OA11966A - Benzimidazole compound crystal. - Google Patents

Description

1 11966

DESCRIPTION

Benzimidazole Compound Crystal

TECHNICAL FIELD

The présent invention relates to a crystal of abenzimidazole compound showing antiulcer action.

BACKGROUND ART 2-1 [ [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl 3methyl] suif inyl ]-ΙΗ-benzimidazole or a saitthereof having an antiulcer action is reported in JP-A-61-50978, etc.

There is a demand for a more stable and excellentlyabsorbable antiulcer agent.

DISCLOSURE OF INVENTION

Having chiral suif ur in the molecular structure thereof,2-[ £ [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl3-lH-benzimidazole occurs in twokinds of optical isomers. After extensive exploration, the

I présent inventors succeeded in optically resolving andcrystallizing the (R)-isomer of 2-[[[3-methyl-4-(2.2,2-trif luoroethoxy} - 2 -pyr idinyl 3 methyl ] suif inyl 3-1H-benzimidazole, for the first time found that this crystalserves satisfactorily as a pharmaceutical, made furtherinvestigation based on this finding, and developed theprésent invention.

Accordingly, the présent invention relates to: [1] a crystal of (R)-2-[[[3-methyl-4-(2,2,2-trif luoroethoxy ) - 2 -pyridinyl ] methyl ] suif inyl 3 - 1H-benzimidazole or a sait thereof; [2] a crystal of (R)-2-[[t3-methyl-4-(2,2,2-trif luoroethoxy ) - 2 -pyridinyl ] methyl 3 suif inyl J - 1H-benzimidazole; (33 a crystal according to the above [2] wherein the X-ray 11966 2 powder diffraction analysis pattern has characteristic peaksat interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43, 4.09, 3.94, 3.89, 3.69, 3.41 and 3.11 Angstrom; [4] a pharmaceutical composition which comprises thecrystal according to the above [13; [ 5 ] a pharmaceutical composition according to the above [ 4 ],which is for treating or preventing digestive ulcer; [6] a method for treating or preventing digestive ulcer ina mammal in need thereof which comprises administering to saidmammal an effective amount of the crystal according to theabove [1] with a pharmaceutically acceptable excipient, î carrier or diluent; [71 use of the crystal according to the above [1] formanufacturing a pharmaceutical composition for treating orpreventing digestive ulcer, and so forth.

The "sait" of "(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]suifinyl]-1H-benzimidazole or a sait thereof" includes, for example, métalsalts, salts with organic bases, salts with basic araino acids,and so forth. Preferred are physiologically acceptablesalts. Métal salts include, for example, alkali métal saltssuch as sodium sait and potassium sait; and alkaline earthmétal salts such as calcium sait, magnésium sait and bariumsait. Salts with organic bases include, for example, saltswith trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, Ν,Ν-dibenzylethylenediamine, etc.

Salts with basic amino acids include, for example, salts witharginine, lysine, etc.

The crystal of (R)-2-[ [[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methyl]suifinyl]-1H-benzimidazole or a sait thereof may be a hydrate or not.

Said "hydrate" includes 0.5 hydrate to 5.0 hydrate. 3 11966

Among others, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate and 2.5 hydrate are pref erred. More preferred is 1.5 hydrate.

The crystal of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinylJmethyl]suifinyl]-1H-benzimidazole or a sait thereof can be produced by subjecting2 - [ [[3-methyl-4-{2,2,2-trifluoroethoxy)-2-pyridinyl]methyl)suifinyl)-ΙΗ-benzimidazole or a saitthereof to an optical resolution or subjecting 2-[[{3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl)methyl]thio]-ΙΗ-benzimidazole to an asymmetricaloxidization to obtain the (R)-isomer, followed bycrystallizing the résultant isomer.

Methods of optical resolution includes per se knownmethods, for example, a fractional recrystallization method,a chiral column method, a diastereomer method, and so forth.Asymmetric oxidation includes per se known method.

The "fractional recrystallization method" includes amethod in which a sait is formed between a racemate and anoptically active compound [e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.], which sait is separated byfractional recrystallization etc., and, if desired,subjected to a neutralization process, to give a free opticalisomer.

The "chiral column method" includes a method in whicha racemate or a sait thereof is applied to a column for opticalisomer séparation (chiral column). In the case of liguidchromatography, for example, optical isomers are separatedby adding a racemate to a chiral column such as ENANTIO-OVM(produced by Tosoh Corporation) or the DAICEL CHIRAL sériés(produced by Daicel Corporation), and developing the racematein water, a buffer (e.g., phosphate buffer), an organicsolvent (e.g., hexane, éthanol, methanol, isopropanol, 11966 4 acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.), or a solvent mixture thereof. In thecase of gas chromatography, for example, a chiral column suchas CP-Chirasil-DeX CB (produced by GL Science) is used toseparate optical isomers.

The "diastereomer method" includes a method in which aracemate and an optically active reagent are reacted(preferably, an optically active reagent is reacted to the1-position of the ben2imidazole group) to give a diastereomermixture, which is then subjected to ordinary séparation mean s(e.g., fractional recrystallization, chromatography, etc.)to obtain either diastereomer, which is subjected to aChemical reaction (e.g., acid hydrolysis, base hydrolysis,hydrogenolysis, etc. ) to eut off the optically active reagentmoiety, whereby the desired optical isomer is obtained. Said"optically active reagent" includes, for example, anoptically active organic acids such as MTPA [a-methoxy-a-(trifluoromethyl)phenylacetic acid] and (-)-menthoxyaceticacid; and an optically active alkoxymethyl halides such as(lR-endo)-2-(chloromethoxy)-1,3,3- trimethylbicyclo[2.2.1]heptane, etc. 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole or a saitthereof is produced by themethods described in JP-A-61-50978,USP 4,628,098 etc. or analogous methods thereto.

Methods of crystallization includes per se known methods,for example, a crystallization from solution, acrystallization from vapor, and a crystallization frommoltenf orm.

Methods of the "crystallization from solution” include,for example, a concentration method, a slow cooling method,a reaction method (diffusion method, electrolysis method),a hydrothermal growth method, a fusing agent method, and soforth. Solvents to be used include, for example, aromatichydrocarbons (e.g., benzene, toluene, xylene, etc.). 11966 5 halogenated hydrocarbons (e.g. , dichloromethane, chloroform,etc.), saturated hydrocarbons (e.g., hexane, heptane,cyclohexane, etc.), ethers (e.g., diethyl ether, diisopropylether, tetrahydrofuran, dioxane, etc.), nitriles (e.g.,acetonitrile, etc.), ketones (e.g., acetone, etc.),suifoxides (e.g., dimethylsulfoxide, etc.), acid amides(e.g., Ν,Ν-dimethylformamide, etc.), esters (e.g., ethylacetate, etc.), alcohols (e.g., methanol, éthanol, isopropylalcohol, etc.), water, and so forth. These solvents may beused singly or in mixture of two or more kinds in appropriâteratios (e.g., 1:1 to 1:100).

Methods of the "crystallization from vapor" include. forexample, a gasification method (sealed tube method, gasstream method), a gas phase reaction method, a Chemicaltransportation method, and so forth.

Methods of the "crystallization from molten form"include, for example, a normal freezing method (pulling-upmethod, température gradient method, Bridgman method) , a zonemelting method (zone leveling method, float zone method), aspécial growth method (VIS method, liquid phase epitaxismethod), and so forth.

For analyzing the crystal obtained, X-ray diffractioncrystallôgraphie analysis is commonly used. In addition,crystal orientation can also be determined by a mechanicalmethod, an optical method, etc.

Thus obtained crystal of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)- 2-pyridiny1]methy1]suif iny1]-1H-benzimidazole or a sait thereof (hereinafter also referredto as "crystal of the présent invention") is useful as apharmaceutical because it shows excellent antiulcer action,gastric acid secretion-inhibiting action, mucosa-protectingaction, anti-Hélicobacter pylori action, etc. , and becauseit is of low toxicity. Furthermore, by crystallizing the(R)-isomer, not only its stability is improved but also itshandling is f acilitated so that it can be prepared as a solid 11966 6 pharmaceutical composition with good reproducibility. Inaddition, when orally administered, the crystal of theprésent invention is more absorbable and more rapidly showsits action than the racemate. In addition, when administered,the crystal of the présent invention shows a higher Cmax(maximum blood concentration) and a greater AUC (area underthe concentration-time curve) than the racemate, and becomesmore unlikely to be metabolized partly because of theincreased protein-binding rate, thus showing an extendedduration of action. The crystal of the présent invention istherefore useful as a pharmaceutical of low doses and lowprevalence of adverse reactions.

The crystal of the présent invention is useful inmammals(e.g., humans, monkeys, sheep, bovines, horses, dogs, cats,rabbits, rats, roice, etc.) for the treatment and. préventionof digestive ulcer (e.g., gastric ulcer, duodenal ulcer,stomal ulcer, Zollinger-Ellison syndrome, etc.), gastritis,reflux esophagitis, NUD (non-ulcer dyspepsia), gastriccancer and gastric MALT lymphoma; Hélicobacter pyloriéradication; suppression of upper gastrointestinalhemorrhage due to digestive ulcer, acute stress ulcer andhémorrhagie gastritis; suppression of upper gastrointestinalhemorrhage due to invasive stress (stress from major surgerynecessitating intensive management after surgery, and fromcérébral vascular disorder, head trauma, multiple organfailure and extensive burn necessitating intensivetreatment ) ; treatment and prévention of ulcer caused by anonsteroidal anti-inflammatory agent; treatment andprévention of hyperacidity and ulcer due to postoperativestress; pre-anesthetic administration etc.

The crystal of the présent invention is of low toxicityand can be safely administered orally or non-orally (e.g.,topical, rectal and intravenous administration, etc.), assuch or in the form of pharmaceutical compositions formulatedwith a pharmacologically acceptable carrier, e.g., tablets 11966 7 (including sugar-coated tablets and film-coated tablets),powders, granules, capsules (including soft capsules),orally disintegrating tablets, liquids, injectablepréparations, suppositories, sustained-releasepréparations and patches, in accordance with a commonly knownmethod.

The content of the crystal of the présent invention inthe pharmaceutical composition of the présent invention isabout 0.01 to 100% by weight relative to the entirecomposition. Varying depending on sub ject of administration,route of administration, target disease etc., its dose isnormally about 0.5 to 1,500 mg/day, preferably about 5 to 150mg/day, based on the active ingrédient, for example, when itis orally administered as an antiulcer agent to an adult human(60 kg). The crystal of the présent invention may beadministered once daily or in 2 to 3 divided portions per day.

Pharmacologically acceptable carriers that may be usedto produce the pharmaceutical composition of the présentinvention include various organic or inorganic carriersubstances in common use as pharmaceutical materials,including excipients, lubricants, binders, disintegrants,water-soluble polymers and basic inorganic saits for solidpréparations; and solvents, dissolution aids, suspendingagents, isotonizing agents, buffers and soothing agents forliquid préparations. Other ordinary pharmaceuticaladditives such as preservatives, antioxidants, coloringagents, sweetening agents, souring agents, bubbling agentsand flavorings may also be used as necessary.

Such "excipients" include, for example, lactose,sucrose, D-mannitol, starch, cornstarch, crystallinecellulose, light silicic anhydride and titanium oxide.

Such "lubricants" include, for example, magnésiumstéarate, sucrose fatty acid esters, polyethylene glycol,talc and stearic acid.

Such "binders" include, for example, hydroxypropyl 11966 8 cellulose, hydroxypropylmethyl cellulose, crystallinecellulose, α-starch, polyvinylpyrrolidone, gum arablepowder, gelatin, pullulan and low-substitutionalhydroxypropyl cellulose.

Such "désintégrants" include (1) crosslinked povidone,(2) what is called super-disintegrants such as crosslinkedcarmellose sodium (FMC-Asahi Chemical) and carmellosecalcium (Gotoku Yakuhin), (3) carboxymethyl starch sodium(e.g., product of Matsutani Chemical), (4) low-substitutedhydroxypropyl cellulose (e.g., product of Shin-EtsuChemical), (5) cornstarch, and so forth. Said "crosslinkedpovidone" may be any crosslinked polymer having the Chemicalname l-ethenyl-2-pyrrolidinone homopolymer, includingpolyvinylpyrrolidone (PVPP) and l-vinyl-2-pyrrolidinonehomopolymer, and is exemplified by Colidon CL (produced byBASF), Polyplasdon XL (produced by ISP), Polyplasdon XL-10(produced by ISP) and Polyplasdon INF-10 (produced by ISP).

Such “water-soluble polymers" include, for example,éthanol-soluble water-soluble polymers [e.g., cellulosedérivatives such as hydroxypropyl cellulose (hereinafteralso referred to as HPC), polyvinylpyrrolidone] andethanol-insoluble water-soluble polymers [e.g., cellulosedérivatives such as hydroxypropylmethyl cellulose(hereinafter also referred to as HPMC), methyl cellulose andcarboxymethyl cellulose sodium, sodium polyacrylate,polyvinyl alcohol, sodium alginate, guar gum].

Such "basic inorganic salts" include, for example, basicinorganic salts of sodium, potassium, magnésium and/orcalcium. Preferred are basic inorganic salts of magnésiumand/or calcium. More preferred are basic inorganic salts ofmagnésium. Such basic inorganic salts of sodium include, forexample, sodium carbonate, sodium hydrogen carbonate,disodium hydrogenphosphate, etc. Such basic inorganic saltsof potassium include, for example, potassium carbonate,potassium hydrogen carbonate, etc. Such basic inorganic 9 1 19 6 6 *

P salts of magnésium include, for example, heavy magnésium carbonate, magnésium carbonate, magnésium oxide, magnésium hydroxide, magnésium metasilicate aluminate, magnésium silicate, magnésium aluminate, synthetic hydrotalcite 5 [Mg6Al2(OH)16,CO3,4H2O], alumina hydroxide magnésium, and so forth. Among othèrs, preferred is heavy magnésium carbonate,magnésium carbonate, magnésium oxide, magnésium hydroxide,etc. Such basic inorganic salts of calcium include, forexample, precipitated calcium carbonate, calcium hydroxide, 10 etc.

Such "solvents" include, for example, water forinjection, alcohol, propylene glycol, macrogol, sesame oil,corn oil and olive oil.

Such "dissolution aids" include, for example, 15 polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, éthanol, trisaminomethane, cholestérol,triethanolamine, sodium carbonate and sodium citrate.

Such "suspending agents" include, for example,surfactants such as stearyltriethanolamine, sodium lauryl 20 sulfate, laurylaminopropionic acid, lecithin, benzalkoniumchloride, benzéthonium chloride and monostearic glycerol;and hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethyl cellulose sodium,methyl cellulose, hydroxymethyl cellulose, hydroxyethyl 25 cellulose and hydroxypropyl cellulose.

Such "isotonizing agents" include, for example, glucose, D-sorbitol, sodium chloride, glycerol and D-mannitol.

Such "buffers" include, for example, buffer solutions of phosphates, acétates, carbonates, citrates etc. 30 Such "soothing agents" include. for example, benzyl alcohol.

Such "preservatives" include, for example, p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol,phenethyl alcohol, dehydroacetic acid and sorbic acid.

Such "antioxidants" include, for example, sulfites. 35 11966 10 ascorbic acid and a-tocopherol.

Such "coloring agents" include, for example, food colorssuch as Food Color YellowNo. 5, Food Color Red No. 2 and FoodColor Blue No. 2; and food lake colors and red oxide.

Such "sweetening agents" include, for example,saccharin sodium, dipotassium glycyrrhetinate, aspartame,stevia and thaumatin.

Such "souring agents" include, for example, citric acid{citric anhydride), tartaric acid and malic acid.

Such "bubbling agents" include, for example, sodiumbicarbonate. i

Such "flavorings" may be synthetic substances ornaturally occurring substances, and include, for example,lemon, lime, orange, menthol and strawberry.

The crystal of the présent invention may be prepared asa préparation for oral administration in accordance with acommonly known method, by, for example, compression-shapingit in the presence of an excipient, a disintegrant, a binder,a lubricant, or the like, and subseguently coating it asnecessary by a commonly known method for the purpose of tastemasking, enteric dissolution or sustained release. For anenteric préparation, an intermediate layer may be providedby a commonly known method between the enteric layer and thedrug-containing layer for the purpose of séparation of thetwo layers.

For preparing the crystal of the présent invention asan orally disintegrating tablet, available methods include,for example, a method in which a core containing crystallinecellulose and lactose is coated with the crystal of theprésent invention and a basic inorganic sait, and is furthercoated with a coating layer containing a water-solublepolymer, to give a composition, which is coated with anenteric coating layer containing polyethylene glycol,further coated with an enteric coating layer containingtriethyl citrate, still further coated with an enteric 119 6 6 11 coating layer containing polyethylene glycol, and stïll yetfurther coated with mannitol, to give fine granules, whichare mixed with additives and shaped. The above-mentioned"enteric coating layer" includes, for example, aqueousenteric polymer substrates such as cellulose acetatephthalate (CAP), hydroxypropylmethyl cellulose phthalate,hydroxymethyl cellulose acetate succinate, methacrylic acidcopolymers [e.g., Eudragit L30D-55 (trade name; produced byRohm), Colicoat MAE30DP (trade name; produced by BASF),Polykid PA30 (trade name; produced by San-yo Chemical)],carboxymethylethyl cellulose and shellac; sustained-releasesubstrates such as methacrylic acid polymers [e.g., EudragitNE30D (trade name), Eudragit RL30D (trade name), EudragitRS30D (trade name), etc.]; water-soluble polymers;plasticizers such as triethyl citrate, polyethylene glycol,acetylated monoglycerides, triacetine and castor oil; andmixtures thereof. The above-mentioned "additive" includes,for example, water-soluble sugar alcohols (e.g., sorbitol,mannitol, multitol, reduced starch saccharides, xylitol,reduced paratinose, erythritol, etc. ), crystalline cellulose[e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, AvicelPH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose ·carmellose sodium)], low-substituted hydroxypropylcellulose [e.g., LH-22, LH-32, LH-23, LH-33 (Shin-EtsuChemical) and mixtures thereof]; binders, souring agents,bubbling agents, sweetening agents, flavorings, lubricants, coloring agents, stabilizers, excipients, disintegrants etc.are also used.

The crystal of the présent invention may be used incombination with 1 to 3 other active ingrédients.

Such "other active ingrédients" include, for example,anti-Hélicobacter pylori activity substances, imidazolecompounds, bismuth salts, quinolone compounds, and so forth.Of these substances, preferred are anti-Hélicobacter pyloriaction substances, imidazole compounds etc. Such "anti- 11966 12 Hélicobacter pylori action substances" include, for example,antibioticpenicillins (e.g., amoxicillin, benzylpenicillin,piperacillin, mecillinam, etc.), antibiotic cefems (e.g.,cefixime, cefaclor, etc.), antibiotic macrolides (e.g.,erythromycin, clarithromycin. etc.), antibiotic tetracyclines (e.g., tétracycline, minocycline, streptomycin, etc.), antibiotic aminoglycosides (e.g.,gentamicin, amikacin, etc.), imipenem. and so forth. Ofthese substances, preferred are antibiotic penicillins,antibiotic macrolides etc. Such "imidazole compounds"include, for exemple, metronidazole, miconazole, etc. Such“bismuth salts" include, for example, bismuth acetate,bismuth citrate, etc. Such "guinolone compounds” include,for example, ofloxacin, ciploxacin, etc.

Such "other active ingrédients" and the crystal of theprésent invention may also be used in combination as a mixtureprepared as a single pharmaceutical composition [e.g.,tablets, powders, granules, capsules (including softcapsules), liguids, in jec table préparations, suppositories,sustained-release préparations, etc.], in accordance with acommonly known method, and may also be prepared as separatepréparations and administered to the same subjectsimultaneously or at a time interval.

BEST MODE FOR CARRYING OUT THE INVENTION

The présent invention is hereinafter described in moredetail by means of, but is not limited to, the followingreference examples, examples and experimental examples.

In the following reference examples and examples, theterm “room température" indicates about 15 to 30 ‘C.

Melting points were measured using the Micro MeltingPoint Apparatus (produced by Yanagimoto Seisakusho) , anduncorrected values are shown. ^•H-NMR spectra were determined with CDC13 as the solventusing Varian Gemini-200; data are shown in Chemical shift 13 1196 6 δ (ppm) from the internai standard tetramethylsilane. IR was determined using SHIMADZU FTIR-8200. UV was determined using the HITACHI U-3200 spectrophotometer.

Optical rotation [ct]D was determined at 20 °C using the DIP-370 digital polarimeter (produced by JASCO).

Optical purity was determined byHPLC (column: CHIRALCELOD4.6mmdia. * 250mm, température: about 20 °C, mobile phase:hexane/2-propanol « 80/20 or hexane/2-propanol « 85/15, flowrate: l.Oml/min, détection wavelength: 285 nm) using a chiralcolumn.

Crystal X-ray diffraction data for determining theabsolute structure of sulfoxide were obtained by means of a4-circle diffractometer (RIGAKU AFC5R) using the Cu-Kxa ray.After the initial phase was determined by the direct method,the fine structure was analyzed using SHELXL-93. X-raypowder diffraction was determined using the X-ray PowderDiffraction meter Rigaku RINT2500 (ultraX18) No. PX-3.

The other symbols used herein hâve the followingdéfinitions: s : singletd : doublett : tripletg : guartetm : multipletbs: broad singletJ : binding constant

Examples

Reference Example 1

Isolation of (R)-2-[([3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl3methyl3 suifinyl3 -1H-benzimidazole ( R ( + ) -lansoprazole) 2-[[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl ] methyl 3 suif inyl 1-1H-benzimidazole 11966 14 (lansoprazole) (racemate) (3.98 g) was dissolved in thefollowing mobile phase (330 ml) and acetonitrile (37 ml) andfractionated by HPLC (column: CHIRALCEL OD 20 mm dia. χ 250mm, température: 30 °C, mobile phase: hexane/2- propanol/éthanol - 255/35/10, flowrate: 16ml/min, détectionwavelength: 285 nm, 1 shot: 20-25 mg). Fractions of opticalisomers of shorter rétention time were combined andconcentrated; the individual lots were combined and dissolvedin éthanol and filtered through a 0.45 μτη fil ter ; af ter hexanewas added, the filtrate was again evaporated to dryness toyield R(+ )-lansoprazole (1.6 g, optical purity > 97.6%ee) asan amorphous substance.

The amorphous substance obtained was subjected tofractionation and isolation in the same manner as above toyield R(+)-lansoprazole (1.37 g. optical purity > 99.9%ee)as an amorphous substance.

[a]D - + 174.3° (C = 0.994%, CHC13)

Reference Example 2

Isolation of (R)-2-I[[3-methyi-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl)sulfinyl3-ΙΗ-benzimidazole (R(+)-lansoprazole)

Lansoprazole (racemate) (34.2 g) was dissolved in 2-propanol (1,710 ml) and hexane (1,140 ml) containingtriethylamine (0.2%) and fractionated by HPLC (column:CHIRALCEL OD 50 mm dia. * 500 mm, température: roomtempérature, mobile phase: hexane/2-propanol = 85/15, flowrate: 60 ml/min, détection wavelength: 285 nm, 1 shot: about300 mg) to isolate the individual optical isomers. Fractionsof an optical isomer of shorter rétention time were combinedand concentrated; the individual lots were combined anddissolved in éthanol (250 ml) ; after triethylamine (3 ml) wasadded, the solution was filtered through a 0.45 pm filter.After the filtrate was concentrated, hexane was added, andthe filtrate was again evaporated to dryness to yield 11966 15 R(+)-lansoprazole (9.31 g, optical purity 98.3%ee) as anamorphous substance.

Example 1 5 Crystal of (R)-2-[([3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]suifinyl]-lH-benzimidazole (R(+)-lansoprazole)

Amorphous R(+)-lansoprazole as obtained in ReferenceExample 1 (100 mg) was dissolved in acetonitrile (1 ml), which 10 was gradually evaporated at room température in a nitrogenstream. After a crystal began to form, diethyl ether (1.5ml) was added and the container was stoppered and keptstanding at room température.

The crystal thus formed was subjected to X-ray 15 structural analysis, and the absolute configuration of sulfoxide was found to be the R-configuration by a methodusing a Flack parameter. The remaining portion of the crystalwas collected by filtration, twice washed with diethyl ether(1 ml), and dried under reduced pressure, to yield crystals 20 of R(+)-lansoprazole (38 mg).m.p.: 144.0-144.5 °C (dec.)

Elemental analysis

Calculated: C: 52.03, H: 3.82, N: 11.38, S: 8.68, F: 15.43,0:8.66 25 Found: C: 52.08, H: 3.76, N: 11.58, S: 8.75, F: 15.423-H-NMR: 2.25(3H,s), 4.40( 2H, q, J=7.8Hz ) , 4.68(1H,d,J=13.8Hz), 4.85(1H,d,J=13.8Hz), 6.69{1H,d,J=6.0Hz), 7.29-7.39(2H,m), 7.52(lH,m),7.81(lH,m), 8.37(lH,d,J=6.0Hz),11.00(lH.bs). 30 IR(Vcm_1): 3081, 3042, 2984, 1586, 1478, 1441, 1306. 1267,1163. UVmax(CHCl3): 283.7 nm [a]D = + 199.2° (c = 0.202%, CHC13) 11966 16

Table 1

Crystal Data and Structure Refinement Parameters

Molecular formula

Molecular weightCrystal color, habitCrystal DimensionCrystal SystemLattice constants

Space group :

Z

Density (calculated) :

Effective reflectionnumber/parameter number :

Rds 2σ(Ι>)

Flack parameter :

C16HlA°2F3S 369.36

Colorless, tabular0.40 x 0.30 x 0.04 (mm)Monoclinic a » 8.549(1) (À)b - 23.350(1) (Â)c = 8.720(2) (À)β - 103.90(1) (·) V « 1,689.8(4) (À) P2 j 4 1.452 (g/cm^) 9.12 0.036 -0.02(2) 5 Example 2

Crystal of (R) -2- [ [ [3-methyl-4- ( 2,2,2-trifluoroethoxy) -2-pyridinyl)methyl]suifinyl] -lH-benzimidazole (R( + ) -lansoprazole)

Amorphous (R)-2-[[[3-raethyl-4-(2,2,2- 10 trif luoroethoxy ) - 2-pyridinyl Jmethyl ] suif inyl ] - 1H- benzimidazole as obtained in Reference Example 2 (9.17 g) wasdissolved in acetone (20 ml), and water (15 ml) was added withgentle heating. After the solution was kept standing at roomtempérature overnight, water (20 ml) was added, followed by 15 ultrasonication. After being collected by filtration, thesolid was washed with water (30 ml, 20 ml), then washed withdiisopropyl ether (20 ml), and dried under reduced pressure, 11966 17 to yield a solid (9.10 g). The solid obtained (9.00 g) wasdissolved in acetone (30 ml), and after the solution wasfiltered, diisopropyl ether (50 ml) was added to the filtrate.A crystal seed was placed, and the mixture was kept standingat room température overnight. Precipitated crystals werecollected by filtration, washed 3 times with diisopropylether (10 ml), and dried under reduced pressure, to yieldcrystals (7.85 g). The crystals obtained (7.80 g) weredissolved under heating in acetone (22.5 ml) and water (30ml), and this solution was kept standing at room températurefor 1 hour. A precipitated solid was collected by filtration,washed with acetone-water (1:4) (15 ml), and dried underreduced pressure, to yield a solid (3.88 g). The solidobtained (3.88 g) was dissolved under heating in acetone (4ml) and diisopropyl ether (14 ml) was added. This solutionwas kept standing at room température for 30 minutes.Precipitated crystals were collected by filtration, twicewashed with diisopropyl ether (6 ml), and dried under reducedpressure, to yield crystals of R(+)-lansoprazole (3.40 g,optical purity 99.8%ee). m.p.: 147.0-148.0 °C (dec.)

Elemental analysis

Calculated: C: 52.03, H: 3.82, N: 11.38, S: 8.68. F: 15.43,O: 8.66

Found: C: 51.85, H: 3.92, N: 11.26, S: 8.82, F: 15.22 1H-NMR: 2.24(3H,S), 4.38(2H,q,J=7.8Hz). 4.74(lH,d,J=13.6Hz), 4.87(1H,d.J=13.6Hz), 6.68(1H,d,J=5.8Hz), 7.26-7.36(2H,m), 7.45(lH,m),7.78(lH,m), 8.35(lH,d,J=5.8Hz). IRiVcm"1): 3083, 3034, 2975, 1586, 1478, 1441, 1306, 1267,1163 UVmax(CHCl3): 283.6 nm [a)D = + 180.3° (c = 1.004%, CHC13) 18 X-ray Powder Diffraction Data 11966

Table 2 20 (e ) Half-value width d-value (Â) Relativeintensity {%) 7.560 0.141 11.6841 100 13.060 0.165 6.7733 44 15.160 0.141 5.8394 55 15.440 0.141 5.7342 84 20.040 0.165 4.4271 23 21.720 0.165 4.0883 89 22.560 0.141 3.9380 24 22.820 0.141 3.8937 24 24.080 0.165 3.6927 37 26.120 0.118 3.4088 32 28.680 0.165 3.1100 20

Exemple 3

Crystal of (R)-2-[[[3-methyl-4-(2,2,2~trifluoroethoxy)-2-pyridinyl3methyl)sulf inyl3-lH-benzimidazole (R(+)-lansoprazole) 1.5 hydrate

Amorphous (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy ) - 2 -pyridinyl Jmethyl ] suif inyl ] - 1H-benzimidazole as obtained in Reference Example 1 (100 mg) wasdissolved in éthanol ( 0.15 ml), and water ( 0.15 ml) was added.After a seed was placed, the solution was kept standing atroom température for 1 hour. Precipitated crystals werecollected by filtration, twice washed with water (2 ml) , anddried under reduced pressure, to yield crystals of (R)-2-[ [ [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinylJmethylJsuifinyll-lH-benzimidazole (R(+)-lansoprazole) 1.5 hydrate (96 mg).

m.p.: 76.0-80.0 °C

Elemental analysis

Calculated: C: 48.48, H: 4.32, N: 10.60, S: 8.09, F: 14.38,O: 14.13 11966 19

Pound: C: 48.52, H: 4.44, N: 10.49

Table 3 X-ray Powder Diffraction Data 2Θ C ) Half-value width d-value (A) Relativeintensity (%) 6.680 0.165 13.2212 9 9.200 0.165 9.6046 21 9.960 0.141 8.8734 25 10.980 0.165 8.0513 42 13.380 0.141 6.6120 22 14.960 0.141 5.9170 63 15.680 0.165 5.6469 100 17.640 0.212 5.0237 34 19.760 0.212 4.4892 33 25.420 0.188 3.5010 23 29.800 0.188 2.9957 20

Experimental Example 1

Suppressive action on gastric mucosal injury due tostress of water immersion restraint in rat

Male SD rats (7 weeks of âge, weighing 230 to 250 g) were 10 fasted for 24 hours, after which they were stressed by beinghoused in restraint cages and immersed to below the xiphoidprocess in a standing position in a 23 °C constant-températurewater cbamber. After 5 hours, the rats were removed from thecages and sacrificed using gaseous carbon dioxide, and their 15 stomachs excised. After the lower portion of the esophaguswas clipped, a 1% formalin solution (10 ml) was injected intothe stomach via the duodénum, which was then occluded, andthe stomach was immersed in thesame solution. After 10minutes, an incision was made along the greater curvature, 20 and the length (mm) of each mucosal in jury was measured undera stereomicroscope. The overall sum of the in jury lengthsin each stomach was taken as the gastric mucosal in jury index. 119 66 20

The crystals of (R)-2-[[[3-methyl-4-( 2,2,2-trifluoroethoxy ) - 2-pyridinyl ]methyl ] suif inyl ] - 1H-benzimidazole (R(+)-lansoprazole) as obtained in Example 2were suspended in 0.5% methyl cellulose (pH 9.5) containing0.05 M NaHCO3 and orally administered at 30 minutes beforestressing (dosing volume 2 ml/kg). Each treatment groupcomprised 9 animais. The control group (solventadministration group) and the drug administration group werecompared by Steel's test.

The results are shown in Table 4.

Table 4

Sample Dose Gastric mucosal Suppression (mg/kg) injury index (mm) rate (%) Control - 10.9 ± 1.9 - (R)-lansoprazolecrystal 3 0.2 ± 0.2* 98.0

Each figure of gastric mucosal injury index is the mean ±standard error for the 9 animais in each group. *p < 0.01 (versus control group, Steel·s test)

Experimental Example 2

The crystals of R( + ) -lansoprazole as obtained in Example2 (about 5 mg) and amorphous R(+ )-lansoprazole as obtainedin Reference Example 1 (about 5 mg) were each taken in acolorless glass bottle, and their stability during storageat 60 ‘C (stopper removed) was examined. A 25 ml solution(concentration: about 0.2 mg/ml) of the sample aftercompletion of storage in the mobile phase, along with astandard solution prepared using the initial lot, wasanalyzed under the HPLC conditions shown below, and theR{+)-lansoprazole content (residual percentage) wascalculated from the peak area obtained. The results are shownin Table 5. HPLC analytical conditions Détection wavelength : UV 275 nm 11966 21

Column : YMC Pro C18, 4.6 χ 150 mm

Mobile phase : Fluid prepared by adding phosphoric acid towater/acetonitrile/triethylamine (63:37:1) to reach pH 7.

Flow rate : 1.0 ml/min

Column température : 40 "C

Sample injection volume : 10 μΐ

Table 5

Stability of R(+)-Lansoprazole Crystal and Amorphous

Sample Duration ofstorage Description Content (Residualpercentage) Crystal 1 week Light-brown 97.0 2 weeks Brown 93.8 4 weeks Brown 91.7 Amorphous 1 week Brown 70.8 2 weeks Blackish brown 57.5

When the sample was stored at 60 ’C (exposed), thecrystal of Example 2 retained a content exceeding 90% for upto 4 weeks, whereas the amorphous form of Reference Example1 showed réduction in content to 70.8% after 1 week and 57.5%after 2 weeks. This finding demonstrates that the crystalof R(+)-lansoprazole is more stable and more préférable foruse as a pharmaceutical etc. than the amorphous form.

INDUSTRIAL APPLICABILITY

The crystal of the présent invention is useful as apharmaceutical because it shows excellent antiulcer action,gastric acid secretion-inhibit action, mucosa-protectingaction, anti-Hélicobacter pylori action etc. , and because itis of low toxicity. Furthermore, by crystallizing the(R)-isomer, not only its stability is improved but also itshandling is facilitated so that it can be prepared as a solidpharmaceutical composition with good reproducibility. In 11966 22 addition, wheh orally administered, the crystal of theprésent invention is more absorbable and more rapidly showsits action than the racemate. In addition, when administered,the crystal of the présent invention shows a higher Cmax and5 a greater AUC than the racemate, and becomes more unlikelyto be metabolized partly because of the increasedprotein-binding rate, thus showing an extended duration ofaction. The crystal of the présent invention is thereforeuseful as a pharmaceutical of low doses and low prevalenceof adverse reactions. 10

Claims (6)

11966 23 CLAIMS 1. A crystal of (R) -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole or is known from those. 2. A crystal of (R) -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl) methyl] sulfonyl] -1H-benzimidazole. 3. A diffraction analysis pattern has characteristic peaks at interplanar spacings (d) of 11.68, 6.77, 5.84, 5.73, 4.43.4.09, 3.94, 3.89, 3.69, 3.41 and 3.11 Angstrom. 4. A pharmaceutical composition which includes thecrystal according to claim 1. 15 5. A pharmaceutical composition according to Claim 4, which is for treating or preventing digestive ulcer. Use of the crystal according to Claim 1 for pharmaceutical composition for treating or preventing ulcer.