-yl) methyl]sulfonyl ⁇ -l H- benzimidazole
  • Impurity C 5-Methoxy-2- ⁇ (S)-[(4-nitro- 3,5-dimethylpyridin-2-yl) methyl]sulfinyl ⁇ -l H- benzimidazole
  • Impurity D 5-Methoxy-2 ⁇ (S)-[(4-chloro-3,5-dimethylpyridin-2-yl)methyl]sulfinyl ⁇ -lH- benzimidazole
  • Impurity E 5-Methoxy-2- ⁇ [(4-methoxy-3,5-dimethylpyridih-2-yl) methyl]thio ⁇ -lH- benzimidazole
  • Impurity F 5-Methoxy-2- ⁇ [(3,5-dimethyl-4-nitropyridin-2-yl)methyl] thio ⁇ -lH- benzimidazole
  • Impurity G 5-Methoxy-2- ⁇ [(4-chloro-3,5-dimethylpyridin-2-yl) methyl]thio ⁇ -lH- benzimidazole

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

Abstract

L'invention concerne un procédé de préparation d'ésoméprazole sous forme amorphe par séchage par pulvérisation.
PCT/IN2011/000042 2010-02-02 2011-01-20 Procédé de préparation d'ésoméprazole amorphe Ceased WO2011095984A1 (fr)

Applications Claiming Priority (2)

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IN243/MUM/2010 2010-02-02
IN243MU2010 2010-02-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3062129A1 (fr) * 2017-01-23 2018-07-27 Minakem Procede d'obtention du sel de magnesium dihydrate de l'esomeprazole

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1728997A (zh) * 2002-10-22 2006-02-01 兰贝克赛实验室有限公司 (es)奥美拉唑的无定形盐
US20070043085A1 (en) * 2005-08-19 2007-02-22 Glenmark Pharmaceuticals Limited Process for the preparation of amorphous form of neutral esomeprazole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1728997A (zh) * 2002-10-22 2006-02-01 兰贝克赛实验室有限公司 (es)奥美拉唑的无定形盐
US20070043085A1 (en) * 2005-08-19 2007-02-22 Glenmark Pharmaceuticals Limited Process for the preparation of amorphous form of neutral esomeprazole

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3062129A1 (fr) * 2017-01-23 2018-07-27 Minakem Procede d'obtention du sel de magnesium dihydrate de l'esomeprazole

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