HUE033030T2 - Kristályos minociklin bázis, és eljárások ennek elõállítására - Google Patents

Kristályos minociklin bázis, és eljárások ennek elõállítására Download PDF

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HUE033030T2
HUE033030T2 HUE08709507A HUE08709507A HUE033030T2 HU E033030 T2 HUE033030 T2 HU E033030T2 HU E08709507 A HUE08709507 A HU E08709507A HU E08709507 A HUE08709507 A HU E08709507A HU E033030 T2 HUE033030 T2 HU E033030T2
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base
crystalline
minocycline
solvent
minoeikin
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Zita Mendes
Jose Rafael Antunes
Susana Marto
William Heggie
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Hovione Scientia Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

(12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 237I26<200601) 12.10.2016 Bulletin 2016/41 (86) International application number: (21) Application number: 08709507.1 PCT/GB2008/000625 (22) Date of filing: 22.02.2008 (87) International publication number: WO 2008/102161 (28.08.2008 Gazette 2008/35)
(54) CRYSTALLINE MINOCYCLINE BASE AND PROCESSES FOR ITS PREPARATION
KRISTALLINE MINOCYCLINBASE UND VERFAHREN ZU DEREN HERSTELLUNG BASE DE MINOCYCLINE CRISTALLINE ET PROCEDES DE PREPARATION (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-2007/014154
HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR · BERNARDI L ET AL: "Tetracycline derivatives"
FARMACO, EDIZIONE SCIENTIFICA, SOCIETA (30) Priority: 23.02.2007 PT 10366107 CHIMICA ITALIANA, PAVIA, vol. 30, no. 9,1
January 1975 (1975-01-01), pages 736-741, (43) Date of publication of application: XP009101407 ISSN: 0430-0920 02.12.2009 Bulletin 2009/49 · CHURCH ET AL.: "Synthesis of 7-Dimethylamino-6-demethyl-6-deoxytetracyc (73) Proprietor: Hovione Scientia Limited line (Minocycline) via
Ringaskiddy, Co. 9-nitro-6-demethyl-6-deoxytetracycline."J.ORG.
Cork (IE) CHEM., vol. 36, no. 5,1971, pages 723-725, XP002485261
(72) Inventors: · CAIRA MR: "CRYSTALLINE POLYMORPHISM OF
• MENDES, Zita ORGANIC COMPOUNDS" TOPICS IN CURRENT P-1000-260 Lisbon (PT) CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198,1 • ANTUNES, Jose, Rafael January 1998 (1998-01-01), pages 163-208, P-2900-524 Setubal (PT) XP001156954 ISSN: 0340-1022
• MARTO, Susana · YU L: "AMORPHOUS PHARMACEUTICAL
P-2825-334 Costa da Caparica (PT) SOLIDS: PREPARATION, CHARACTERIZATION
• HEGGIE, William AND STABILIZATION" ADVANCED DRUG P-2950-656 Palmela (PT) DELIVERY REVIEWS, ELSEVIER BV, AMSTERDAM, NL, vol. 48, no. 1, 16 May 2001 (74) Representative: Turner, Craig Robert (2001-05-16), pages 27-42, XP009065056 ISSN:
A.A. Thornton &amp; Co. 0169-409X 10 Old Bailey
London EC4M 7NG (GB) Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
Description [0001] The present invention provides crystalline minocycline base including three new polymorphic forms thereof, and also describes a process to obtain pure minocycline base in a crystalline form wherein all the impurities are controlled, especially the impurity 4-epi minocycline, to very low levels.
Background of the Invention [0002] Minocycline is a member of the broad spectrum tetracycline antibiotics, which has a broader spectrum than the other members of this group of compounds.
[0003] Minocycline is widely used in therapy, primarily to treat acne and rosacea at a once daily dose of 100mg.
[0004] The preparation of minocycline is disclosed in US 3 148 212; US 3 226 436 and US 4 849 136.
[0005] Minocycline may be used as base per se or as non-toxic acid addition salts of organic or inorganic acids, e.g. sulfonic, trichloroacetic or hydrochloric acid.
[0006] Minocycline base, previously known before this invention only in the amorphous form, is not as stable as the corresponding acid addition salts and hence, methods to provide a stable form of minocycline base which makes its use promising as an active ingredient have been examined.
[0007] Minocycline free base has been prepared in the documents Bernardi L. et Al., Farmaco, Edizione Scien-tifica, Societa Chimica Italiana, Pavia, 1975, p. 736-741, CHURCH et Al., J. Org. Chem., 1971, p. 723-725 and WO-A-2007/014154.
Detailed Description [0008] The present invention describes crystalline minocycline base, including new polymorphicforms of crystalline minocycline base and novel processes for their preparation.
[0009] The present inventors have now found that, surprisingly, minocycline base can in fact be provided in a stable crystalline form. They have also found three new polymorphic forms of crystalline minocycline base.
[0010] Accordingly, in its broadest aspect, the invention provides crystalline minocycline base.
[0011] In one aspect, polymorphic Form I of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art.
[0012] Crystalline Form I of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.1 and an infrared spectrum of Fig.2.
[0013] Crystalline Form 1 is characterised by an X-ray diffraction pattern having peaks at 5.2, 7.6, 8.8, 12.8, 14.5, 15.0, 15.3, 15.9, 16.4, 17.8, 19.3, 19.5,20.7,21.3, 21.8, 22.3, 23.1,24.0, 25.3, 25.7 and 26.5 ± 0.2° 2Θ, as given in Fig.1. It is further characterised by an infrared spectrum having peaks at1646,1602,1581,1470,1397, 1364, 1286, 1218, 1182, 1134, 1072, 1061, 1023, 1001, 969, 950, 874, 850, 716, 636, 620 and 545 ± 4 cm"1 as given in Fig. 2.
[0014] In another aspect, the invention provides a process for the preparation of polymorphic Form I of crystalline minocycline base, which process comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallization from the mixture.
[0015] Preferably, the process comprises suspending amorphous minocycline base in an organic solvent chosen from ethers, cooling the heterogeneous mixture to a temperature of from 0°C to 30°C, the preferred range being from 10°C to 15°C and isolating Form I from the reaction mixture.
[0016] Any suitable ether solvent may be used, but is preferred to use methyl tert-butyl ether.
[0017] In another aspect, polymorphic Form II of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art.
[0018] Crystalline Form II of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.3and an infrared spectrum of Fig.4.
[0019] Crystalline Form II is characterised by an X-ray diffraction pattern having peaks at 3.4, 6.8, 8.0, 10.0, 13.0, 13.8, 14.6, 14.9, 15.5, 16.1, 17.6, 17.8, 18.6, 19.5, 20.2, 20.6, 21.9, 22.6, 23.9, 24.2, 25.4, 26.3, 27.1,27.5, 28.0 and 29.1 ± 0.2° 2Θ, as given in Fig.3. It is further characterised by an infrared spectrum having peaks at 1644, 1607, 1582, 1469, 1453, 1413, 1396, 1358, 1287, 1251,1217, 1186,1166, 1136,1061,999,970,874,716, 621 and 585 ± 4 cm-1, as given in Fig. 4.
[0020] In another aspect, a process for the preparation of polymorphic Form II of crystalline minocycline base comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from esters followed by crystallization from the mixture.
[0021] Preferably, the process comprises suspending amorphous minocycline base in an organic solvent chosen from esters, cooling the heterogeneous mixture to a temperature of from 0°C to 30°C, the preferred range being from 10°C to 15°C and isolating the Form II from the reaction mixture.
[0022] Any suitable ester may be used as solvent, but it is preferred to use ethyl acetate.
[0023] In another aspect, polymorphic Form III of crystalline minocycline base is provided. That this is a crystalline form of minocycline base, which up until now has only been known in its amorphous form, is demonstrated by physical attributes whose application in this area is well known to those skilled in the art.
[0024] Crystalline Form III of minocycline base has a characteristic X-ray diffraction pattern shown in Fig.5 and an infrared spectrum of Fig.6.
[0025] Crystalline Form III is characterised by anX-ray diffraction pattern having peaks at 6.5, 10.0, 13.2, 15.1, 16.5, 17.9, 19.6, 20.2, 21.1,22.3, 23.7, 24.8, 26.4, 28.1 and 30.5 ± 0.2° 2Θ, as given in Fig. 5. It is further characterised by an infrared spectrum having peaks at 1647, 1605, 1581,1470, 1399, 1307, 1286, 1251,1216, 1195, 1179,1136,1094,1058,1024,1000, 973, 950, 870, 825, 806, 716, 680, 634, 615, 584, 515,496 and 413 ± 4 cm"1, as given in Fig. 6.
[0026] In another aspect, a process for the preparation of polymorphic Form III of crystalline minocycline base comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from alcohols followed by crystallization from the mixture.
[0027] Preferably, the process comprises suspending amorphous minocycline base in an organic solvent chosen from alcohols, cooling the heterogeneous mixture to a temperature of from CPC to 30°C, the preferred range being from 10°C to 15°C and isolating the Form III from the reaction mixture.
[0028] Any suitable alcohol may be used a solvent, but it is preferred to use ethanol.
[0029] The crystalline minocycline bases in Forms I, II and III obtained by the processes described above have a high purity with all the impurities controlled, especially 4-epi minocycline, which is typically below 1.2% w/w (ie by weight of the base).
[0030] In another aspect, therefore, the invention provides crystalline minocycline base substantially free of 4-epi minocycline. By substantially free, we mean that no more than about 1.2% impurity by weight of the polymorph (w/w) is present. Preferably the impurity level is less than 1.2% w/w.
[0031] In a further aspect, therefore, the invention provides crystalline minocycline base comprising less than 1.2% w/w (by weight of the base) of 4-epi minocycline.
[0032] Another aspect of the invention provides processes for preparing amorphous minocycline base on an industrial scale, wherein the minocycline base is obtained in high purity, especially maintaining low levels of the content of 4-epi-minocycline.
[0033] In one aspect, there is provided a process for preparing amorphous minocycline base, which process comprises spray drying a solution or suspension of minocycline, in an organic solvent, preferably chosen from methyl tert-butyl ether, dichloromethane or isopropyl acetate [0034] A preferred process for preparing amorphous minocycline base comprises: 1) dissolving minocycline base in one or more organic solvents to form a solution or a suspension 2) spray drying the solution or suspension obtained in step 1) 3) optionally drying the amorphous minocycline base so obtained , if necessary under vacuum, at a temperature of from 25°C to 45°C, preferably from 35°C to 45 °C.
[0035] Any suitable solvent may be used, and preferred solvents include methyl tert-butyl ether, dichloromethane or isopropyl acetate.
[0036] Anysuitabletechniqueforthespraydrying may be used. For example, conventional spray drying techniques (as will be clear to those skilled in the art) may be employed.
EXAMPLES
[0037] The following examples are provided to illustrate the present invention and do not in any way limit its scope. EXAMPLE 1: Preparation of Form I of crystalline minocycline base [0038] Amorphous minocycline base (0.5g) is suspended in methyl tert-butyl ether (4ml) and the resulting heterogeneous mixture stirred for about 2 hours at a temperature between 0°C and 30°C, preferably between 10°C and 15°C.
[0039] The product is filtered, washed with methyl tert-butyl ether (1 ml) and dried under vacuum at about 45°C-50°C to yield crystalline minocycline base.
Yield: 0.38g [0040] The XRPD pattern and infrared are presented in Fig 1 and Fig .2. 4-epi minocycline: 0.06% in area (HPLC)
Melting point: 113°C EXAMPLE 2: Preparation of Form I of crystalline minocycline base [0041] Amorphous minocycline base (0.5g) is dissolved in methyl tert-butyl ether (6ml) and the resulting solution stirred at a temperature between 0°C and 30°C, preferably between 10°C and 15°C.
[0042] After about 5 minutes Form I of crystalline minocycline base precipitates from the solution.
[0043] The resulting suspension is filtered, washed with methyl tert-butyl ether(1 ml) and dried under vacuum at about 45°C-50°C to yield Form I of crystalline minocycline base.
Yield: 0.45g.
Melting point: 113°C EXAMPLE 3: Preparation of Form II of crystalline minocycline base [0044] Amorphous minocycline base (20g) is suspended in ethyl acetate (160ml) and the resulting heterogeneous mixture stirred for about 3 hours at a temperature between 0°C and 30°C, preferably between 10°C and 15°C.
[0045] The product is filtered, washed with ethyl acetate (10ml) and dried under vacuum at about 45°C-50°C to yield crystalline minocycline base.
Yield: 17. 4g HPLC purity: 99.5% in area 4-epi minocycline: 0.11% in area.
Melting point: 187°C
[0046] The XRPD pattern and infrared are presented in Fig.3 and Fig.4. EXAMPLE 4: Preparation of Form II of crystalline minocycline base [0047] Amorphous minocycline base (5 g) is dissolved in ethyl acetate (40ml) and the resulting solution stirred for about 3 hours at a temperature between 0°C and 30°C, preferably between 10°C and 15°C whereupon Form II of crystalline minocycline base precipitated.
[0048] The product is filtered, washed with ethyl acetate (5ml) and dried under vacuum at about 45°C-50°C to yield Form II of crystalline minocycline base.
Yield: 3.2g Melting point: 187°C. EXAMPLE 5: Preparation of Form III of minocycline base [0049] Amorphous minocycline base (0.5g) is suspended in ethyl alcohol (2.5ml) and the resulting heterogeneous mixture stirred for at least 10 hours at a temperature between 0°C and 30°C preferably between 10°C and 15°C.
[0050] The product is filtered, washed with ethyl alcohol (0.5ml) and dried under vacuum at about 45°C-50°C to yield Form III of crystalline minocycline base.
Yield: 0.44g [0051] The XRPD pattern and infrared are presented in Fig.5 and Fig.6. 4-epi minocycline: 0.12% in area (HPLC)
Melting point: 193°. EXAMPLE 6: Preparation of amorphous minocycline base [0052] A solution of minocycline base in dichlorometh- ane, isopropyl acetate or methyl tert-butyl ether was isolated by spray drying in conventional spray drying equipment using an inlet temperature between 45°C and 105°C, and an outlet temperature between 30°C and 75°C.
[0053] The isolated product can be used directly to obtain any of the Forms of crystalline minocycline base or can be subjected to a post drying step under vacuum at about 45°C to yield pure amorphous minocycline base.
Yield: 24.5 g HPLC purity: 98.6% in area [0054] The XRPD pattern and infra red are presented in Fig 7 and Fig 8.
Claims 1. Minocycline base characterized by being crystalline. 2. Crystalline minocycline base, Form I, characterised by an X-ray diffraction pattern having peaks at 5.2, 7.6,8.8,12.8,14.5,15.0,15.3,15.9,16.4,17.8,19.3, 19.5, 20.7, 21.3, 21.8, 22.3, 23.1, 24.0, 25.3, 25.7 and 26.5 ± 0.2° 2Θ, as given in Fig.1. 3. Crystalline minocycline base, Form I, according to claim 2 further characterized by an infrared spectrum having peaks at 1646,1602,1581,1470,1397, 1364, 1286, 1218, 1182, 1134, 1072, 1061, 1023, 1001,969, 950, 874, 850, 716, 636, 620 and 545 ± 4 cm-1 as given in Fig. 2. 4. A process for preparing crystalline minocycline base, Form I, which process comprises dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallization from the mixture. 5. A process according to claim 4, wherein the organic solvent is methyl tert-butyl ether. 6. Crystalline minocycline base, Form II, characterised by an X-ray diffraction pattern having peaks at 3.4, 6.8, 8.0, 10.0, 13.0, 13.8, 14.6, 14.9, 15.5, 16.1, 17.6, 17.8, 18.6, 19.5, 20.2, 20.6, 21.9, 22.6, 23.9, 24.2, 25.4, 26.3, 27.1, 27.5, 28.0 and 29.1 ± 0.2° 2Θ, as given in Fig.3. 7. Crystalline minocycline base, Form II, according to claim 6 further characterised by an infrared spectrum having peaks at 1644,1607,1582,1469,1453, 1413, 1396, 1358, 1287, 1251, 1217, 1186, 1166, 1136, 1061, 999, 970, 874, 716, 621 and 585 ± 4 cm-1, as given in Fig. 4. 8. A process for preparing crystalline minocycline, base Form II, which process comprises dissolving and/ or suspending amorphous minocycline base in an organic solvent chosen from esters followed by crystallization from the mixture. 9. A process according to claim 8, wherein the organic solvent is ethyl acetate. 10. Crystalline minocycline base, Form III, characterised by an X-ray difFraction pattern having peaks at 6.5, 10.0, 13.2, 15.1, 16.5, 17.9, 19.6, 20.2, 21.1, 22.3, 23.7, 24.8, 26.4, 28.1 and 30.5 ± 0.2° 2Θ, as given in Fig. 5. 11. Crystalline minocycline base, Form III, according to claim 10 further characterised by an infrared spectrum having peaks at 1647,1605,1581,1470,1399, 1307, 1286, 1251, 1216, 1195, 1179, 1136, 1094, 1058,1024,1000, 973, 950,870,825,806, 716, 680, 634, 615, 584, 515, 496 and 413 ± 4 cm'1, as given in Fig. 6. 12. A process for preparing crystalline minocycline base, Form III, which process comprises dissolving and/ or suspending amorphous minocycline base in an organic solvent chosen from alcohols followed by crystallization from the mixture. 13. A process according to claim 12, wherein the organic solvent is ethanol. 14. A process for preparing amorphous minocycline base, which process comprises spray drying a solution of minocycline in an organic solvent. 15. A process according to claim 14, wherein the solvent is methyl tert-butyl ether, dichloromethane or isopropyl acetate. 16. A process according to any one of claims 4-5, 8-9 or 12-13, wherein the content of 4-epi minocycline is below 1.2% w/w. 17. Crystalline minocycline base according to claim 1 substantially free of 4-epi minocycline. 18. Crystalline minocycline base prepared according to the process of claim 16 comprising less than 1.2% w/w of 4-epi minocycline.
Patentansprüche 1. Minocyclinbase, dadurch gekennzeichnet, dass sie kristallin ist. 2. Kristalline Minocyclinbase, Form I, dadurch ge kennzeichnet, dass ein Röntgenbeugungsmuster Peaks bei 5,2; 7,6; 8,8; 12,8; 14,5; 15,0; 15,3; 15,9; 16,4; 17,8; 19, 3; 19, 5; 20, 7; 21,3; 21,8; 22, 3; 23, 1; 24,0; 25, 3; 25,7; und 26,5 ± 0,2° 2Θ, wie in Fig. 1 dargelegt, aufweist. 3. Kristalline Minocyclinbase, Form I, nach Anspruch 2, ferner dadurch gekennzeichnet, dass ein Infrarotspektrum Peaks bei 1646, 1602, 1581, 1470, 1397, 1364, 1286, 1218, 1182, 1134, 1072, 1061, 1023, 1001,969, 950, 874, 850, 716, 636, 620 und 545 ± 4 cnr1, wie in Fig. 2 dargelegt, aufweist. 4. Verfahren zur Herstellung einer kristallinen Minocyclinbase, Form I, welches Verfahren das Auflösen und/oder Suspendieren einer amorphen Minocyclinbase in einem aus Ethern ausgewählten organischen Lösungsmittel, gefolgt vom Kristallisieren aus dem Gemisch umfasst. 5. Verfahren nach Anspruch 4, wobei das organische Lösungsmittel Methyl-tert-butylether ist. 6. Kristalline Minocyclinbase, Form II, dadurch gekennzeichnet, dass ein Röntgenbeugungsmuster Peaks bei 3,4; 6,8; 8,0; 10,0; 13,0; 13,8; 14,6; 14,9; 15,5; 16,1; 17,6; 17,8; 18,6; 19, 5; 20,2; 20,6; 21,9; 22,6; 23, 9; 24,2; 25,4; 26,3; 27,1; 27,5; 28,0 und 29,1 ± 0,2° 2Θ, wie in Fig. 3 dargelegt, aufweist. 7. Kristalline Minocyclinbase, Form II, nach Anspruch 6, ferner dadurch gekennzeichnet, dass ein Infrarotspektrum Peaks bei 1644, 1607, 1582, 1469, 1453, 1413, 1396, 1358, 1287, 1251, 1217, 1186, 1166, 1136, 1061,999,970, 874,716,621 und 585 ± 4 cm-1, wie in Fig. 4 dargelegt, aufweist. 8. Verfahren zur Herstellung einer kristallinen Minocyclinbase, Form II, welches Verfahren das Auflösen und/oder Suspendieren der amorphen Minocyclinbase in einem aus Estern ausgewählten organischen Lösungsmittel, gefolgtvom Kristallisieren aus dem Gemisch umfasst. 9. Verfahren nach Anspruch 8, wobei das organische Lösungsmittel Ethylacetat ist. 10. Kristalline Minocyclinbase, Form III, dadurch gekennzeichnet, dass ein Röntgenbeugungsmuster Peaks bei 6,5; 10,0; 13,2; 15,1; 16,5; 17, 9; 19,6; 20,2; 21, 1; 22,3; 23,7; 24,8; 26,4; 28,1 und 30,5 ± 0,2° 2Θ, wie in Fig. 5 dargelegt, aufweist. 11. Kristalline Minocyclinbase, Form III, nach Anspruch 10, ferner dadurch gekennzeichnet, dass ein Infrarotspektrum Peaks bei 1647, 1605, 1581, 1470, 1399, 1307, 1286, 1251, 1216, 1195, 1179, 1136, 1094, 1058, 1024, 1000, 973, 950, 870, 825, 806, 716, 680, 634, 615, 584, 515, 496 und 413 ± 4cnr1, wie in Fig. 6 dargelegt, aufweist. 12. Verfahren zur Herstellung einer kristallinen Minocyclinbase, Form III, welches Verfahren das Auflösen und/oder Suspendieren einer amorphen Minocyclinbase in einem aus Alkoholen ausgewählten organischen Lösungsmittel, gefolgt vom Kristallisieren aus dem Gemisch umfasst. 13. Verfahren nach Anspruch 12, wobei das organische Lösungsmittel Ethanol ist. 14. Verfahren zur Herstellung einer amorphen Minocyclinbase, welches Verfahren das Sprühtrocknen einer Minocyclin-Lösung in einem organischen Lösungsmittel umfasst. 15. Verfahren nach Anspruch 14, wobei das Lösungsmittel Methyl-tert-butylether, Dichlormethan oder Isopropylacetat ist. 16. Verfahren nach einem der Ansprüche 4 bis 5, 8 bis 9 oder 12 bis 13, wobei der Gehalt an 4-Epiminocy-clin unter 1,2 % (w/w) liegt. 17. Kristalline Minocyclinbase nach Anspruch 1, im Wesentlichen frei von 4-Epiminocyclin. 18. Kristalline Minocyclinbase, hergestellt nach dem Verfahren von Anspruch 16, umfassend weniger als 1,2 % (w/w) 4-Epiminocyclin.
Revendications 1. Minocycline sous forme de base caractérisée en ce qu’elle est cristalline. 2. Formende la minocycline sous forme de base cristalline, caractérisée par un diagramme de diffraction des rayons X ayant des pics à 2Θ de 5,2, 7,6, 8,8, 12,8, 14,5, 15,0, 15,3, 15,9, 16,4, 17,8, 19,3, 19,5, 20,7, 21,3, 21,8, 22,3, 23, 1, 24,0, 25,3, 25,7 et 26,5 ± 0,2°, tel que donné dans la fig. 1. 3. Forme I de la minocycline sous forme de base cristalline selon la revendication 2 caractérisée en outre par un spectre infrarouge ayant des pics à 1646, 1602, 1581, 1470, 1397, 1364, 1286, 1218, 1182, 1134,1072,1061,1023,1001,969, 950, 874, 850, 716, 636, 620 et 545 ± 4 cm-1 tel que donné dans la fig. 2. 4. Procédé pour la préparation de forme I de la minocycline sous forme de base cristalline, lequel procédé comprend la dissolution et/ou la mise en suspension de minocycline sous forme de base amorphe dans un solvant organique choisi parmi les éthers suivies de la cristallisation à partir du mélange. 5. Procédé selon la revendication 4, dans lequel le solvant organique est l’éther de tert-butyle et de méthyle. 6. Forme II de la minocycline sous forme de base cristalline, caractérisée par un diagramme de diffraction des rayons X ayant des pics à 2Θ de 3,4, 6,8, 8,0, 10,0, 13,0, 13,8, 14,6, 14,9, 15,5, 16,1, 17,6, 17.8, 18,6, 19,5, 20, 2, 20, 6, 21, 9, 22, 6, 23, 9, 24, 2, 25, 4, 26, 3, 27,1,27, 5, 28,0 et 29,1 ± 0,2°, tel que donné dans la fig. 3. 7. Forme II de la minocycline sous forme de base cristalline selon la revendication 6 caractérisée en outre par un spectre infrarouge ayant des pics à 1644, 1607, 1582, 1469, 1453, 1413, 1396, 1358, 1287,1251,1217,1186,1166,1136,1061,999,970, 874, 716, 621 et 585 ± 4 cm"1, tel que donné dans la fig. 4. 8. Procédé pour la préparation de forme II de la minocycline sous forme de base cristalline, lequel procédé comprend la dissolution et/ou la mise en suspension de minocycline sous forme de base amorphe dans un solvant organique choisi parmi les esters suivies de la cristallisation à partir du mélange. 9. Procédé selon la revendication 8, dans lequel le solvant organique est l’acétate d’éthyle. 10. Forme III de la minocycline sous forme de base cristalline, caractérisée par un diagramme de diffraction des rayons X ayant des pics à 2Θ de 6,5, 10,0, 13,2, 15,1, 16,5, 17,9, 19,6, 20,2, 21,1,22,3, 23,7, 24.8, 26,4, 28,1 et 30,5 ± 0,2°, tel que donné dans la fig. 5. 11. Forme III de la minocycline sous forme de base cristalline selon la revendication 10 caractérisée en outre par un spectre infrarouge ayant des pics à 1647, 1605, 1581, 1470, 1399, 1307, 1286, 1251, 1216, 1195, 1179, 1136, 1094, 1058, 1024, 1000, 973, 950, 870, 825, 806, 716, 680, 634, 615, 584, 515,496 et 413 ± 4 cm-1, tel que donné dans la fig. 6. 12. Procédé pour la préparation de forme III de la minocycline sous forme de base cristalline, lequel procédé comprend la dissolution et/ou la mise en suspension de minocycline sous forme de base amorphe dans un solvant organique choisi parmi les alcools suivies de la cristallisation à partir du mélange. 13. Procédé selon la revendication 12, dans lequel le solvant organique est l’éthanol. 14. Procédé pour la préparation de minocycline sous forme de base amorphe, lequel procédé comprend le séchage par pulvérisation d’une solution de minocycline dans un solvant organique. 15. Procédé selon la revendication 14, dans lequel le solvant est l’éther de tert-butyle et de méthyle, le dichlorométhane ou l’acétate d’isopropyle. 16. Procédé selon l’une quelconque des revendications 4-5, 8-9 ou 12-13, dans lequel la teneur en 4-épi-minocycline est au-dessous de 1,2 % p/p. 17. Minocycline sous forme de base cristalline selon la revendication 1 pratiquement exempte de 4-épi-mi-nocycline. 18. Minocycline sous forme de base cristalline préparée selon le procédé de la revendication 16 comprenant moins de 1,2 % p/p de 4-épi-minocycline.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • US 3148212 A [0004] · US 4849136 A [0004] • US 3226436 A [0004] · WO 2007014154 A [0007]
Non-patent literature cited in the description • BERNARDI L. et al. Farmaco, Edizione Scientifica, · CHURCH et al. J. Org. Chem, 1971,723-725 [0007]
Societa Chimica Italiana, Pavia, 1975, 736-741 [0007]

Claims (6)

  1. KRISTÁIYÖB hUNÖCÍKUN BÁZIS, ÉS ELJÁRÁSOK ENNEK ELŐÁLLÍTÁSÁRA SZABADALMI IGÉNYPONTOK
    1. Minoeikíin (mfeócplifts) bázis, azzal jellemezve, hogy Rnsíályös. I. Krisfályős minoeiklin bázis, I, forma, azzal jélfémezséj bogf flhtgerísLgár eakciós mintázata (X-ray diffraotioh patiérni a következő helyekén rendelkezik OsSúcsokkal: 5,2; 7,6; 6,8; 12.8; 14,5; 15,3; 15,3.15,9; 16,4; 17,8; 18,3,19,5, 20,7, 21,3; 21,8, 22,3. 23.1; 24,0; 28,3; 25,7 és 26,5 ±0,2^29, ahogyan «2 meg van adva p 1. éóE|5afs. 3. A 2 igénypont szerinti kristályos minoeikiin bázis, i. forma, továbbá sXZai Jellemezve, hogy infravörös spektruma a kővetkező csúc®kk#:fetL 1:646; 1601 45811470; 1397; 1364; 1286:1218: H82,1134; 1872; Ml; 1923; 1861:; 889; 956: 874; 853; 718; 338;; 628; és 545 * 4 cm1, ahogyan ez meg van adva a 2. ábrában.
  2. 4. Sprás kristályos mihoeíídfh bása, 1, tenm. eipljilására, áméiy eljárás tan^niasa áhyiíl n^no^P öázis léföldását Mvagy szyszpendáiását ggy: szorvos oldószerben. amely éterek kozülváiaszíható ki, és azt követi a knsíályosüss akeverőkbcí. 5. A4. igénypont szerinti eljárás, ahol a szerves oldószer metsí-ierc-butii-éter. 8: Kristályos minoeikiin bázis, It forma, azzal jellemezve, hogy röntgensugár diffrakciós mintázata (X-ray diffraction oattern) a pvstkezó helyékén téhdfeikézík osúesokkal: 3,4:8,8; 8,0; 10,3:13,0;: 13,8; 14,6; 14,6; 15,5:16,1; 1?J; Í7M 18,8; 19,5; 29,2; 28,6; 21,S, 22.6; 23,9; 24 J; 25,4; 23,3:27,1,27,5; 2$βΜΜΛ 10,2*20,. áciva a 3 ábrában. 7. A 6, igénypont széiMi kfiéliyos minöcikiin bázis, íí. fcrnm továbbá azzal jalteméZVé, hogy infravörös spekthiífia a kővetkéző csúcsokkal bír 1344; 1837; 1582; 1469M4S3; 1413; 1398:1366;: 1267; 12§t 1217; 1166; 1165:1136; 1061;: 899; 970: 674; 713; 621 és 585 * 4 cm4, ahogyan ez még: várnáévá a 4, ábrában,
  3. 8. Eljárás kristályos minoeikiin bázis, ILÍbrma, előállítására, amely spfp.'^ifetníi^L^s^f ^mirtöcikiin: ö^ífeloiásái és/vasy szgszpenbáiását egy szerves oioöszerbsn, ameiy észterek kozttt választható ki, és ezt ^vétí-:a)sri^áip^^í.S KéVe?#Mk 9. A 4. igénypont szerinti eljárás, ahol a szerves oldószer etii-acétát.
  4. 10. Kristályos minoeikiin -bázis, ül, forma, azzal jellemezve* högy fénigshsugár diffrakciós; mintázata (X^ray difiraopn plémj a Követkélő helyeken rendéikozik csúcsokkal. 6,5:10,0; 13.2:15.1; 13,5; 17,9; 19,8; 20,2; 21,1; 22,3; 23,7; 24.8; 26.4; 28.1: és 30.5 * 9,24 28, ahogyan ez meg van adva az 5. ábrában. II. A19. igénypont szerinti kristályos minoeikiin bázis, ül íorma. továbbá azzal jellemezve* hogy infravörös spektruma a kővetkező: csúcsokkal bir::1:847; 1365; 1681; 1470,1399.1307; 1286; 1251. 1218; 1195; 1179; 1138; 1094; 4058; 1:024; 1600; 973:350; 370: :625;: 805,: 716;;883::634; 645; 534; 515,495 és 4T3 ± 4 cm·1, ahogyan ez meg van adva a 6. ábrában,
  5. 12. Eljárás krisfiyos: mihoeikiiri bázis, ül. forma,.előállítására, amely o|átas tartalmazza amorf minccikfin bázis feloldását és/vagy szaszpéndálásátegy sprNaa: oldószerben, amely alkoholok közti! vipzlhatöikí.: és ezt: követi akostályositás a keverékből. 13. A12. igánypontazerinttépfás. ahol a szerves oldőszér éfénoL 14. |p?ás amorf mísöbíkiifi élőállítására, amely épfás pérmétézve szárítPÉ (spray drying} agy szerves oldószerben. 15..A14. igénypbLs«m5 eprás, ahol m οΐΟόδζρτηβδί-ΐδΓδ^ΡΙ^όΙόη 18, Α:4^·, 8Ό: 12-13: igénypontok bármepka szerinti epfÉs, ahol a 4-spbmihöoikP tor falam 1,215 (tömeg/fömegl alatt van, |7. Az 1. igénypont szerinti kristályos rninociklin bázis, amely lényegében mentes tt-epi-minocikiintői.
  6. 18, All. igénypont eprása szerint készileit kfisíips minooíkiin bázis, amely ksvésóbb, mint ig tartalmaz.
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