WO2008077866A1 - Process for manufacturing microcrystalline lansoprazole form i - Google Patents
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- Publication number
- WO2008077866A1 WO2008077866A1 PCT/EP2007/064255 EP2007064255W WO2008077866A1 WO 2008077866 A1 WO2008077866 A1 WO 2008077866A1 EP 2007064255 W EP2007064255 W EP 2007064255W WO 2008077866 A1 WO2008077866 A1 WO 2008077866A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lansoprazole
- water
- acetonitrile
- hydrate
- process according
- Prior art date
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- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical group CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 title claims abstract description 129
- 229960003174 lansoprazole Drugs 0.000 title claims abstract description 129
- 238000000034 method Methods 0.000 title claims abstract description 90
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 81
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000012453 solvate Substances 0.000 claims description 30
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 25
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 21
- 239000002245 particle Substances 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 4
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical group CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 2
- 239000010419 fine particle Substances 0.000 abstract description 11
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 22
- 239000013078 crystal Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 238000012937 correction Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 238000002803 maceration Methods 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 101000939456 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 29 Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102100029818 Ubiquitin carboxyl-terminal hydrolase 29 Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- ZFSFDELZPURLKD-UHFFFAOYSA-N azanium;hydroxide;hydrate Chemical compound N.O.O ZFSFDELZPURLKD-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 238000004438 BET method Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 238000001159 Fisher's combined probability test Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000013038 hand mixing Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002879 macerating effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- -1 or their admixtures Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
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
Definitions
- the present invention relates to a new process for manufacturing a crystal form of Lansoprazole, form characterized by a particularly fine particle size, especially suitable for industrial use.
- Lansoprazole itself is characterized by an intrinsic instability and therefore, during its manufacturing or the subsequent work-up, it tends to give degradation by-products, especially under acidic conditions.
- raw Lansoprazole generally contains several impurities and shall be consistently purified in order to achieve the high standards required for pharmaceuticals, with a significant reduction of yields and, more generally, with a worsening in the overall process economy.
- the finished Lansoprazole powder shall disclose specific physical properties too (such as density, porosity, wettability, flowability, hygroscopicity, dissolution rate etc.), properties which significantly impact on stability, formulation and bioavailability of the API and which depend - inter alia - on the particle size, the surface area, the crystal or amorphous form, the crystal habitus and the possible presence of residual solvents.
- specific physical properties such as density, porosity, wettability, flowability, hygroscopicity, dissolution rate etc.
- Form A (page 4) can be prepared by crystallization from methanol, n-butanol, acetone, methylethylketone, ethyl acetate, dimethylsulfoxide, dimethylformamide, optionally in admixture with water;
- Form D (page 5) by crystallization from 2-propanol - water;
- Form E (page 5) by crystallization from 2- propanol-water and subsequent drying at a temperature lower than 40 0 C or by grinding Form D (page 7); the amorphous form (page 6) by crystallization from 2-propanol - water and subsequent drying at a temperature between 40 and 50 0 C;
- Form F (page 7) by exposure of a methanol solution to methanol-water saturated vapors.
- WO07/078154 in the name of Daewoong Pharmaceutical discloses a process for manufacturing Lansoprazole Form A by crystallization from ethanol and water.
- US6002011 highlights the instability of Lansoprazole solvated forms, especially in the final drying stage, and describes the manufacturing of a stable desolvated form by suspending crystalline solvated Lansoprazole in warm water under stirring;
- Example 1 describes said preparation from crystalline Lansoprazole hydrate ethanolate by suspension in water at 30 0 C, under stirring for 1 hour.
- the final product has a water and ethanol content equal to 0.01% and 63 ppm respectively and melting point of 177-8°C (dec).
- KR100433735 in the name of Chem Tech Research Inc.
- C-TRI discloses a method for purification and conversion of the crystal Form II into Form I by suspending under stirring in organic solvents and their admixtures, preferably in hexane/i-propylether or hexane/acetone admixtures.
- solvents of low polarity hexane, i-propyl ether or methylene dichloride, ex 1, 11, 12 or hexane: acetone 2-5:1 admixtures, ex. 3-7) while more polar solvents (acetone, ethyl acetate, acetonitrile ex. 8-10 or the hexane:acetone 1 :1 admixture, ex.
- the international application WO2006/74952 in the name of Krka describes a process for manufacturing solid Lansoprazole with a high surface area, which essentially comprises a first precipitation stage (a'-c' steps) and a second maceration stage (d'-e' steps).
- the first stage comprises precipitating Lansoprazole by cooling and/or water addition to its aqueous, ethanol, acetone, 1 -methyl-2-pyrrolidone, or their admixtures, solutions in the presence of a base.
- Lansoprazole crystal Form A with a surface area between 1.5 and 7.0 m 2 /g (measured according to the BET method as described at page 12 of the Krka application) is obtained.
- the examples only describe the use of water for the suspension stage and the only value of surface area therein reported (4.67 m 2 /g; ex. 4) is referred to a sample subjected to a double maceration in water.
- object of the present invention is a process for manufacturing microcrystalline Lansoprazole Form I which comprises: a) contacting Lansoprazole with a liquid medium comprising acetonitrile and water, in which the percentage of water in the resulting admixture is between 0.6 and l ⁇ % (w/w), b) bringing the temperature of the medium at a value between 15 and 50 0 C, c) keeping the contact up to complete conversion; and d) separating the so obtained microcrystalline Lansoprazole Form I.
- Microcrystalline Lansoprazole Form I prepared according to the present process, is a desolvated form, namely a form with a low content of residual solvents, generally comprising water in amount lower than 0.5% (w/w), preferably lower than 0.1%, acetonitrile in amount lower than 400 ppm, preferably lower than 300 ppm, and optionally traces of other solvents coming from Lansoprazole used as starting material in step a).
- w/w residual solvents
- acetonitrile in amount lower than 400 ppm, preferably lower than 300 ppm
- optionally traces of other solvents coming from Lansoprazole used as starting material in step a for example, starting from Lansoprazole hydrate ethanolate a product comprising also ethanol, in amount generally lower than 50 ppm, preferably lower than 10 ppm, will be obtained.
- Microcrystalline Lansoprazole Form I prepared according to the conversion process of the invention, shows a very good filtrability and is characterized by a particularly fine particle size, generally lower than the one obtainable with the processes of Takeda (US6002011), Krka (WO2006/74952) and Chem Tech Research Inc (KRl 00433735) previously described (see comparative examples 12, 15 and 16).
- the particle size of the Lansoprazole powder prepared according to the present process is generally lower than 40 ⁇ m, preferably between 15 and 30 ⁇ m, more preferably between 20 and 25 ⁇ m, and - as D 50 - generally lower than 20 ⁇ m, preferably lower than 15 ⁇ m.
- Lansoprazole shows an overall content of impurities generally lower than 0.6 % , preferably lower than 0.3%, more preferably lower than 0.2 %, detected by HPLC method (Pharmacopoeia USP29 HPLC method).
- step a) of the present conversion process Lansoprazole means a crystalline form of
- Lansoprazole optionally solvated and/or in admixture with other crystalline forms and/or with the amorphous form, preferably a single crystalline form optionally solvated.
- Lansoprazole may be selected among the forms described in the literature such as Lansoprazole hydrate ethanolate (US6002011), Lansoprazole ethanolate (Farm. Vest. 48, 242-243, 1997), Lansoprazole A, B, D, E or F forms (WO03/082857),
- Lansoprazole forms I or II (WO00/078729), the solid forms obtained from l-methyl-2- pyrrolidone by precipitation according to the process described in WO2006/74952 (Krka, ex.
- Lansoprazole hydrate acetonitrile solvate a new form prepared and characterized as described at example 1 of the present experimental part.
- the starting Lansoprazole for the conversion process is selected among
- Lansoprazole hydrate acetonitrile solvate is prepared according to a process which comprises: e) dissolving Lansoprazole in an admixture of acetonitrile and water, at a pH value higher than 10; f) acidifying the solution up to a pH between 8 and 10; g) collecting the precipitated Lansoprazole hydrate acetonitrile solvate.
- the acetonitrile/water weight ratio in the admixture is generally from 2:1 to 8:1 for acetonitrile and from 0.25:1 to 1 :1 for water, preferably it is of about 4:1 for acetonitrile and 0.5: 1 for water with respect to Lansoprazole (w/w).
- Lansoprazole used in step e) may be anyone of the known pure crystalline or amorphous forms or their admixtures or, preferably, a raw form as obtained after work-up of the oxidation reaction of the sulfide of formula II.
- the pH of the admixture in step e) is suitably corrected at a pH higher than 10, preferably higher than 11 , more preferably at about 13 with a base, preferably with an alkaline or earth- alkaline base, more preferably with sodium hydroxide.
- a base preferably with an alkaline or earth- alkaline base, more preferably with sodium hydroxide.
- sodium hydroxide is used in an equivalent ratio between 1 :1 to 2:1, preferably between 1.1 :1 and 1.5:1 with respect to Lansoprazole.
- the resulting solution may be, optionally, decolorized and filtered according to known techniques, and then subjected to step f).
- step f) of the present process the pH of the, optionally decolorized and filtered, solution is generally brought up to a value between 8 and 10, preferably between 8.5 and 9.5, more preferably at about 9, by adding a suitable amount of an acid, preferably a weak acid, such as ammonium acetate, benzoic acid, p-methoxybenzoic acid or acetic acid, more preferably acetic acid.
- a weak acid such as ammonium acetate, benzoic acid, p-methoxybenzoic acid or acetic acid
- the solution is seeded with crystals of Lansoprazole Form I.
- the resulting admixture is generally left, under rest or stirring conditions, preferably under stirring conditions; it is preferably cooled below room temperature, more preferably at about 0-5 0 C, in order to favor the precipitation of Lansoprazole hydrate acetonitrile solvate.
- the precipitated Lansoprazole hydrate acetonitrile solvate is then collected, preferably by filtration (step g), dried or, preferably, directly subjected to the conversion process object of the present invention.
- Lansoprazole hydrate acetonitrile solvate is characterized by the following analysis: IR (method USP 29) (cm 1 ): 3433.2; 3258.1; 2360.3; 1640.3; 1583.2; 1475.5; 1408.3; 1313.1 ; 1266.4; 1223.0; 1173.3; 1112.2; 1086.0; 1047.1; 973.8; 914.0; 858.8; 802.2; 763.9; 744.3.
- X-ray powder diffraction (instrument Broker D8 Advance equipped with Cu anode (1.54 Angst); Current 40 mA; Voltage 40 kV; Measurement range: 3-35°; Step Size: 0.02°; Scan rate: 2 sec/step): 2-theta (degrees! 0.05) and relative intensities are reported in Table III.
- K.F. water content between 1 and 4, preferably between 1.5 and 2.5, more preferably at about 2.2 (% w/w).
- Lansoprazole hydrate acetonitrile solvate in a preferred embodiment, can be directly subjected to the conversion process object of the present invention without a forced drying, with evident advantages in terms of stability, time and costs.
- the conversion process object of the present invention may also be performed by using "non standard" Lansoprazole as starting material in step a), meaning with this term a Lansoprazole whose IR analysis does not exactly correspond to that of one of the forms previously mentioned (example 10 of the present invention).
- step a) of the present process the term “contacting” means to put in contact Lansoprazole with the indicated liquid medium, thus obtaining a solid-liquid biphasic system in which Lansoprazole remains substantially undissolved.
- the liquid medium in step a) comprises acetonitrile and water, wherein water is present in the final admixture in a percentage between 0.6 and 10% (w/w), preferably between 2 and 6%, more preferably between 3 and 4%.
- the liquid medium may optionally comprise other solvents too, such as for example ethanol or dimethylacetamide, generally in low percentages, but preferably comprises acetonitrile, water and only possible traces of other solvents deriving from the starting Lansoprazole solvates, such as for example ethanol in case Lansoprazole hydrate ethanolate is used.
- the water percentage in the admixture is referred to the final admixture of Lansoprazole, acetonitrile, water and other optional solvent, namely to the admixture obtained by contacting Lansoprazole with the liquid medium, preferably under stirring and, optionally, by correcting the same water content up to the desired value.
- the order of addition of the admixture components and the way of correction of water content do not represent a limitation of the present invention, provided that the final admixture comprises water according to the desired percentages.
- the admixture can be prepared by first suspending Lansoprazole in water and then by adding acetonitrile or by directly suspending Lansoprazole in prearranged admixtures of acetonitrile and water or, preferably, by suspending Lansoprazole in acetonitrile alone and by adding water up to the desired percentage.
- the way of correction above mentioned may include more variants, for example water and/or acetonitrile content may be increased, by their separated or contemporaneous addition, or decreased by controlled removal, for example by more or less forced drying of the starting Lansoprazole or by acting on the admixture by azeotropic distillation or other compatible dewatering techniques, always provided that the final water percentage is within the desired values.
- the amount of water present in the system before the correction may vary depending on several factors, for example on the hydration of the starting Lansoprazole or the water content of the acetonitrile used, but it generally does not represent a limitation of the process of the present invention.
- the skilled in the art may proceed by measuring the water content of the admixture and, accordingly, may decide any correction needed in order to bring the water percentage within the desired limits.
- the measure of the water content in the admixture may be performed according to any suitable method, preferably by Karl-Fischer method.
- the liquid medium is generally used in a ratio between 2:1 and 20:1 (v/w), preferably between 2:1 and 10:1, more preferably between 2:1 and 5:1, even more preferably at about 3 : 1 with respect to the starting Lansoprazole.
- the use of such little volumes of liquid medium is particularly advantageous from the industrial point of view and generally, it consents to maintain a good stirring of the admixture and to plainly proceed with the subsequent filtration.
- the liquid medium may optionally comprise an organic base, for example an amine such as triethylamine, methylamine, pyridine, ethanolamine, sodium or potassium acetate or an inorganic base, for example alkaline or alkaline-earth hydroxides, ammonia, preferably ammonium hydroxide.
- the present process just because avoids the dissolution of Lansoprazole and the substantial use of water - conditions under which Lansoprazole is more easily subjected to degradation - consents to minimize the amount of base instead.
- the base in a molar ratio lower than 1 :1, more preferably lower than 0.5:1, even more preferably at about 0.3:1 with respect to Lansoprazole, with significant industrial advantages.
- the percentage of water in the final admixture shall be measured and, optionally, corrected by considering the water coming from the added basic solution too.
- step b) of the present process the admixture of Lansoprazole, acetonitrile, water and, optionally, base is brought to a temperature generally between 15 and 50 0 C, preferably between 25 and 40 0 C, more preferably at about 35°C and kept at such temperature, preferably under stirring, up to complete conversion of the crystal form and/or obtainment of the desired fine particle size (step c).
- the conversion times of the present process are short and, generally, shorter than those of the processes described in the prior art - for example in WO2006/074952 (Krka, ex. 2e two hours, ex. 4 two macerations of two hours each) or by US6002011 (Takeda, ex.
- the admixture is preferably cooled at temperatures generally comprised between 0 and 10 0 C, preferably between 0 and 5°C, and microcrystalline Lansoprazole Form I is isolated according to conventional techniques, such as for example by decantation, centrifugation or, preferably, filtration (step d).
- the product cake is then, preferably, washed with admixtures of acetonitrile, water and, preferably, traces of a base, such as ammonium hydroxide.
- the final product drying is performed at a temperature between 20 and 50 0 C, preferably at about 40 0 C, at atmospheric pressure or, preferably, under vacuum, for industrial times generally shorter than 20 hours, preferably for about 8-10 hours, in any case for variable times depending on several factors such as for example the amount of the product to be dried, the dryer used and the vacuum conditions applied.
- liquid medium herein used substantially acetonitrile with a controlled percentage of water, avoids the typical degradations associated with the use of an aqueous medium. Further, due to the lower polarity with respect to water alone, it may exert a selective purification towards possible less polar impurities which the aqueous medium alone is not able to eliminate.
- Another advantage of the present process due to the higher volatility of the liquid medium in comparison with water alone, is represented by a drying step under milder conditions and/or with reduced times and, consequently, by a lower degradation of the product and retention of the white colour of the powder.
- the process object of the present invention is additionally characterized by high yields, generally higher than 90%, preferably than 93%, more preferably than 95%. Further the present process, unlike the reporting of, for example, WO2006/074952 (Krka, ex.
- Lansoprazole hydrate acetonitrile solvate (prepared according to example 1), acetonitrile (3 v/w) and 30% aq. ammonium hydroxide (0.08 v/w) are introduced into a reactor at room temperature, under stirring.
- the percentage of water in the admixture is measured (K.F.). Water is added up to a K.F. 3.5-4%, the admixture is brought at 35°C and kept under stirring for about 30 minutes. It is cooled at about 0-5 0 C and it is left under stirring at that temperature for about 2 hours. It is filtered, the cake is washed with acetonitrile/water/30% ammonium hydroxide (35:1:1 v/v/w with respect to
- Example 1 Preparation Lansoprazole hydrate acetonitrile solvate.
- 340 g of raw Lansoprazole prepared for example as described in EPl 74726
- 1530 ml of ACN 85 ml of water
- 101 g of 30 % aq. NaOH (1.1 eq) up to a pH of about 13 were charged into a 5 1 reactor at room temperature, under stirring.
- a complete dissolution was obtained.
- the solution was decolorized with charcoal (15 g) and dicalite (22 g), kept under stirring for 30 min., filtered and washed with 340 ml of 90 % aq. ACN.
- AcOH 33 g, 0.9 eq
- Example 2 preparation of Lansoprazole hydrate ethanolate Lansoprazole hydrate ethanolate was prepared as described in the reference example 6 of US6002011 (Takeda).
- Example 3 a preparation of Lansoprazole Form I Lansoprazole Form I was prepared as described in WO00/78729.
- Example 3b preparation of Lansoprazole Form I hydrate ethanolate 53.8 Kg of humid raw Lansoprazole (corresponding to 46 Kg of dried) and 276 1 of ethanol were introduced into a reactor at room temperature under stirring and the admixture was kept under stirring for about 10 minutes. 74 1 of demineralized water and 5.4 1 of 30% ammonium hydroxide were added, the mass was heated at 35-40 0 C and kept under stirring for 30 minutes, then cooled at 0-5 0 C under stirring at that temperature for 2 hours. The admixture was centrifugated, the mother liquors removed and the cake washed with a solution of water, ethanol and 30% aq. ammonia (32 1, 13.5 1, 0.64 1). The humid product was discharged and weighed (67 Kg).
- Example 4 discloses the preparation of Lansoprazole Form I starting from the new form Lansoprazole hydrate acetonitrile solvate
- example 5 highlights the quick drying of the final product prepared according to the present invention
- example 6 demonstrates that, even without a base, the product does not turn yellow and shows a colour complying with Pharmacopoeia requirements
- examples 7 and 8 point out the effect of the temperature on the conversion process
- example 9 illustrates the efficacy of the present process in conferring a fine particle size and in removing the impurities
- example 10 highlights how the present process is also usable starting from admixtures of forms or not complying Lansoprazole forms.
- Comparative experiments Examples 11-21 The comparative experiments of the examples 11-21 were performed by substantially repeating the process according to the example 5 above by following the conditions and with the final results reported in table II. Comments on table II
- Example 11 (slurrying with water alone at 15°C, Krka process) points out the formation of Lansoprazole Form I but with a particle size significantly higher than the one obtainable according to the process of the present invention; example 12 (slurrying with water alone at 30 0 C, Takeda process) also leads to Lansoprazole Form I but with a higher particle size and yellowing of the product after drying; example 13 (slurrying with water alone at 40 0 C, Takeda process) shows the more difficult drying conditions of Takeda process with respect to those of the present invention (example 5); example 14 (slurrying with water and ammonia alone at 25°C) also points out the troublesome drying; example 15 (slurrying with acetonitrile, admixture KF: 0.6%) demonstrates the relevance of the water content within the admixture in order to confer the fine particle size which characterizes the process of the present invention: in fact in this example a non homogeneous sample of Lansoprazole Form I with a
- Example 22 a 1 : 1 admixture of Lansoprazole Form I and Lansoprazole hydrate acetonitrile solvate was prepared by simple hand-mixing of the powders prepared according to example 3 a and 1 respectively. Table I
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Abstract
A process for manufacturing crystalline Lansoprazole form I with aparticularly fine particle size comprising the heating of a mixture ofcrystalline Lansoprazole, acetonitrile and water, up to complete conversion,is described, said process beingparticularly advantageous on industrialscale in terms of rapidity, simplicity, yield and purity.
Description
PROCESS FOR MANUFACTURING MICROCRYSTALLINE LANSOPRAZOLE
FORM I
Field of the invention
The present invention relates to a new process for manufacturing a crystal form of Lansoprazole, form characterized by a particularly fine particle size, especially suitable for industrial use.
State of the art Lansoprazole is a known anti-ulcerative drug of formula I:
(Merck Index n. 5373, Ed. 1996) described for the first time in the patent EPl 74726 in the name of Takeda.
Several processes for manufacturing Lansoprazole are described in the literature, said processes comprising the oxidation of the sulfide of formula II, as illustrated by the following scheme:
II I being said oxidation performed with different agents. Generally these reactions are characterized by oxidative by-products, the side oxidations being at the nitrogen atoms of the heterocyclic rings - as N-oxides - and/or at the sulfur atom - as sulfones - respectively. Lansoprazole itself is characterized by an intrinsic instability and therefore, during its
manufacturing or the subsequent work-up, it tends to give degradation by-products, especially under acidic conditions. As a consequence, at the end of the oxidation, raw Lansoprazole generally contains several impurities and shall be consistently purified in order to achieve the high standards required for pharmaceuticals, with a significant reduction of yields and, more generally, with a worsening in the overall process economy. In addition to the above mentioned purity requirements, as any other active pharmaceutical ingredient (API), the finished Lansoprazole powder shall disclose specific physical properties too (such as density, porosity, wettability, flowability, hygroscopicity, dissolution rate etc.), properties which significantly impact on stability, formulation and bioavailability of the API and which depend - inter alia - on the particle size, the surface area, the crystal or amorphous form, the crystal habitus and the possible presence of residual solvents. Several different crystal forms of Lansoprazole are known from the literature, for example those named Form A, B (Eur. J. Pharm. Sci. (1996), 4, 182), D, E, F (WO03/082857 in the name of Teva), I, II (WO00/078729 in the name of Instytut Farmaceutyczny), desolvated forms or forms solvated with water and/or ethanol (US6002011 in the name of Takeda) or the amorphous form, prepared for example by spray-drying (Farm. Vest. 50, (1999), 347). Among those forms Form I, which corresponds to the reference product of US Pharmacopoeia (USP Ed. 29), is particularly interesting from the commercial point of view because stable under the standard manufacturing and storing conditions of finished dosage forms.
Generally these crystal forms are prepared by crystallization, by drying, by exposure to solvents vapors or by suspension in solvents admixtures. For example, according to WO03/082857, Form A (page 4) can be prepared by crystallization from methanol, n-butanol, acetone, methylethylketone, ethyl acetate, dimethylsulfoxide, dimethylformamide, optionally in admixture with water; Form D (page 5)
by crystallization from 2-propanol - water; Form E (page 5) by crystallization from 2- propanol-water and subsequent drying at a temperature lower than 400C or by grinding Form D (page 7); the amorphous form (page 6) by crystallization from 2-propanol - water and subsequent drying at a temperature between 40 and 500C; Form F (page 7) by exposure of a methanol solution to methanol-water saturated vapors. The suspension of Lansoprazole Form A in a 2-propano I/water admixture (99.9/0.1 v/v) under stirring (ex. 6, page 13) provides a 1 :1 admixture of Forms A and D. WO00/078729 describes the preparation of Form I by crystallization of Form II from acetone (ex. 1, pages 9-10).
WO07/078154 in the name of Daewoong Pharmaceutical discloses a process for manufacturing Lansoprazole Form A by crystallization from ethanol and water. US6002011 highlights the instability of Lansoprazole solvated forms, especially in the final drying stage, and describes the manufacturing of a stable desolvated form by suspending crystalline solvated Lansoprazole in warm water under stirring; Example 1, in particular, describes said preparation from crystalline Lansoprazole hydrate ethanolate by suspension in water at 300C, under stirring for 1 hour. The final product has a water and ethanol content equal to 0.01% and 63 ppm respectively and melting point of 177-8°C (dec). KR100433735 in the name of Chem Tech Research Inc. (C-TRI) discloses a method for purification and conversion of the crystal Form II into Form I by suspending under stirring in organic solvents and their admixtures, preferably in hexane/i-propylether or hexane/acetone admixtures. According to the experimental description, the best results are obtained with solvents of low polarity (hexane, i-propyl ether or methylene dichloride, ex 1, 11, 12 or hexane: acetone 2-5:1 admixtures, ex. 3-7) while more polar solvents (acetone, ethyl acetate, acetonitrile ex. 8-10 or the hexane:acetone 1 :1 admixture, ex. 2) are disappointing due to significantly lower yields.
The above prior art neither mentions nor gives any suggestion on the surface area or particle size of Lansoprazole powders prepared according to the processes therein described. Generally the manufacturing process of a solid API, after crystallization or conversion into the desired crystal form, comprises a final stage of grinding or of another equivalent treatment, whose aim is to impart a specific particle size to the powder, size which may vary according to the intrinsic properties of the compound and to the final use thereof. Even this last treatment may be rather difficult and expensive: for example, in the case of grinding methods, the heating of the powder may cause a partial chemical degradation and/or amorphization and/or conversion of the crystal form into another undesired form, to the detriment of the chemical and crystal purity of the finished product. This effect is more relevant in case the requested particle size is fine and the active product is unstable. Nevertheless some particularly advantageous methods which avoid grinding and which anyway furnish a powder characterized by a particular particle size are known. For example the international application WO2006/74952 in the name of Krka describes a process for manufacturing solid Lansoprazole with a high surface area, which essentially comprises a first precipitation stage (a'-c' steps) and a second maceration stage (d'-e' steps). In particular the first stage comprises precipitating Lansoprazole by cooling and/or water addition to its aqueous, ethanol, acetone, 1 -methyl-2-pyrrolidone, or their admixtures, solutions in the presence of a base.
In the second stage, the separated solid is suspended under stirring in water, ethanol, acetone or their admixture, preferably water at pH=8-l 1, at a temperature generally between 15 and 200C. After filtering, washing and drying, Lansoprazole crystal Form A with a surface area between 1.5 and 7.0 m2/g (measured according to the BET method as described at page 12 of the Krka application) is obtained. In fact the examples only describe the use of water for the suspension stage and the only value of surface area therein reported (4.67 m2/g; ex. 4) is
referred to a sample subjected to a double maceration in water.
As far as we know, no one of the processes described in the literature simultaneously allows the conversion into crystal Form I and the obtainment of a Lansoprazole powder with a particularly fine particle size.
In fact the process described in KRl 00433735 (C-TRI), even if useful for converting the crystal form, does not afford the desired fine particle size (see comparative example 15 of the present invention). Similarly, the processes described in US6002011 (Takeda) and WO2006/74952 (Krka) provide for a powder characterized by a single crystal form but with a particle size not particularly fine (see comparative examples 12 and 16 of the present invention). In addition, the use of water at industrial level does not seem particularly suitable for a product as labile as Lansoprazole: in fact the product may degrade and turn yellow during both the suspension stage and, especially, the subsequent prolonged drying stage needed for removing superficial water (see comparative example 12 of the present application).
Finally, the slurrying process disclosed in WO03/082857 (Teva), which uses an organic polar solvent with water in traces (2 -propano I/water 99.9/0.1) and which would require milder conditions during the drying stage with respect to the use of water alone, only leads to a partial conversion of the crystal form. We have now surprisingly found a new process for manufacturing Lansoprazole with high chemical and crystal purity which allows - with a single treatment - both to completely convert the crystal form and to impart a fine particle size to the powder, powder characterized by a faster dissolution rate and improved bulk properties. This process is particularly suitable for industrial application due to mild conversion and drying conditions, reduced solvent volume, simple feasibility, rapidity, reproducibility and high yields.
General description of the invention
Hence object of the present invention is a process for manufacturing microcrystalline Lansoprazole Form I which comprises: a) contacting Lansoprazole with a liquid medium comprising acetonitrile and water, in which the percentage of water in the resulting admixture is between 0.6 and lθ % (w/w), b) bringing the temperature of the medium at a value between 15 and 500C, c) keeping the contact up to complete conversion; and d) separating the so obtained microcrystalline Lansoprazole Form I. Detailed description of the invention
The process of the present invention allows the manufacturing of crystalline Lansoprazole in a stable form, which according to XRD and IR analysis corresponds to Form I as described in WO00/078729, with a high purity and particularly fine particle size. Herein after this process will be also named as the "conversion process". Microcrystalline Lansoprazole Form I, prepared according to the present process, is a desolvated form, namely a form with a low content of residual solvents, generally comprising water in amount lower than 0.5% (w/w), preferably lower than 0.1%, acetonitrile in amount lower than 400 ppm, preferably lower than 300 ppm, and optionally traces of other solvents coming from Lansoprazole used as starting material in step a). For example, starting from Lansoprazole hydrate ethanolate a product comprising also ethanol, in amount generally lower than 50 ppm, preferably lower than 10 ppm, will be obtained.
Microcrystalline Lansoprazole Form I, prepared according to the conversion process of the invention, shows a very good filtrability and is characterized by a particularly fine particle size, generally lower than the one obtainable with the processes of Takeda (US6002011), Krka (WO2006/74952) and Chem Tech Research Inc (KRl 00433735) previously described
(see comparative examples 12, 15 and 16).
The particle size of the Lansoprazole powder prepared according to the present process, expressed as D90, is generally lower than 40 μm, preferably between 15 and 30 μm, more preferably between 20 and 25 μm, and - as D50 - generally lower than 20 μm, preferably lower than 15 μm.
In addition, the so prepared Lansoprazole shows an overall content of impurities generally lower than 0.6 % , preferably lower than 0.3%, more preferably lower than 0.2 %, detected by HPLC method (Pharmacopoeia USP29 HPLC method). In step a) of the present conversion process, Lansoprazole means a crystalline form of
Lansoprazole, optionally solvated and/or in admixture with other crystalline forms and/or with the amorphous form, preferably a single crystalline form optionally solvated.
For example the starting Lansoprazole may be selected among the forms described in the literature such as Lansoprazole hydrate ethanolate (US6002011), Lansoprazole ethanolate (Farm. Vest. 48, 242-243, 1997), Lansoprazole A, B, D, E or F forms (WO03/082857),
Lansoprazole forms I or II (WO00/078729), the solid forms obtained from l-methyl-2- pyrrolidone by precipitation according to the process described in WO2006/74952 (Krka, ex.
2 e) i-vi, pages 23-24) or Lansoprazole hydrate acetonitrile solvate, a new form prepared and characterized as described at example 1 of the present experimental part. Preferably the starting Lansoprazole for the conversion process is selected among
Lansoprazole Form I, Lansoprazole hydrate acetonitrile solvate and their admixtures, more preferably is Lansoprazole hydrate acetonitrile solvate.
In a preferred embodiment of the present invention, Lansoprazole hydrate acetonitrile solvate is prepared according to a process which comprises: e) dissolving Lansoprazole in an admixture of acetonitrile and water, at a pH value higher than 10;
f) acidifying the solution up to a pH between 8 and 10; g) collecting the precipitated Lansoprazole hydrate acetonitrile solvate.
In step e) of the present process the acetonitrile/water weight ratio in the admixture is generally from 2:1 to 8:1 for acetonitrile and from 0.25:1 to 1 :1 for water, preferably it is of about 4:1 for acetonitrile and 0.5: 1 for water with respect to Lansoprazole (w/w). Lansoprazole used in step e) may be anyone of the known pure crystalline or amorphous forms or their admixtures or, preferably, a raw form as obtained after work-up of the oxidation reaction of the sulfide of formula II. The pH of the admixture in step e) is suitably corrected at a pH higher than 10, preferably higher than 11 , more preferably at about 13 with a base, preferably with an alkaline or earth- alkaline base, more preferably with sodium hydroxide. Preferably sodium hydroxide is used in an equivalent ratio between 1 :1 to 2:1, preferably between 1.1 :1 and 1.5:1 with respect to Lansoprazole. The resulting solution may be, optionally, decolorized and filtered according to known techniques, and then subjected to step f).
In step f) of the present process the pH of the, optionally decolorized and filtered, solution is generally brought up to a value between 8 and 10, preferably between 8.5 and 9.5, more preferably at about 9, by adding a suitable amount of an acid, preferably a weak acid, such as ammonium acetate, benzoic acid, p-methoxybenzoic acid or acetic acid, more preferably acetic acid. Preferably, during the acidification step f), more preferably when the pH of the solution is at about 10, the solution is seeded with crystals of Lansoprazole Form I. The resulting admixture is generally left, under rest or stirring conditions, preferably under stirring conditions; it is preferably cooled below room temperature, more preferably at about 0-50C, in order to favor the precipitation of Lansoprazole hydrate acetonitrile solvate.
The precipitated Lansoprazole hydrate acetonitrile solvate is then collected, preferably by
filtration (step g), dried or, preferably, directly subjected to the conversion process object of the present invention.
Lansoprazole hydrate acetonitrile solvate is characterized by the following analysis: IR (method USP 29) (cm 1): 3433.2; 3258.1; 2360.3; 1640.3; 1583.2; 1475.5; 1408.3; 1313.1 ; 1266.4; 1223.0; 1173.3; 1112.2; 1086.0; 1047.1; 973.8; 914.0; 858.8; 802.2; 763.9; 744.3. X-ray powder diffraction (XRD): (instrument Broker D8 Advance equipped with Cu anode (1.54 Angst); Current 40 mA; Voltage 40 kV; Measurement range: 3-35°; Step Size: 0.02°; Scan rate: 2 sec/step): 2-theta (degrees! 0.05) and relative intensities are reported in Table III.
K.F.: water content between 1 and 4, preferably between 1.5 and 2.5, more preferably at about 2.2 (% w/w).
Lansoprazole hydrate acetonitrile solvate, in a preferred embodiment, can be directly subjected to the conversion process object of the present invention without a forced drying, with evident advantages in terms of stability, time and costs.
The conversion process object of the present invention may also be performed by using "non standard" Lansoprazole as starting material in step a), meaning with this term a Lansoprazole whose IR analysis does not exactly correspond to that of one of the forms previously mentioned (example 10 of the present invention). In step a) of the present process, the term "contacting" means to put in contact Lansoprazole with the indicated liquid medium, thus obtaining a solid-liquid biphasic system in which Lansoprazole remains substantially undissolved. This procedure, which is clearly different from the classical crystallization wherein the solid is completely dissolved in the solvent system thus giving a solution, is also defined with equivalent terms such as slurrying, suspending, digesting or macerating, and may be effected under rest or, preferably, under stirring.
The liquid medium in step a) comprises acetonitrile and water, wherein water is present in the final admixture in a percentage between 0.6 and 10% (w/w), preferably between 2 and 6%, more preferably between 3 and 4%. The liquid medium may optionally comprise other solvents too, such as for example ethanol or dimethylacetamide, generally in low percentages, but preferably comprises acetonitrile, water and only possible traces of other solvents deriving from the starting Lansoprazole solvates, such as for example ethanol in case Lansoprazole hydrate ethanolate is used. The water percentage in the admixture is referred to the final admixture of Lansoprazole, acetonitrile, water and other optional solvent, namely to the admixture obtained by contacting Lansoprazole with the liquid medium, preferably under stirring and, optionally, by correcting the same water content up to the desired value.
The order of addition of the admixture components and the way of correction of water content do not represent a limitation of the present invention, provided that the final admixture comprises water according to the desired percentages. For example, the admixture can be prepared by first suspending Lansoprazole in water and then by adding acetonitrile or by directly suspending Lansoprazole in prearranged admixtures of acetonitrile and water or, preferably, by suspending Lansoprazole in acetonitrile alone and by adding water up to the desired percentage. Also the way of correction above mentioned may include more variants, for example water and/or acetonitrile content may be increased, by their separated or contemporaneous addition, or decreased by controlled removal, for example by more or less forced drying of the starting Lansoprazole or by acting on the admixture by azeotropic distillation or other compatible dewatering techniques, always provided that the final water percentage is within the desired values. The amount of water present in the system before the correction may vary depending on several factors, for example on the hydration of the starting Lansoprazole or the water
content of the acetonitrile used, but it generally does not represent a limitation of the process of the present invention. In fact the skilled in the art may proceed by measuring the water content of the admixture and, accordingly, may decide any correction needed in order to bring the water percentage within the desired limits. The measure of the water content in the admixture may be performed according to any suitable method, preferably by Karl-Fischer method.
In step a) of the present process, the liquid medium is generally used in a ratio between 2:1 and 20:1 (v/w), preferably between 2:1 and 10:1, more preferably between 2:1 and 5:1, even more preferably at about 3 : 1 with respect to the starting Lansoprazole.
The use of such little volumes of liquid medium is particularly advantageous from the industrial point of view and generally, it consents to maintain a good stirring of the admixture and to plainly proceed with the subsequent filtration. The liquid medium may optionally comprise an organic base, for example an amine such as triethylamine, methylamine, pyridine, ethanolamine, sodium or potassium acetate or an inorganic base, for example alkaline or alkaline-earth hydroxides, ammonia, preferably ammonium hydroxide.
With respect to the crystallization and slurrying processes described in the known art, which count for the presence of weak bases in significant amount (see for example EP1465890 in the name of Teva wherein the molar ratio ammonium hydroxide/Lansoprazole is higher than 1 :1), the present process, just because avoids the dissolution of Lansoprazole and the substantial use of water - conditions under which Lansoprazole is more easily subjected to degradation - consents to minimize the amount of base instead. In particular it is preferable to use the base in a molar ratio lower than 1 :1, more preferably lower than 0.5:1, even more preferably at about 0.3:1 with respect to Lansoprazole, with significant industrial advantages. In case aqueous bases are used, the percentage of water in the final admixture shall be
measured and, optionally, corrected by considering the water coming from the added basic solution too.
In step b) of the present process, the admixture of Lansoprazole, acetonitrile, water and, optionally, base is brought to a temperature generally between 15 and 500C, preferably between 25 and 400C, more preferably at about 35°C and kept at such temperature, preferably under stirring, up to complete conversion of the crystal form and/or obtainment of the desired fine particle size (step c). The conversion times of the present process are short and, generally, shorter than those of the processes described in the prior art - for example in WO2006/074952 (Krka, ex. 2e two hours, ex. 4 two macerations of two hours each) or by US6002011 (Takeda, ex. 1, one hour) - being variable dependently on the amount of product too, generally between 15 minutes and 2 hours, preferably between 15 minutes and 1 hour, more preferably at about 30 minutes. Once the conversion of the crystal form is completed - completion which may be evaluated with any suitable analytical technique, preferably by IR or XRD - the admixture is preferably cooled at temperatures generally comprised between 0 and 100C, preferably between 0 and 5°C, and microcrystalline Lansoprazole Form I is isolated according to conventional techniques, such as for example by decantation, centrifugation or, preferably, filtration (step d). The product cake is then, preferably, washed with admixtures of acetonitrile, water and, preferably, traces of a base, such as ammonium hydroxide.
Generally the final product drying, after separation, is performed at a temperature between 20 and 500C, preferably at about 400C, at atmospheric pressure or, preferably, under vacuum, for industrial times generally shorter than 20 hours, preferably for about 8-10 hours, in any case for variable times depending on several factors such as for example the amount of the product to be dried, the dryer used and the vacuum conditions applied.
In the present conversion process the minimal amount of water, the controlled temperatures
and the short contact times allow to minimize product degradation and by-products formation.
In addition the liquid medium herein used, substantially acetonitrile with a controlled percentage of water, avoids the typical degradations associated with the use of an aqueous medium. Further, due to the lower polarity with respect to water alone, it may exert a selective purification towards possible less polar impurities which the aqueous medium alone is not able to eliminate.
Another advantage of the present process, due to the higher volatility of the liquid medium in comparison with water alone, is represented by a drying step under milder conditions and/or with reduced times and, consequently, by a lower degradation of the product and retention of the white colour of the powder.
The process object of the present invention is additionally characterized by high yields, generally higher than 90%, preferably than 93%, more preferably than 95%. Further the present process, unlike the reporting of, for example, WO2006/074952 (Krka, ex.
4), in which the high surface area is obtained by repeating the treatment twice (double maceration), allows to impart the desired fine particle size with a single short-lasting treatment.
In a particularly preferred embodiment, Lansoprazole hydrate acetonitrile solvate (prepared according to example 1), acetonitrile (3 v/w) and 30% aq. ammonium hydroxide (0.08 v/w) are introduced into a reactor at room temperature, under stirring. The percentage of water in the admixture is measured (K.F.). Water is added up to a K.F. 3.5-4%, the admixture is brought at 35°C and kept under stirring for about 30 minutes. It is cooled at about 0-50C and it is left under stirring at that temperature for about 2 hours. It is filtered, the cake is washed with acetonitrile/water/30% ammonium hydroxide (35:1:1 v/v/w with respect to
Lansoprazole) and it is dried under vacuum at 400C for about 10 hours.
The processes object of the present invention will be now illustrated by the following experiments, herein reported for better exemplifying and not for limiting the invention.
EXPERIMENTAL PART Keys: ACN=acetonitrile; AcOH= acetic acid; KF= water content (percentage) according to Karl Fisher method; TEA=triethylamine.
Preparation of starting Lansoprazole
Example 1 : Preparation Lansoprazole hydrate acetonitrile solvate. 340 g of raw Lansoprazole (prepared for example as described in EPl 74726), 1530 ml of ACN, 85 ml of water, 101 g of 30 % aq. NaOH (1.1 eq) up to a pH of about 13 were charged into a 5 1 reactor at room temperature, under stirring. A complete dissolution was obtained. The solution was decolorized with charcoal (15 g) and dicalite (22 g), kept under stirring for 30 min., filtered and washed with 340 ml of 90 % aq. ACN. AcOH (33 g, 0.9 eq) was added up to pH 9. At pH 10, before the precipitation started, the crystallization was induced by seeding with crystals of Lansoprazole Form I (USP 29). The admixture was kept for 30 min at 20-22 0C, checking that pH was stable at about 9, then it was cooled at 0-50C for about 20 hours, it was filtered and washed with 100 ml of 90 % aq. ACN. It was dried in oven at about 40 0C under vacuum for 18 hours. 250 g of dried light yellow powder were obtained. Analysis: KF: about 2.2%, IR (method USP 29) cm4: 3433.2; 3258.1; 2360.3; 1640.3; 1583.2; 1475.5; 1408.3; 1313.1; 1266.4; 1223.0; 1173.3; 1112.2; 1086.0; 1047.1; 973.8; 914.0; 858.8; 802.2; 763.9; 744.3.
XRD (Broker D8 Advance equipped with Cu anode (1.54 Angst); Current 40 mA; Voltage 40 kV; Measurement range: 3-35°; Step Size: 0.02°; Scan rate: 2 sec/step): see Table III Example 2: preparation of Lansoprazole hydrate ethanolate Lansoprazole hydrate ethanolate was prepared as described in the reference example 6 of US6002011 (Takeda).
Example 3 a: preparation of Lansoprazole Form I Lansoprazole Form I was prepared as described in WO00/78729. Example 3b: preparation of Lansoprazole Form I hydrate ethanolate 53.8 Kg of humid raw Lansoprazole (corresponding to 46 Kg of dried) and 276 1 of ethanol were introduced into a reactor at room temperature under stirring and the admixture was kept under stirring for about 10 minutes. 74 1 of demineralized water and 5.4 1 of 30% ammonium hydroxide were added, the mass was heated at 35-400C and kept under stirring for 30 minutes, then cooled at 0-50C under stirring at that temperature for 2 hours. The admixture was centrifugated, the mother liquors removed and the cake washed with a solution of water, ethanol and 30% aq. ammonia (32 1, 13.5 1, 0.64 1). The humid product was discharged and weighed (67 Kg).
IR (cm 1): 2802; 1580; 1435; 1265; 1267; 1246; 1081; 1018; 913; 743. Preparation of microcrystalline Lansoprazole Form I according to the invention (Examples 4 to 10)
Example 4
250 g of Lansoprazole hydrate acetonitrile solvate prepared as described at ex. 1, 750 ml of ACN, 20 ml of 30% aq. ammonia, 20 ml of demineralized water (K.F. of the admixture between 3.5 and 4%) were charged into a reactor. The admixture was heated at about 35- 400C, kept under stirring for 30 minutes, cooled at about 0-50C in 1 hour and kept for 2 hours under stirring at 0-50C. It was filtered and washed with 250 ml of the admixture of ACN/water/ammonia 35/1/1, it was dried under vacuum at 400C for about 10 hours. 238 g of dried product were obtained. Yields: 95.2%. IR complying with Form I (USP 29) (cm 1): 3236; 2984; 2930; 1580; 1476; 1457; 1401; 1282; 1267; 1254; 1170; 1118; 1087; 1038; 972; 921; 858; 814; 801; 750; 699; 658. Particle size: D90: 20 μm D50: 9 μm.
Example 5
10.2 g of Lansoprazole Form I hydrate ethanolate, prepared as described at the example 3b, 30 ml of ACN, 0.82 ml 30% aq. ammonia, 0.74 ml of demineralized water (admixture K.F. 3.9%) were charged in a flask at room temperature. The admixture was heated at about 300C and kept under stirring for 30 minutes, cooled at about 0-50C under stirring for 2 hours, filtered and washed with ACN/water/30% aq. ammonia (admixture 9.5 ml/0.28 ml/0.28 ml). The cake was dried at 400C under vacuum by measuring residual water (KF) at 2 hours (0.06%) and 4 hours (<0.01%) and weighed (8.6 g). IR: complying with Form I (USP29) Examples 6-10
The experiments of the examples 6-10 were performed by repeating the process according to the example 5 above by following the conditions and with the final results reported in table I.
Comments on Table I Example 4 discloses the preparation of Lansoprazole Form I starting from the new form Lansoprazole hydrate acetonitrile solvate, example 5 highlights the quick drying of the final product prepared according to the present invention, example 6 demonstrates that, even without a base, the product does not turn yellow and shows a colour complying with Pharmacopoeia requirements, examples 7 and 8 point out the effect of the temperature on the conversion process, example 9 illustrates the efficacy of the present process in conferring a fine particle size and in removing the impurities while example 10 highlights how the present process is also usable starting from admixtures of forms or not complying Lansoprazole forms.
Comparative experiments Examples 11-21 : The comparative experiments of the examples 11-21 were performed by substantially repeating the process according to the example 5 above by following the conditions and with the final results reported in table II.
Comments on table II
Example 11 (slurrying with water alone at 15°C, Krka process) points out the formation of Lansoprazole Form I but with a particle size significantly higher than the one obtainable according to the process of the present invention; example 12 (slurrying with water alone at 300C, Takeda process) also leads to Lansoprazole Form I but with a higher particle size and yellowing of the product after drying; example 13 (slurrying with water alone at 400C, Takeda process) shows the more difficult drying conditions of Takeda process with respect to those of the present invention (example 5); example 14 (slurrying with water and ammonia alone at 25°C) also points out the troublesome drying; example 15 (slurrying with acetonitrile, admixture KF: 0.6%) demonstrates the relevance of the water content within the admixture in order to confer the fine particle size which characterizes the process of the present invention: in fact in this example a non homogeneous sample of Lansoprazole Form I with a particle size higher than the one obtainable according to the process of the present invention was obtained; example 16 (slurrying with acetone, KF: 3.9% at 30-350C) leads to a form whose IR was complying with Form I but it was unstable, difficult to be dried and with a particle size significantly higher; examples 17, 18, 19, 20 demonstrate that admixtures comprising high amounts of water do not lead to the desired product but on the contrary result in not stirrable and not filtrable masses, troublesome drying (10 days), partial conversion or obtainment of not complying forms respectively; finally example 21 highlights that at the temperature of 5°C the desired conversion of crystal form was not obtained. Example 22: a 1 : 1 admixture of Lansoprazole Form I and Lansoprazole hydrate acetonitrile solvate was prepared by simple hand-mixing of the powders prepared according to example 3 a and 1 respectively.
Table I
' Ex Crystalline Form Parts Parts Parts K.F. T Crystalline Particle size KF % Notes starting H2O NH4OH ACN admixture (0C) Form micron
(IR) ml/g 30% ml/g final after drying ml/g (IR) (time)
4 hydrate acetonitrile 0.08 3 2.7 35 Form I D50 = 9 0.05 Yield: 95 % solvate D90 = 20 HPLC: sulfide
(KF= 2.2%) 0.22%; sulfone
(prep. ex. 1) 0.08%
5 Form I 0.08 3 3.9 30 Form I n.d. 0.06 (2h) Drying
(hydrate ethanolate) <0.01 (4 h) Experiments
(prep. ex. 3b)
6 Form I - 3 3.7 35 Form I n.d. 0.05 30' Yield: 92 %
(hydrate ethanolate) white powder
(prep. ex. 3b)
7 Form I 0.08 3 3.1 15 Form I n.d. 1 .0 ( t=0) Difficult to be
(hydrate ethanolate) 0.04 (30') stirred and
(prep. ex. 3b) filtered
8 Form I 0.08 3 3.1 25 Form I n.d. 3 (1=0) Stirrable, good
(hydrate ethanolate) 0.32 (30') filtrability
(prep. ex. 3b) 0.26 (2h)
9 Form I 0.08 3 3.7 35/40 ' Form I D50 = 12 0.3 Yield: 91 %
(prep. ex. 3 a) D90 = 26 HPLC: 99.84%
(sulfide 0.03%; sulfone 0.01%)
10 admixture 0.08 3 2.2 35 Form I D50 = 14 0.01 Yield: 92%
Form I and hydrate D90 = 26 acetonitrile solvate
(prep. ex. 22)
Table II: comparative examples
Ex Crystalline Form Vol. Vol. Vol. K.F. T Crystalline Particle size KF % Notes starting H2O NH4OH ACN admixt (0C) Form (micron) (IR) (ml/g) 30% (ml/g) ure final after drying ml/g (IR) (time)
11 hydrate acetonitrile 15 Form I D50 = 21 0.04 (Krka) solvate (KF= 2.: D90 = 53 (prep. ex. 1)
12 hydrate acetonitrile 30 Form I D50 = 17 0.03 (Takeda) solvate (KF= 2.2%) D90 = 46 light yellow product
(prep. ex. 1)
13 Form I 40 Form I n.d. 0.15 (2h) Yield: 93 % (hydrate ethanolate) 0.15 (4h) (Takeda)
(prep. ex. 3b) 0.12 (2Oh)
14 Form I 4.6 0.02 n.d. 25 Form I n.d. n.d. drying: constant (hydrate ethanolate) weight after 96 h. 40
(prep. ex. 3b) 0C under vacuum
15 Form I TEA 0.6 35 Form I D50 = 19 0.03 (30') not homogeneous (hydrate ethanolate) D90 = 43 sample
(prep, ex 3b) Yield: 92 %
16 hydrate acetonitrile 0.03 acetone 3.9 30 - Form I D50 = 37 0.6 Yield: 79 % (Krka) solvate (KF= 2.2%) 3 35 D90 = 70 unstable product
(prep. ex. 1) (no (takes up water in the ACN) air, after 6h KF =3%)
17 Form I from from from 2.4 25 Form I n.d. Non stirrable mass. (hydrate ethanolate) 2.4 0.06 H2O-ACN added
(prep. ex. 3b) to 8.4 to 0.17 to 8.4 Bad filtration
18 Form I 5.45 0.11 5.45 25 Form I n.d. 0.2 Drying 10 days
(hydrate ethanolate)
(prep. ex. 3b)
19 Form I 6 0.12 6 - 45 admixture n.d. n.d. Partial form (hydrate ethanolate) conversion
(prep. ex. 3b)
20 Form I - 0.08 " 3 " 10.2 35 " not n.d. 1.7 (hydrate ethanolate) complying
(prep. ex. 3b)
21 Form I - 0.08 3 " 4 5 " not n.d. 1.5 (2Oh) Very difficult to be (hydrate ethanolate) complying stirred and filtered
(prep. ex. 3b)
K*
O
Table III X-ray powder diffraction pattern of Lansoprazole hydrate acetonitrile solvate
Angular Positions Relative
2-theta Intensity
(degrees ± 0.05)
4.33 92
100
8.82 50
9.76 41 sO ^ 81
69
15.02 45
16.25 40
86
27
18.68 30
19.55 19
25
^ - V> 30
21.45 53
25.82 33
17
Nr -^ 22
28.72 21
31.74 16
Claims
CLAIMS 1) A process for manufacturing microcrystalline Lansoprazole Form I which comprises: a) contacting Lansoprazole with a liquid medium comprising acetonitrile and water, in which the percentage of water in the resulting admixture is between 0.6 and lθ % (w/w), b) bringing the temperature of the medium at a value between 15 and 500C, c) keeping the contact up to complete conversion; and d) separating the so obtained microcrystalline Lansoprazole Form I.
2) The process according to claim 1 wherein said Lansoprazole of step a) is selected among Lansoprazole hydrate ethanolate, Lansoprazole ethanolate, Lansoprazole Form I or II or Lansoprazole hydrate acetonitrile solvate and their admixtures.
3) The process according to claim 2 wherein said Lansoprazole of step a) is selected among Lansoprazole Form I, Lansoprazole hydrate acetonitrile solvate and their admixtures, preferably Lansoprazole hydrate acetonitrile solvate.
4) The process according to claims 1 to 3 wherein steps a), b) and c) are performed under stirring.
5) The process according to claims 1 to 4 wherein the liquid medium of step a) comprises acetonitrile and water, in which the percentage of water in the resulting admixture is between 2 and 6% (w/w), preferably between 3 and 4%.
6) The process according to claims 1 to 5 wherein the liquid medium of step a) is used in a ratio between 2:1 and 20:1 (v/w), preferably between 2:1 and 10:1, more preferably between 2:1 and 5:1, even more preferably of about 3:1 with respect to the starting Lansoprazole.
7) The process according to claims 1 to 6 wherein the liquid medium of step a) further comprises a base in a molar ratio lower than 1 :1, preferably lower than 0.5:1, more preferably of about 0.3:1 with respect to Lansoprazole.
8) The process according to claims 1 to 7 wherein the temperature of the medium in step b) is between 25 and 40 0C, preferably at about 35°C.
9) The process according to claims 1 to 8 wherein the time of conversion in step b) is between 15 minutes and 2 hours, preferably between 15 minutes and 1 hour, more preferably at about 30 minutes.
10) Macrocrystalline Lansoprazole Form I, prepared according to the processes of claims 1 to 9, characterized by a particle size, expressed as D90, generally lower than 40 μm, preferably comprised between 15 and 30 μm, more preferably between 20 and 25 μm.
11) The microcrystalline Lansoprazole Form I according to claim 10 further characterized by a particle size, expressed as D50, lower than 20 μm, preferably lower than 15 μm.
12) Microcrystalline Lansoprazole Form I, prepared according to the processes of claims 1 to 9, characterized by a water content lower than 0.5% (w/w), preferably lower than 0.1% and an acetonitrile content lower than 400 ppm, preferably lower than 300 ppm.
13) Microcrystalline Lansoprazole Form I, prepared according to the processes of claims 1 to 9, characterized by an overall impurities content lower than 0.6%, preferably lower than 0.3%, more preferably lower than 0.2% (HPLC method Pharmacopoeia USP 29).
14) Lansoprazole hydrate acetonitrile solvate showing the following IR peaks (cm4): 3433.2; 3258.1; 2360.3; 1640.3; 1583.2; 1475.5; 1408.3; 1313.1; 1266.4; 1223.0; 1173.3; 1112.2; 1086.0; 1047.1; 973.8; 914.0; 858.8; 802.2; 763.9; 744.3.
15) Lansoprazole hydrate acetonitrile solvate showing the following X-ray powder diffraction pattern:
Angular Positions Relative
2-theta Intensity
(degrees ± 0.05)
4.33 92
100
8.82 50
9.76 41
10.18 81
69
15.02 45
16.25 40 r! Ϊ ^ 86
27
18.68 30
19.55 19
?0..: S 25
30
21.45 53
25.82 33
17
22
28.72 21
31.74 16
16) A process for manufacturing Lansoprazole hydrate acetonitrile solvate according to claims 14 or 15 which comprises: e) dissolving Lansoprazole in an admixture of acetonitrile and water, at a pH value higher than 10; f) acidifying the solution up to a pH between 8 and 10;
g) collecting the precipitated Lansoprazole hydrate acetonitrile solvate.
17) The process according to claim 16 wherein the acetonitrile/water weight ratio in step e) is from 2:1 to 8:1 for acetonitrile and from 0.25:1 to 1 :1 for water, preferably of about 4:1 for acetonitrile and 0.5: 1 for water with respect to Lansoprazole (w/w).
18) The process according to claim 16 wherein the pH in step e) is brought to a value higher than 11, preferably at about 13.
19) The process according to claim 16 wherein the pH of the solution in step f) is brought to a value between 8.5 and 9.5, preferably at about 9. 20) A process for manufacturing microcrystalline Lansoprazole Form I according to claims 1 to 9 wherein said Lansoprazole of step a) is Lansoprazole hydrate acetonitrile solvate prepared according to the processes of claims 16 to 19.
21) Use of Lansoprazole hydrate acetonitrile solvate for manufacturing microcrystalline Lansoprazole Form I.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009088857A1 (en) * | 2007-12-31 | 2009-07-16 | Takeda Pharmaceutical Company Limited | Crystalline solvated forms of (r) -2- [ [ [3-methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1h-benz imidazole |
WO2010104314A2 (en) * | 2009-03-09 | 2010-09-16 | 한미약품 주식회사 | Method for preparing non-crystalline (+)-lansoprazole and (+)-lansoprazole alcoholate used in same |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US6002011A (en) * | 1996-11-14 | 1999-12-14 | Takeda Chemical Industries, Ltd. | Crystals of benzimidazole derivatives and their production |
WO2000078729A1 (en) * | 1999-06-18 | 2000-12-28 | Instytut Farmaceutyczny | Crystalline forms of lansoprazole |
KR20030000779A (en) * | 2001-06-27 | 2003-01-06 | 주식회사 씨트리 | Transformation of Lansoprazole crystalline form and its Purification |
WO2004072061A1 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Method of stabilizing lansoprazole |
WO2006074952A1 (en) * | 2005-01-14 | 2006-07-20 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing lansoprazole |
-
2006
- 2006-12-22 IT ITMI20062481 patent/ITMI20062481A1/en unknown
-
2007
- 2007-12-19 WO PCT/EP2007/064255 patent/WO2008077866A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US6002011A (en) * | 1996-11-14 | 1999-12-14 | Takeda Chemical Industries, Ltd. | Crystals of benzimidazole derivatives and their production |
WO2000078729A1 (en) * | 1999-06-18 | 2000-12-28 | Instytut Farmaceutyczny | Crystalline forms of lansoprazole |
KR20030000779A (en) * | 2001-06-27 | 2003-01-06 | 주식회사 씨트리 | Transformation of Lansoprazole crystalline form and its Purification |
WO2004072061A1 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Method of stabilizing lansoprazole |
WO2006074952A1 (en) * | 2005-01-14 | 2006-07-20 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing lansoprazole |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009088857A1 (en) * | 2007-12-31 | 2009-07-16 | Takeda Pharmaceutical Company Limited | Crystalline solvated forms of (r) -2- [ [ [3-methyl-4- (2, 2, 2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1h-benz imidazole |
WO2010104314A2 (en) * | 2009-03-09 | 2010-09-16 | 한미약품 주식회사 | Method for preparing non-crystalline (+)-lansoprazole and (+)-lansoprazole alcoholate used in same |
WO2010104314A3 (en) * | 2009-03-09 | 2010-12-09 | 한미약품 주식회사 | Method for preparing non-crystalline (+)-lansoprazole and (+)-lansoprazole alcoholate used in same |
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