Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
  • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine

Definitions

• the present invention relates to a process for the preparation of optically pure or optically enriched omeprazole and the pharmaceutically acceptable salts and solvates thereof by optical resolution.
• the invention also provides intermediates useful for the preparation of optically pure omeprazole.
• Omeprazole is the common name for 5-methoxy-2- [ [4-methoxy-3, 5- dimethyl-2-pyridyl) methyl] sulfinyl] -lH-benzimidazole .
• Omeprazole was first described in EP-A-O 005 129 and is well known as an effective gastric acid secretion inhibitor.
• omeprazole exists in two enantiomeric forms, i.e. the (R) -enantiomer and the (S) -enantiomer, otherwise known as (R) -omeprazole and (S)- omeprazole, respectively.
• (S) -Omeprazole is also referred to as esomeprazole .
• omeprazole is obtained as a racemic mixture. Due to differences in pharmacokinetic properties of the (R)- and (S) -isomers of omeprazole, there is a general demand for methods allowing for the preparation of optically pure omeprazole.
• DE-A-40 35 455 (BYK GULDEN LOMBERG CHEM. FAB.) relates to a resolution process for obtaining optically pure omeprazole via formation of diastereomeric ethers.
• WO-A-94/27988 discloses optical resolution of omeprazole using esters of omeprazole with chiral organic acids such as (R) - mandelic acid.
• WO-A-96/02535 discloses a process for the preparation of the single enantiomers of omeprazole by asymmetric oxidation of the corresponding "prochiral" sulfide.
• the process employs an oxidizing agent in the presence of a chiral titanium complex.
• Optical resolution of omeprazole by bioreduction is described in WO-A-96/17077
• an enantioselective preparation of omeprazole by biooxidation is described in WO-A-96/17076.
• WO-A-97/02261 discloses a process for the optical purification of certain enantiomerically enriched benzimidazole derivatives using a crystallization method.
• WO-A-02/098423 relates to an inclusion complex of (S)- omeprazole with cyclodextrin .
• CN-A-1223262 relates to a process for the preparation of certain optically pure benzimidazole derivatives by inclusion complexation with binaphthyl phenol derivatives.
• WO-A-2007/074099 relates to an analogous process using (S)- 1,1, 2-triphenyl-l , 2-ethanediol .
• Cinchona alkaloids have found a number of applications as re- solving agents for the fractionated crystallization of chiral acids as diastereomeric salts [P. Newman, Optical Resolution Procedures for Chemical Compounds, Volume 2, Part I and II, Optical Resolution Information Center, Manhattan College, Riverdale, N. Y. 10471, 1981].
• the racemic pantho- tenic acid has been resolved by means of quinine or cinchon- idine methohydroxide as described in J. Amer. Chem. Soc. 1941, 63, 1237. Resolution of racemic substituted ⁇ -butyrolactone with cinchona methohydroxide is described in J. Amer. Chem. Soc. 1941, 63, 1368.
• IPCOM000126473D discloses an optical resolution process wherein the diastereomeric pair of omeprazole N-benzyl cin- choninium salts is prepared by reactions under non-homogeneous conditions or under conditions employing a large excess of omeprazole. These procedures have not been found practical and economical on an industrial scale.
• the invention relates to a process for the preparation of substantially optically pure or enantiomeri- cally enriched omeprazole by optical resolution.
• the invention relates to a process for the preparation of enantiomerically enriched omeprazole by resolution of omeprazole with a resolving agent, more particularly with different resolving agents selected from chiral amines which form with omeprazole chemical interaction and could be treated as diastereomeric salts.
• an “enantiomerically enriched omeprazole” in the context of this general embodiment means a form of omeprazole which contains more than 50 % of one of the enantiomers, preferably more than 65 %, even more preferably more than 80% of (R)- or (S) -enantiomer of omeprazole.
• resolving agents include (+) -quinidine, (-)- strychnine, (-) -ephedrine, (-)-brucine, (-) -quinine, (-)- cinchonidine, (+) -hydroquinidine, (-) or (+) ) - ⁇ -methylben- methylbenzylamine, (-) -benzyl- ⁇ -methylbenzylamine, (-) -2- amino-butanol, (+) -2-amino-l-phenyl-l, 3-propanediol, ( (-) or ( + ) ) -phenylalaninol, ( + ) -prolinol, ( ( + ) or (-) ) -1-phenyl- propylamine, (+) -cinchonine, (+) -benzyl- ⁇ -methylbenzyl-amine, (+) -dehydro-abietyl amine, (-) -2-
• this general embodiment relates to a proc ⁇ ess for the preparation of enantiomerically enriched omepra- zole by resolution of omeprazole with a resolving agent se ⁇ lected from ( + ) -quinidine, (-)-brucine, (-) -cinchonidine and (+) - ⁇ -methylbenzylamine .
• the resolution can be performed in any suitable organic or in ⁇ organic solvent.
• the solvent used for resolution is selected from water, hydrocarbon, halogenated hydrocarbon, ether, ester, ketone, nitrile and alcohol or a mixture thereof. More preferably, the solvent used for resolution is selected from methanol, ethanol, propanol, isopropanol and isobutanol .
• Enantiomerically enriched omeprazole can be isolated from precipitated diastereomeric salt by dissolving the diastereomeric salt in acidic solution and further extraction with suitable organic solvent. In the case of isolation of enantiomerically enriched omeprazole from remaining diastereomeric salt solution, the solution is acidified and extracted with any suitable organic solvent.
• the organic solvent for extraction is selected from hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles or alcohol or a mix- ture thereof.
• the solvent for extraction is ethyl acetate.
• Diastereomeric salts have different physical properties and one can apply several methods to separate such salts. The methods can apply for instance difference in solubility, difference in adsorption, difference in partitioning coefficient and so on. Crystallizations, liquid/liquid and liquid/solid extractions, and several chromatographic principles for purification could be applied for separation of diastereomeric salt of omeprazole.
• the enantiomerically enriched omeprazole can be further purified with the chromatographic methods disclosed according to general embodiment 3 below or with the chromatographic methods disclosed in prior art such as WO-A-2003/051867. Pure (R)- or (S) -omeprazole prepared according to this general embodiment can be further used in the preparation of pharmaceutically acceptable salts such as magnesium esomeprazole .
• the invention relates to a process for the preparation of sub- stantially optically pure omeprazole, or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of:
• the process according to this preferred embodiment of the invention offers several advantages. It proceeds with high yield and high enantiomeric purity > 90% e.e. Furthermore, the re- solving agents can be readily recovered after optical resolution.
• the process is easily industrialisable using tailored chiral amines or chiral quaternary ammonium salts and can be carried out under very mild, homogenous conditions. Moreover, the process does not require toxic solvents and can be applied without chromatographic separations.
• a “substantially optically pure” isomer in the context of this preferred embodiment of the invention means an isomer with a diastereomeric excess (d.e.) or enantiomeric excess (e.e.) ac- ceptable for a chiral compound prepared on industrial scale.
• d.e. and e.e. values are readily determined by a person skilled in the art.
• a process is suitable for preparation on industrial scale with an d.e. or e.e. of at least 85 %, preferably of at least 90 % and more preferably of at least 95 %.
• Omeprazole used according to this preferred embodiment of the invention can be prepared by any known methods, for example such as those disclosed in EP-A-5129, EP-A-103 553, EP-A- 302 720, EP-A-369 208, EP-A-533 752, EP-A-533 264 and EP-A- 484 265.
• the crystal form of omeprazole can be A, B or C according to WO-A-99/08500; Ohishi et al . , Acta Cryst. 1989, C45, 1921-1923; and WO-A-2002/085889 respectively.
• the resolving agent is selected from the group consisting of (-)-brucine, (+) - ⁇ -methylbenzylamine, (-)- ephedrine, N, N-dimethylephedrine, bis- (1-phenylethyl) amine, cinchona bases, derivatives thereof and quaternary salts thereof .
• the resolving agent is a quaternary cinchona salt of formula (I) :
• Z is hydrogen or methoxy
• Y is hydrogen, benzyl or allyl
• R is hydrogen or phenyl
• X is iodine, bromine, chlorine or hydroxy
• Quaternary salts of cinchona alkaloids as resolving agents are inexpensive, commercially available or can easily be prepared in both enantiomeric forms, and are also non-toxic and recov- erable. It is particularly preferred that the resolving agent is a quaternary salt of a cinchona base selected from the group consisting of (-) -quinine, (+) -quinidine, (+) -cinchonine and (-) -cinchonidine .
• racemic or optionally enantiomerically enriched omeprazole or a salt thereof is contacted with a resolving agent as defined above in a suitable solvent.
• the contacting may be carried out in a conventional manner such as under stirring at ambient temperature.
• the solvent of step (a) comprises at least one solvent which is selected from the group consisting of (Ci-C 5 ) alcohols, (C3-C6) ketones, acetoni- trile, dimethylformamide, aromatic (C ⁇ -Cg) hydrocarbons, tetra- hydrofuran, aliphatic (Ci-C 4 ) esters, halogenated aliphatic
• (C1-C9) hydrocarbons and optionally comprises up to 50 vol-% water.
• said solvent is selected from the group consisting of methanol, ethanol, acetone, butanone, di- methylformamide, tetrahydrofuran, dichloromethane, and aceto- nitrile. It is particularly preferred that the solvent comprises no more than 35 vol-%, preferably no more than 20 vol-%, most preferably no more than 15 vol-% water.
• the resolving agent may generally be applied in any suitable molar amount.
• the resolving agent is used in an amount of at least 0.7 equivalents, particularly at least 0.9 equivalents, most preferably at least 1 equivalent, based on the molar amount of omeprazole.
• step (b) separation of the diastereomeric pair of omeprazole ammonium salts comprises crystalliz- ing omeprazole ammonium salt from a suitable solvent for crystallization.
• the solvent for crystallization comprises at least one solvent selected from the group consisting of (Ci-C 5 ) alcohols, (C3-C6) ketones, acetonitrile, dimethyl- formamide, aromatic (C ⁇ -Cg) hydrocarbons, tetrahydrofuran, ali- phatic (Ci-C 4 ) esters, halogenated aliphatic (C1-C9) hydrocarbons.
• the solvent for crystallization of step (b) may be the same or different from the solvent of step (a) .
• step (b) is re- peated at least once, such as once, twice, three times, etc.
• the omeprazole ammonium salt is recrystallized, thereby resulting in a considerable rise in d.e. reproducibly giving omeprazole ammonium salt of > 90 % d.e.
• omeprazole ammonium salt obtained from a first crystallization is typically subjected to recrystallization .
• Recrystallization can be ef- fected in the same solvent system as defined above and can be carried out at a temperature in the range of from ambient temperature to the reflux temperature of the solvent. Finally the batch is usually filtered and washed with solvent.
• Crystallization and recrystallization of omeprazole ammonium salt from a suitable solvent system may be carried out in a conventional manner.
• Diastereomeric salt resolution proved to be a dynamic process with the diastereomeric excess (d.e.) of the crystals enriching over time.
• a sample of the solids is isolated from the crystallization mixture for d.e. determination (e.g. d.e. criterion >90% d.e.).
• converting the omepra- zole ammonium salt comprises contacting the omeprazole ammonium salt with at least one compound selected from the group consisting of an acid, e.g. hydrochloric acid, an acidic salt, e.g. MgCl2 or NH 4 Cl, and an acidic ion exchanger, e.g. Dowex 5OW H + .
• an acid e.g. hydrochloric acid
• an acidic salt e.g. MgCl2 or NH 4 Cl
• an acidic ion exchanger e.g. Dowex 5OW H + .
• the conversion of step (c) is carried out in a suitable solvent system comprising water and at least one water-immiscible solvent.
• the water-immiscible solvent is selected from the group consisting of aromatic (Ce- Cg) hydrocarbons, aliphatic (C 2 -Cs) ethers, aliphatic (Ci-C 4 ) esters, halogenated aromatic or aliphatic (Ci-Cg) hydrocarbons, and mixtures thereof.
• Particularly preferred are toluene, di- chloromethane, ethyl or butyl acetate and tert-butyl methyl ether.
• Enantiomerically enriched esomeprazole can be further optically purified by preparative chromatography, such as HPLC or SMB chromatography.
• preparative chromatography such as HPLC or SMB chromatography.
• methods generally disclosed in WO-A-2003/051867, CN-A-1683368 or WO-A-2007/071753 can be used.
• an alkaline or al- kaline earth metal salt of omeprazole can be isolated directly in a substantially optically pure form from the aqueous phase by conventional methods.
• the alkaline metal cation can be replaced by another metal cation prior to isolation by treatment with an appropriate alkaline earth metal salt such as an alka- line earth halide such as magnesium chloride as described for example in WO-A-94/27988.
• neutral optically pure omeprazole can optionally be subsequently transformed into a pharmaceutically acceptable optically pure omeprazole salt with an appropriate base by conventional methods, in particular into an alkaline, alkaline earth or transitional metal salt such as a lithium, sodium, potassium, magnesium, calcium, barium or zinc salt.
• a lithium, sodium, potassium, magnesium, calcium, barium or zinc salt such as sodium and magnesium salts are particularly preferred.
• Other non-metal salts such as amine salts can also be prepared.
• the pharmaceutically acceptable solvate is (S) -omeprazole magnesium dihydrate form A.
• (S) -omeprazole magnesium dihydrate form A can be obtained according to the method disclosed in example 6 of WO-A-98/54171. According to the process of this preferred embodiment of the present invention, selective formation of either one of the two diastereomeric ammonium salts can be advantageously con- trolled by using a suitable chiral quaternary ammonium salt.
• the proc- ess can be controlled such that crystals of the (S) -compound are obtained from fractionated crystallization, and crystals of the (R) -compounds may subsequently be isolated from the mother liquor.
• the process can be controlled such that crystals of the (R) -compound are obtained from frac- tionated crystallization and crystals of the (S) -compound may subsequently be isolated from the mother liquor.
• racemic compound is dissolved in ethanol, acetone, dimethylformamide, dichloromethane, tetrahydrofuran or the like organic solvent.
• the reaction is not sensitive to water, thus a limited amount of water may be there such as up to 50 vol-%.
• N- benzylcinchonine hydroxide solution in an aforementioned solvent is added thereto in an equivalent molar amount, and then the mixture is concentrated in vacuo to obtain N-benzyl cinchoninium salt of the corresponding compound as a solid material.
• the isolated substance is dissolved in ethanol, isopro- panol, butanol, methyl ethyl ketone, ethyl acetate or mixtures thereof, and the solution is left to stand to form crystals.
• the crystals are recovered by filtration of the solution and subjected to recrystallization to obtain the N- benzylcinchoninium salt of (S) -compound.
• the salt is treated with hydrochloric acid and recrystallized from an organic solvent in a conventional manner to obtain the desired (S)- compound.
• the mother liquor may be concentrated by evaporation of solvent to obtain N-benzyl cinchoninium salt of the compound mainly containing the (R) -compound and which may subsequently be treated with hydrochloric acid to obtain crystals of the compounds contain- ing mainly the (R) -compound.
• an alkali metal salt of the racemic starting compound is dissolved in methanol, dimethylformamide, acetonitrile, tetrahydrofuran or the like organic solvent and/or water, and N-methyl cin- chonidine iodide in an aforementioned organic solvent is added thereto in an equivalent molar amount.
• Water-immiscible solvents also may be occasionally used.
• the organic solvent is then concentrated in vacuo to obtain the N-methyl cinchonidine salt of the corresponding compound as a solid material.
• the diastereomeric pair of salts is dissolved in ethanol, isopro- panol, butanol, methyl ethyl ketone, ethyl acetate or the like organic solvent and left to stand to obtain crystals which are recrystallized to obtain N-methylcinchonidinium salt of the (R) -compound.
• the mother liquor may be concentrated by evaporation of solvent to obtain N-methylcinchonidinium salts of the compounds mainly containing the (S) -compound.
• the (S) -salt is acidified with hydrochloric acid and recrystallized from an organic solvent to obtain the desired (S) -compound.
• the desired (S) -compound is liberated straightforward from the mother liquor by addition of acid.
• the invention also relates to a process for preparing a phar- maceutical composition comprising substantially optically pure omeprazole, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one pharmaceutically acceptable carrier, which includes the step of preparing the substantially optically pure omeprazole or the pharmaceuti- cally acceptable salt or solvate thereof according to the pro- cess of the invention.
• the solvate is (S)- omeprazole magnesium dihydrate form A.
• the particle size of the (S) -omeprazole and pharmaceutically acceptable salts or solvates used in the processes of the present invention is preferably in the range of 0.1-250 microns. If smaller particles are needed, they can be milled or mi- cronized optionally together with other excipients. During this process the mechanical force on the particle surface leads to a particle size reduction.
• an air jet mill, a ball mill or a hammer mill are commonly used as milling equipment.
• the basic principle of the treatment in an air jet mill is collision and attrition between particles suspended within a high velocity air stream, which introduces the power to the milling chamber.
• compositions according to the invention are preferably in the form of pellets or tablets, in particular those which have an enteric coating layer.
• the pellets can be filled into hard gelatine capsules or sachets which hence also represent preferred embodiments of the composition.
• the tablets can be prepared from the pellets or from a powder mixture .
• the pellets preferably comprise
• the tablets preferably comprise (a) a core including the pharmaceutically acceptable salt or solvate according to the invention,
• the pharmaceutically acceptable salt is included in the core in form of a layer covering the core.
• the pharmaceutical compositions are in the form of multiple-unit tablets which are obtainable by compressing a mixture of the pellets with tablet excipients.
• the present invention also relates to intermediates useful for the preparation of optically pure omeprazole.
• the intermediate is an omeprazole ammonium salt, wherein the ammonium moiety is derived from a chiral amine selected from the group consisting of (-)-brucine, (+) - ⁇ -methylbenzylamine, (-) -ephedrine, N, N- dimethylephedrine and bis- (1-phenylethyl) amine .
• the intermediate is an omeprazole ammonium salt having the formula (ID :
• the intermediate is an omeprazole ammonium salt having the formula (III) :
• the invention relates to a pro- cess for the preparation of enantiomerically enriched omeprazole comprising:
• omeprazole or enantiomerically enriched omeprazole used in the process according to the invention can be prepared according to any desired method, many of which are known to those of ordinary skill in the art.
• suitable methods to manufacture omeprazole are given by EP-A-5129, EP-A-124 495, EP-A-533 752, DE-A-40 35 455, EP-A-652 872, EP-A-707 580, EP- A-773 940, EP-A-795 024, EP-A-836 601, EP-A-897 386, EP-A- 946 547, EP-A-984 957, EP-A-964 859, EP-A-I 004 305, EP-A- 1 095 037, EP-A-I 104 417, EP-A-I 230 237, EP-A-I 409 478, EP- A-I 458 709, WO-A-03/08940 , EP-A-I 375 497, WO-A-2004/29
• a ratio of S- (-) -omeprazole and R- (+) -omeprazole in enantiomeric mixture can be changed by enzyme reaction by forming 5- hydroxy and 5-O-desmethyl compounds of the (S) (-) -enantiomer and the (R) (+) -enantiomer of omeprazole.
• the difference in enzyme kinetic properties between the two enantiomers is used to change the percentage of enantiomerically enriched omeprazole.
• (S) (-) -enantiomer and the (R) (+) -enantiomer of omeprazole is prepared by enzyme reaction.
• Hepatic cytochrome P450 enzymes can be used, for example hepatic cytochrome P450 enzyme
• CYP2C19 can be used.
• the enzyme is selected from cytochrome P450 enzyme.
• a particularly preferred enzyme is
• Enzymes can be selected from recombinant or non-recombinant enzymes.
• the process according to this general em- bodiment of the invention can be performed by immobilized enzymes or as a whole cell biotransformation.
• Omeprazole and its enantiomers are extensively metabolized in the liver by the cytochrome P450 enzyme system.
• the main me- tabolites of (S) (-) -enantiomer and the (R) (+) -enantiomer of omeprazole are the 5-hydroxy, 5-O-desmethyl and sulphone metabolites, which are all inactive.
• the metabolism is mediated primarily by CYP2C19 and CYP3A4 enzymes.
• (S) (-)- enantiomer and the (R) (+) -enantiomer differ in the ratio in which they are metabolized by CYP2C19 and CYP3A4.
• the enzyme reaction according to this general embodiment of the invention is carried out in a buffer system.
• Tris- hydrochloride buffer is preferably used for carrying out the reaction .
• a preferred pH of the reaction is in the range of 7 to 9, more preferably in the range 7.2 to 8.0, most preferably in the range 7.3 to 7.5.
• a preferred temperature range for carrying out the reaction is in the range of 25 to 45 0 C, more preferably in the range of 30 to 40 0 C, most preferably in the range of 35 to 39 0 C.
• a preferred reaction is started by adding NADPH, and carried out for a period of time between 0.01 hours and 50 hours, more preferably 0.1 hours and 24 hour, most preferably between 0.1 hours and 10 hours.
• the reaction is stopped by addition of acetoni- trile, methanol, butanol, methylene chloride and mixtures thereof .
• the enantiomerically enriched omeprazole can be further purified with the chromatographic methods disclosed according to general embodiment 3 below.
• General embodiment 3
• racemic or enantiomerically enriched omeprazole and obtained derivatives can be resolved by a chromatography process.
• racemic or enantiomerically enriched omeprazole can be resolved by the chiral chromatography process described below.
• enantiomerically enriched omepra- zole is resolved.
• Enantiomerically enriched omeprazole enables a process wherein higher loads of omeprazole can be applied in a chromatographic process and wherein (S) (-) -enantiomer of omeprazole is obtained in high purity.
• a “racemic omeprazole” in the context of this general embodiment of the invention means a mixture of S- (-) -omeprazole and R- (+) -omeprazole in a ratio of 55:45 to 45:55, preferably in a ratio of about 50:50.
• an "enantiomerically enriched omeprazole” in the context of this general embodiment of the invention means a mixture, wherein the percentage of S- (-) -omeprazole is greater than the percentage of R- (+) -omeprazole .
• enantiomerically enriched omeprazole is a mixture of S- (-) -omeprazole and R- (+) -omeprazole in the ratio of 100:0 to 55:45, preferably in the ratio of 100:0 to 60:40, more preferably 100:0 to 70:30.
• the stationary phase used in the chiral chromatography process may comprise chiral selectors or stationary phases; batch and/or supercritical-fluid chromatography can be used.
• chiral stationary phases can be selected from polysac- charide-derived chiral stationary phases, such as cellulose tris (3, 5-dimethylphenylcarbamate) immobilized on a silica support, amylase tris (3, 5-dimethylphenylcarbamate) immobi- lized on a silica support or from the group of stationary phases of Pirkle type chiral stationary phases, such as ⁇ - electron donor/ ⁇ -electron acceptors.
• the stationary phase comprises dimethyl N-3,5- dinitro-benzoyl- ⁇ -amino-2 , 2-dimethyl-4-pentenyl phosphonate covalently bound to mercaptopropyl silica (commercially available as (R) ⁇ -Burke ® and (S) ⁇ -Burke ® ) ; 3, 5-dinitrobenzoyl derivative of 1, 2-diaminocyclohexane; 3,5-dimethyl phenyl carbamate and tris- (3, 5-dimethylphanyl) carbamoyl cellulose.
• the mobile phase used in the chiral chromatography process comprises an alcohol, another organic solvent, or a mixture thereof.
• the alcohol may comprise methanol, ethanol, propanol, isopropanol, or a mixture thereof.
• the organic sol- vent may comprise acetonitrile, methylenchloride or hexane .
• the mobile phase comprises a mixture of an alcohol with another alcohol or another organic solvent.
• additives such as diethyl amine, triethyl amine or isopropylamine can be added in an amount of 0.01 to 0.5 vol. %, preferably 0.05 to 0.01 vol. %.
• WO-A-94/27988 discloses certain salts, namely Na + , Mg 2+ , Li + , K + , Ca 2+ and N(R) 4 + salts, wherein R is an alkyl with 1-4 carbon atoms, of the single enantiomer of omeprazole and their preparation. These compounds are said to have improved pharmacokinetic properties which give an improved therapeutic profile, such as a lower degree of variation between individuals taking the compound.
• WO-A-98/54171 describes magnesium esomeprazole trihydrate
• WO- A-00/44744 describes specific polymorphs of the potassium salt of esomeprazole
• WO-A-2003/74514 discloses some primary amine salts of esomeprazole
• WO-A-2004/037253 describes certain alkali metal or amine salts of esomeprazole
• WO-A-2004/99182 and WO-A-2004/99181 disclose zinc and barium salts of esomepra- zole, respectively
• EP-A-I 726 305 discloses zinc salts of omeprazole and its enantiomers
• WO-A-2005/023796 discloses adamantan ammonium salts of omeprazole and esomeprazole
• WO-A-2005/023797 describes the 1-cyclohexyl ethyl ammonium salt of inter alia esomeprazole.
• EP-A-I 018 340 describes amino acid salt compounds of benzimidazole derivatives and their inclusion complexes with cyclodextrins .
• the amorphous L- arginine omeprazole salt is described which is produced by spray drying.
• Pharmaceutically acceptable salts of esomeprazole according to the present invention can be prepared according to any of the described methods.
• pharmaceutically acceptable salts can be prepared starting from substantially optically pure or enantiomerically enriched omeprazole prepared by opti- cal resolution according to any of the general and preferred embodiments described herein above.
• Preferred pharmaceutically salts of esomeprazole according to the present invention are esomeprazole magnesium, esomeprazole arginine and esomeprazole zinc, and solvates thereof.
• Esomeprazole magnesium solvates can be selected from the group of monohydrate, dihydrate and trihydrate, preferably dihy- drate .
• the pharmaceutically acceptable salts of esomeprazole can be in crystalline form or in amorphous form, and the latter form may facilitate its processing into pharmaceutical compositions .
• the pharmaceutically acceptable salts of esomeprazole have been characterized by FT-IR spectrum, X-ray powder diffraction pattern and 1 H-NMR spectrum and analyzed in accordance with the article »Enantioselective Analysis of Omeprazole in Pharmaceu- tical Formulations by Chiral High-Performance Liquid Chromatography and Capillary Electrophoresis « (J. Braz. Chem. Soc, Vol. 15, No. 2, 318-323, 2004).
• FT-IR spectra of KBr discs including the pharmaceutically ac- ceptable salts of esomeprazole according to the invention were recorded over a wave number range of 4000 - 400 cm “1 on a Per- kin Elmer Spectrum GX FT-IR spectrometer at a resolution of 4 cm "1 .
• X-ray powder diffraction patterns were obtained by using a Phillips PW3040/60 X' Pert PRO powder diffractometer; CuKa radiation 1.541874 A.
• Crystallinity of esomeprazole and pharmaceutically acceptable salts according to the invention has been characterized according to the method 2.9.33. described in Ph. Eur. 5.6. (2007) .
• A is total area of the peaks arising from diffraction from the crystalline fraction of the sample; B is total area below area A and C is background area (due to air scattering, fluorescence, equipment, etc) .
• the pharmaceutically acceptable salts of esomeprazole accord- ing to the present invention can have a degree of crystallin- tiy in the range 0 % to 100 %.
• Pharmaceutically acceptable salts of esomeprazole of defined degree of crystallinity can be obtained by mixing of pharmaceutically acceptable salt of at least two different degree of crystallinity.
• Degree of crystallinity is preferably in the range of 50 % to 100 %, most preferably in the range 60 % to 90 %.
• Polymorphic form of magnesium esomeprazole dihydrate according to the invention with the degree of crystallinity of 100 % is Form B as defined in Example 5 of EP-B-O 984 957.
• the pharmaceutically acceptable salts of esomeprazole prepared according to the present invention can have a purity level of up to 99.9%.
• the particle size of the esomeprazole and pharmaceutically ac- ceptable salts according to present invention is preferably in the range of 0.1-250 microns. If smaller particles are needed, they can be milled or micronized optionally together with other excipients. During this process the mechanical force on the particle surface leads to a particle size reduction. How- ever, it can also release the structure changes of the material.
• an air jet mill, a ball mill or a hammer mill are commonly used as milling equipment.
• the basic principle of the treatment in an air jet mill is collision and attrition between particles suspended within a high velocity air stream, which introduces the power to the milling chamber.
• compositions according to the invention are preferably in the form of pellets or tablets, in particular those which have an enteric coating layer.
• the pellets can be filled into hard gelatine capsules or sachets which hence also represent preferred embodiments of the composition.
• the tables can be prepared from the pellets or from a powder mix- ture .
• the pellets preferably comprise
• the tablets preferably comprise
• the pharmaceutically acceptable salt is included in the core in form of a layer covering the core.
• the pharmaceutical compositions are in the form of multiple-unit tablets which are obtainable by compressing a mixture of the pellets with tablet excipients.
• Preferred pellets comprise a pellet core, optionally a separating coating, an enteric coating and optionally an over- coating as follows.
• the core is prepared from powders comprising pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient by extrusion-spheronization or direct pelletization in a high-shear mixer or a rotor granulator.
• the core can also be formed by applying a layer containing pharmaceutically acceptable salt to an inert bead.
• a layer containing pharmaceutically acceptable salt is one prepared from starch and sucrose, even though beads of other pharmaceutically acceptable excipients may be used, such as microcrystalline cellulose, vegetable gums, waxes and the like.
• the size of the beads may vary between approximately 0.1 and 2 mm.
• a convenient manner of coating the beads with pharmaceutically acceptable salt is the "powder layering" process in centrifugal equipment, i.e. rotor fluid bed equipment (Glatt Rotor Granulator), or a coating pan, i.e. a conventional coating pan (Pellegrini Coating Pan, GS Coating System) .
• the inert beads are moistened with a solution of binder, and then the active substance together with other excipients is added as a powder and the layered pellets are dried in the same equipment in which the coating is performed or other specialized equipment for drying, such as a drying chamber with or without vacuum, is used.
• the layer with pharmaceutically acceptable salt can also be formed in the "suspension layering" or “solution layering” process by spraying the pharmaceutically acceptable salt suspension or solution onto the inert cores in a fluid bed coater granulator.
• Organic solvents or water can be used during this process .
• the core and in particular the layer with the active ingredient, comprises, pharmaceutically acceptable salt, at least one excipient selected from stabilizers, fillers, disintegrating agents, wetting agents, binders or other pharmaceutically ac- ceptable ingredients, alone or in mixtures.
• the stabilizer is preferably chosen among substances, such as sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids, aluminium hydroxide/sodium bicarbonate coprecipitate, aluminium, calcium and magnesium hydroxides, magnesium oxide or composite substances, such as Al 2 ⁇ 3-6MgOC ⁇ 2-12H 2 0, (Mg 6 Al 2 (OH) 16 CO 3 -4H 2 O) , MgO-Al 2 O 3 -2SiO 2 -nH 2 O or similar compounds, sodium lauryl sulphate, zinc hydroxide or hydroxide carbonate, alkaline reacting amino acids, their esters and salts or other similar, pharmaceutically acceptable pH-buffering substances.
• substances such as sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids, aluminium hydroxide/sodium bicarbonate coprecipitate, aluminium, calcium and magnesium
• the filler is preferably selected from the group consisting of microcrystalline cellulose, sucrose, starch, lactose, mannitol, sorbitol and mixtures thereof.
• the disintegrating agent is preferably selected from the group consisting of starch, starch derivatives such as sodium starch glycolate or pregelatinized starch, low-substituted hydroxy- propyl cellulose, crospovidone, croscarmelose sodium and mixtures thereof.
• the wetting agent is preferably selected from the group consisting of sodium dodecyl sulphate, polyoxyethylene sorbitan fatty acid esters, poloxamers and mixtures thereof.
• the binder is preferably selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose and mixtures thereof.
• said pellets Before applying the enteric coating layer onto the cores present in form of individual pellets, said pellets may optionally be covered with one or more separating layers comprising pharmaceutical excipients optionally including alkaline compounds, such as for instance pH-buffering compounds.
• This layer/these layers separate (s) the core material from the outer enteric coating layer.
• the separating layer can be applied to the core by a coating or layering process in suitable equipment such as a coating pan, coating granulator or in a fluid bed apparatus using water and/or organic solvents for the coating process.
• the separating layer can be applied to the core by using the powder coating technique.
• the materials for separating layers are pharmaceutically acceptable compounds, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures.
• Additives such as plasticizers, colorants, pigments, fillers, anti-tacking agents and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included in the separating layer.
• the separating layer may serve as a diffusion barrier and may act as a pH-buffering zone.
• the pH-buffering properties of the separating layer can be further strengthened by introducing into the layer substances chosen from a group of compounds usually used in antacid formulations, such as magnesium oxide, hydroxide or carbonate, zinc hydroxide or hydroxide carbonate, aluminium or calcium hydroxide, carbonate or silicate, composite aluminium/magnesium compounds, such as Al 2 ⁇ 3-6MgOC ⁇ 2-12H 2 0, (Mg 6 Al 2 (OH) 16 CO 3 -4H 2 O) , MgO-Al 2 O 3 -2SiO 2 -nH 2 O, aluminium hydrox- ide/sodium bicarbonate coprecipitates or similar compounds, or other pharmaceutically acceptable pH-buffering compounds, such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids, or suitable organic bases, includ- ing basic amino acids, their esters and salts.
• Talc or other compounds may be added to increase the thickness of the
• the optionally applied separating layer is not essential for the compositions according to the invention.
• the separating layer may improve the chemical stability of the active substance and/or the physical properties of the final dosage form.
• the separating layer may also protect the enteric coating layer towards cracking during a compaction process.
• the separating layer preferably contains pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness.
• plasticiz- ers are for example triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, dimethyl polysiloxan, cetyl alcohol, stearyl alcohol, polyethylene glycols, propylenglycole, polysorbates or other plasticizers.
• the mechanical properties, i.e. flexibility and hardness of the separating layer are ad- justed so that the acid resistance of the pellets covered with enteric coating layer does not decrease significantly during the compression of pellets into tablets.
• the amount of plasti- cizer is usually 10-50 % by weight of the separating layer forming material.
• Additives such as dispersants, colorants, pigments, polymers, anti-tacking agent and antifoaming agents may also be included into the separating layer.
• the maximum thickness of the applied separating layer is normally only limited by processing conditions.
• enteric coated layers are applied onto the core or onto the core covered with separating layer (s) by using a suitable coating technique.
• the enteric coating layer material may be dispersed or dissolved in either water or in suitable organic solvents and is preferably comprising a polymer.
• enteric coating layer polymers one or more, separately or in combination, of the following can be used: solutions or dis- persions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxy- propyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethyl- cellulose, shellac or other suitable enteric coating layer polymer (s) .
• the enteric coating layers can also contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness.
• plasticizers are for example those mentioned above under 2.
• the amount of plasticizer is optimized for each enteric coating layer formula, in relation to the selected enteric coating layer polymer (s), selected plasticizer (s) and the applied amount of said polymer (s) , in such a way that the me- chanical properties, i.e. flexibility and hardness of the en- teric coating layer (s) are adjusted so that the acid resistance of the pellets covered with enteric coating layer (s) does not decrease significantly during a compression of the pellets into tablets.
• the amount of plasticizer is usually 10- 50 % by weight of the enteric coating layer polymer (s) .
• Additives such as dispersants, colorants, pigments, polymers, anti-tacking agent and antifoaming agents may also be included into the enteric coating layer (s) .
• Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the acid susceptible material.
• the enteric coating layer (s) usually have a thickness of about at least 10 ⁇ m, preferably more than 20 ⁇ m.
• the maximum thickness of the applied enteric coating layer (s) is normally only limited by processing conditions.
• the enteric coated pellets can optionally be covered with one or more over-coating layers.
• the over-coating layer can be ap- plied to the enteric coating layered pellets by coating or layering procedures in suitable equipment, such as a coating pan, a coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process.
• the materials for the over-coating layer are chosen among pharma- ceutically acceptable compounds, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellu- lose, hydroxypropyl methylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium and others, used alone or in mixtures.
• Additives such as plasticizers, colorants, pig- merits, fillers, anti-tacking agents and anti-static agents, such as magnesium stearate, titanium dioxide, talc and other additives may also be included into the over-coating layer.
• the over-coating layer may further prevent potential agglomeration of enteric coating layered pellets and further enhance a subsequent tableting process.
• the over-coating layer may also protect the enteric coating layer towards cracking during a compaction process.
• the over-coating layer contains pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness.
• plasticizers are for example triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, dimethyl polysiloxan, cetyl alcohol, stearyl alcohol, polyethylene gly- cols, propylenglycole, polysorbates or other plasticizers.
• the amount of plasticizer is usually 10-50 % by weight of the over-coating layer forming material.
• Additives such as dispersants, colorants, pigments, polymers, anti- tacking agent and antifoaming agents may also be included into the over-coating layer.
• the maximum thickness of the applied over-coating layer is normally only limited by processing conditions .
• the pellets according to the invention can be used for the preparation of multiple unit tablets.
• enteric coated pellets with or without an over-coating layer are mixed with tablet excipients, such as fillers, binders, disintegrating agents, lubricants and other pharmaceutically acceptable additives, and compressed into tablets.
• tablet excipients such as fillers, binders, disintegrating agents, lubricants and other pharmaceutically acceptable additives
• the compressed tablet is optionally covered with a film forming agent to obtain a smooth surface of the tablet and further enhance the stability of the tablet during packaging and transport.
• the pharmaceutical composition is in form of tablets which comprise a tablet core, optionally a separating coating, and an enteric coating.
• the tablet cores are prepared from powder mixtures comprising the active substance and at least one pharmaceutically acceptable excipient by using the process of direct compression. Alternatively, said tablet cores can also be formed in the process of wet or dry granulation.
• the tablet cores comprise, besides pharmaceutically acceptable salts of esomeprazole, at least one excipient selected from stabilizers, fillers, disintegrating agents, wetting agents, binders or other pharmaceutically acceptable ingredients, alone or in mixtures.
• the stabilizer is preferably chosen among substances such as sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids, aluminium hydroxide/sodium bicarbonate coprecipitates, aluminium, calcium and magnesium hydroxides, magnesium oxide or composite substances such as Al 2 ⁇ 3-6MgOC ⁇ 2-12H 2 0, (Mg 6 Al 2 (OH) 16 CO 3 -4H 2 O) , MgO-Al 2 O 3 -2SiO 2 -nH 2 O or similar compounds, sodium lauryl sulphate, zinc hydroxide or hydroxide carbonate, alkaline reacting amino acids, their esters and salts, or other similar, pharmaceutically acceptable pH-buffering substances.
• substances such as sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids, aluminium hydroxide/sodium bicarbonate coprecipitates, aluminium, calcium and
• the filler is preferably selected from the group consisting of microcrystalline cellulose, sucrose, starch, lactose, mannitol, sorbitol and mixtures thereof.
• the disintegrating agent is preferably selected from the group consisting of starch, starch derivatives such as sodium starch glycolate or pregelatinized starch, low-substituted hydroxy- propyl cellulose, crospovidone, croscarmelose sodium and mixtures thereof.
• the wetting agent is preferably selected from the group consisting of sodium dodecyl sulphate, polyoxyethylene sorbitan fatty acid esters, poloxamers and mixtures thereof.
• the binder is preferably selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose and mixtures thereof.
• said tablet cores may optionally be covered with one or more separating layers comprising pharmaceutical excipients optionally including alkaline compounds, such as pH-buffering compounds.
• This layer/these layers separate (s) the core material from the outer enteric coating layer.
• the separating layer can be applied to the core by a coating or layering pro- cess in suitable equipment, such as a coating pan, a coating granulator or in a fluid bed apparatus using water and/or organic solvents for the coating process.
• the separating layer can be applied to the tablet core by using a suitable coating technique.
• the materials for separating lay- ers are pharmaceutically acceptable compounds, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethyl- cellulose sodium and others, used alone or in mixtures.
• Addi- tives such as plasticizers, colorants, pigments, fillers, anti-tacking agents and anti-static agents, such as magnesium stearate, titanium dioxide, talc and other additives may also be included into the separating layer.
• the separating layer may serve as a diffusion barrier and may act as a pH-buffering zone.
• the pH-buffering properties of the separating layer can be further strengthened by introducing into the layer substances chosen from a group of compounds usually used in antacid formulations, such as magnesium oxide, hydroxide or carbonate, zinc hydroxide or hydroxide carbonate, aluminium or calcium hydroxide, carbonate or silicate, composite aluminium/magnesium compounds, such as Al 2 ⁇ 3-6MgOC ⁇ 2-12H 2 0, (Mg 6 Al 2 (OH) 16 CO 3 -4H 2 O) , MgO-Al 2 O 3 -2SiO 2 -nH 2 O, aluminium hydroxide/sodium bicarbonate coprecipitates or similar compounds, or other pharmaceutically acceptable pH-buffering compounds, such a the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids, or suitable organic bases, including basic amino acids, esters
• Talc or other compounds may be added to increase the thickness of the layer and thereby strengthen the diffusion barrier.
• the optionally applied separating layer is not essential for the tablets according to the invention. However, the separating layer may improve the chemical stability of the active substance and/or the physical properties of the tablet. 3. Enteric layer
• enteric coating layers are applied onto the tablet cores or onto the tablet cores covered with separating layer (s) by using a suitable coating technique.
• the enteric coating layer material may be dispersed or dissolved in either water or in suitable organic solvents and preferably comprises a polymer.
• enteric coating layer polymers one or more, separately or in combination, of the following can be used: solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phtha- late, hydroxypropyl methylcellulose acetate succinate, polyvi- nyl acetate phthalate, cellulose acetate trimellitate, car- boxymethylethylcellulose, shellac or other suitable enteric coating layer polymer (s).
• the enteric coating layers may contain pharmaceutically ac- ceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers.
• plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibu- tyl sebacate, dimethyl polysiloxan, cetyl alcohol, stearyl al- cohol, polyethylene glycols, propylenglycole, polysorbates or other plasticizers.
• the amount of plasticizer is optimized for each enteric coating layer formula, in relation to selected enteric coating layer polymer (s), selected plasticizer (s) and the applied amount of said polymer (s) , in such a way that the mechanical properties, i.e.
• the amount of plasticizer is usually 10-50 % by weight of the enteric coating layer polymer (s).
• Additives such as dispersants, colorants, pigments, polymers, anti-tacking agent and antifoaming agents may also be included into the enteric coating layer (s) .
• Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the acid susceptible material.
• the enteric coating layer (s) constitutes a thickness of about at least 10 ⁇ m, preferably more than 20 ⁇ m.
• the maximum thickness of the applied enteric coating layer (s) is normally only limited by processing conditions.
• racemic omeprazole was tested with different chiral amines as resolving agents:
• (+) -quinidine, (-)-brucine, (-) -cinchonidine and (+) -alpha-phenylethylamine showed the best results, as seen on Tables 1-4.
• the solution of racemic omeprazole was prepared by dissolving 6.2 g of omeprazole in 36.0 ml dichlo- romethane/methanol (2:1) and an aliquot of 62.5 ⁇ l was added to the tube. After evaporation of the solvent, tube was filled up with appropriate solvent and heated slowly up to 80 0 C to ensure clear solution. The solution was allowed to cool to room temperature and then cooled to 0 - 4 0 C. From tube solvent was carefully removed and crystals were treated with 500 ⁇ l of 1 N sulfuric acid solution. The acidic solution was extracted with 200-300 ⁇ l of ethyl acetate. Ethyl acetate layer was sucked off in pre-weighed tube. The solvent was evaporated and tube was weighed. Residue was dissolved in 1 ml of methanol and specific optical rotation was measured.
• a second crop (0.7 g, m.p. 202-204 0 C, 98.5% d.e. determined by chiral HPLC) was obtained by concentrating the combined mother liquor and washings, and twice allowing recrystallization to proceed at room temperature for 24 hours.
• the obtained salt (5.2 g) was dissolved in a mixture of 25 ml of ethanol and 2.5 ml of water. To the solution was added 0.3 N hydrochloric acid solution under stirring in an ice bath to a pH value of 3-3.5, and the mixture was stirred at a temperature of 0 0 C for 1 hour. The solvent was evaporated in vacuo to give a semisolid mass, to which 20 ml of ethyl acetate were added. After stirring the mixture at room tempera- ture, the solid was filtered off. N-Benzylcinchoninium chloride was thus recovered in a yield of 99 % having a purity of 99 % (determined by HPLC) .
• (S) -omeprazole N-methylcinchonidinium salt was obtained from the concentrated mother liquor, i.e. the filtrate after filtration of the crystalline mass.
• the crystalline (S) -omeprazole N-methylcinchoninium salt was twice recrystallized from 2-butanone/butylacetate (1:3) and a small volume of ethanol; m.p 95-107 0 C, 98.5% d.e. (determined by chiral HPLC) .
• the resulting salt was twice recrystallized from 2-butanone and a small volume of ethanol to obtain crystalline (S)- omeprazole N-methylcinchoninium salt (m.p. 110-125 0 C, 99% d.e. (determined by chiral HPLC), [ ⁇ ] +21° (0.7, methanol)).
• To a suspension of the obtained salt (2.5 g) in toluene (70 ml) was added 3% aqueous hydrochloric acid at a temperature of 5-10 0 C to a pH value of 3. The mixture was stirred, filtered and the organic phase was decanted.
• (S) -omeprazole magnesium dihydrate form A was prepared according to example 6 of WO-A-98/54171.
• the (S) -omeprazole magnesium dihydrate form A was dried without subsequent milling.
• the (S) -omeprazole magnesium dihydrate form A was milled on Fitz D6A at 2000 rpm.
• the (S) -omeprazole magnesium dihydrate form A was dried using a fluid bed apparatus .
• the d x value indicates that a certain percentage X by volume of the particles has a size below a certain limit.
• a dgo value of 150 ⁇ m means that 90 % by volume of the particles have a diameter below 150 ⁇ m.
• Figure 1 depicts particle size distribution diagrams of un- milled and milled (S) -omeprazole magnesium dihydrate form A.
• the drug suspension was prepared by suspending (S) -omeprazole magnesium dihydrate form A, which had been obtained according to the invention, into an aqueous solution of povidone and sodium lauryl sulfate.
• Suspension layering of neutral pellets e.g. sugar or microcrystalline spheres
• the spray operation was stopped when the specified amount of bulk liquid had been sprayed.
• the prepared core material was dried until the loss on drying of the pellets was about 1-1.5 %. The pellets were then covered with two separating layers in a Wurster column.
• the suspensions used for preparing the separating layers both consisted of purified water, magnesium hydroxide carbonate heavy and Opadry powder mixture, the latter being composed of polyvinyl alcohol, talc, titanium dioxide and polyethylene glycol.
• the coated pellets were dried until the loss on drying was about 1-1.5 %.
• An enteric coating suspension was prepared using methacrylic acid ethyl acrylate copolymer (Eudragit L 30 D-55) , triethyl citrate, glyceryl monostearate and Polysorbate 80. The suspension was sprayed onto the pellets in a fluid bed apparatus. The spray operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the Wurster column. The obtained pellets were filled into hard gelatine capsules.
• Glycerol monostearate 16 1. 10 %
• Triethyl citrate 6. 47 3. 29 %
• the drug suspension was prepared by suspending (S) -omeprazole magnesium dihydrate form A, which had been obtained according to the invention, into an aqueous solution of povidone and so ⁇ dium lauryl sulfate. Suspension layering of sugar spheres was performed in a fluid bed processor using a bottom spray tech- nique (Wurster column) at a batch size of 3.0 kg. The spray operation was stopped when the specified amount of bulk liquid had been sprayed.
• the prepared core material was dried until the loss on drying of the pellets was about 1-1.5 %.
• the pellets were then cov- ered with a separating layer in a Wurster column.
• the suspension used for forming the separating layer consisted of purified water, methylcellulose and magnesium hydroxide carbonate heavy.
• the enteric coating suspension was prepared using methacrylic acid ethyl acrylate copolymer (Eudragit L 30 D-55) , triethyl citrate, glyceryl monostearate and Polysorbate 80.
• the suspen- sion was sprayed onto the pellets in a fluid bed apparatus. The spray operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the Wurster column.
• the obtained pellets were filled into HPMC capsules.
• the drug suspension was prepared by suspending (S) -omeprazole magnesium dihydrate form A, which had been obtained according to the invention, into an aqueous solution of povidone and so ⁇ dium lauryl sulfate. Suspension layering of sugar spheres was performed in a fluid bed processor using a bottom spray technique (Wurster column) at a batch size of 3.0 kg. The spray operation was stopped when the specified amount of bulk liquid had been sprayed.
• the prepared core material was dried until the loss on drying of the pellets was about 1-1.5 %.
• the pellets were then cov ⁇ ered with a separating layer in a Wurster column.
• the suspension used for preparing the separating layer consisted of purified water, methylcellulose and magnesium hydroxide carbon ⁇ ate heavy.
• the enteric coating suspension was prepared using methacrylic acid ethyl acrylate copolymer (Eudragit L 30 D-55) , triethyl citrate, glyceryl monostearate and Polysorbate 80.
• the suspen ⁇ sion was sprayed onto the pellets in a fluid bed apparatus. The spray operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the Wurster column.
• the assay of (S)- omeprazole in the solution (99.4 % ee) was determined (HPLC; 2.6 g, 7.53 mmol in 1890 ml) and an equivalent amount of a methanolic solution of magnesium methoxide (4.1 ml, 9.6 % solution, 3.76 mmol) was added.
• the solution obtained after magnesium methoxide addition was evaporated at 54 0 C at reduced pressure to obtain an oily residue (3.29 g) .
• the oily residue was dissolved in 6 ml of methanol at room temperature, and then 27 ml of an acetone/water mixture (4:1, v/v) was gradually added to the solution so that the temperature did not exceeded 25 °C.
• the suspension was stirred for 12 hours at 20 ⁇ 2 0 C, then 3 hours at 0 - 5 0 C, filtered and washed with 3 ml of acetone.
• Figure 2 depicts an X-ray powder diffraction pattern (Phillips PW3040/60 X' Pert PRO powder diffractometer; CuKa radiation 1.541874 A) of magnesium esomeprazole form F.
• Figure 3 depicts an X-ray powder diffraction pattern (Phillips PW3040/60 X' Pert PRO powder diffractometer; CuKa radiation 1.541874 A) of magnesium esomeprazole form G.
• the assay of (S)- omeprazole in the solution (98.5 % ee) was determined (HPLC; 1.32 g, 3.82 mmol in 880 ml) and an equivalent amount of methanolic solution of magnesium methoxide (2.1 ml, 9.6 % solution; 1.9 mmol) was added.
• the solution obtained after magnesium methoxide addition was evaporated at 50 0 C at reduced pressure to obtain an oily residue (1.54 g) .
• the oily residue was dissolved in 3 ml of methanol at room temperature, and then 13 ml of an acetone/water mixture (4:1, v/v) was gradually added to the solution so that the temperature did not exceeded 25 0 C.
• the suspension was stirred for 12 hours at 20 ⁇ 2 0 C, then 3 hours at 0 - 5 0 C, filtered and washed with 1.5 ml of acetone.
• Racemic omeprazole was subjected to preparative chromatography using (R) ⁇ -Burke column as the stationary phase and methanol as the mobile phase. Using these conditions R- (+) -omeprazole is the more retained component and will elute after S-(-)- omeprazole.
• Enantiomerically enriched omeprazole (ratio 70:30) was subjected to preparative chromatography using (R) ⁇ -Burke column as the stationary phase and methanol as the mobile phase. Using these conditions R- (+) -omeprazole is the more retained component and will elute after S- (-) -omeprazole . Chromatographic conditions:
• a racemic mixture of omeprazole was dissolved in methanol and sequentially diluted with 40% of methanol in 0.1 M Tris- hydrochloride buffer, pH 9.
• Solution of racemic omeprazole and enzyme (rCYP2C19) was added to 0.1 M Tris-hydrochloride buffer (pH 7.4) (final volume 200 ⁇ l) .
• the final pH value of the incubation mixture was kept at 7.4 and the methanol con- centration was less than 1%. After 5 min preincubation NADPH
• the reaction started by addition of NADPH after a preincubation of 5 min at 37°C. Reaction was conducted at 37°C for 20 min.
• omeprazole An amount of 10.0 g of omeprazole was suspended in 100 ml of acetone, 1.16 g of sodium hydroxide was added and heated to 35-40 0 C.
• Mixtures refer to the composition of the dry part of the mixture (weight / weight) .
• Dissolution in phosphate buffer of initial zinc esomeprazole, spray-dried zinc esomeprazole according to example 26. i. and the physical mixture of zinc esomeprazole and povidone according to example 26. ix. are compared in Figure 4.
• magnesium esomeprazole dihydrate (amorphous)
• magnesium esomeprazole dihydrate (degree of crystallinity
• Magnesium esomeprazole dihydrate according to b.) with defined degree of crystallinity was obtained by mixing of amorphous magnesium esomeprazole dihydrate and magnesium esomeprazole dihydrate with degree of crystallinity of 100 % (Form B according to Example 5 of EP-B-O 984 957) .
• Neutral pellets (microcrystalline cellulose or sugar spheres) were coated with pharmaceutically acceptable salt of esomeprazole in different manners:
• Example 28
• Pellets, obtained according to Example 27 were coated with separating layer.
• the following compositions of the separating layer were used:
• Pellets, obtained according to Example 28 were coated with enteric layer.
• the following compositions of the separating layer were used:
• Pellets, obtained according to Example 29 were coated with enteric layer.
• the following compositions of the overcoating layer were used:
• Pellets, obtained according to Example 30 were further ta- bleted.
• the following compositions of pellets and excipients were used:
• Pellets, obtained according to Example 27 were tableted and further coated with enteric coating.
• the compositions of pellets and excipients were used:
• Tablets obtained according to Example 31 and 32 were further coated with overcoating layer.
• the following composition of excipients was used:
• Example 27 The pharmaceutically acceptable salt of esomeprazole as described in Example 27. (a. - e.) were mixed in a high shear mixer (optionally in biconic blender) , directly compressed and coated according to example 32.
• composition of tablets comprising magnesium salt of esomepra- zole

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