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WO2017167949A1 - Formes cristallines de bilastine - Google Patents

Formes cristallines de bilastine Download PDF

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Publication number
WO2017167949A1
WO2017167949A1 PCT/EP2017/057656 EP2017057656W WO2017167949A1 WO 2017167949 A1 WO2017167949 A1 WO 2017167949A1 EP 2017057656 W EP2017057656 W EP 2017057656W WO 2017167949 A1 WO2017167949 A1 WO 2017167949A1
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WIPO (PCT)
Prior art keywords
bilastine
crystalline
water content
water
product
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Ceased
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PCT/EP2017/057656
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English (en)
Inventor
Alen Kljajic
Monika KUFNER
Darja Pavlin
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KRKA dd
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KRKA dd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to novel solid state forms of bilastine, a process for their preparation, and pharmaceutical compositions comprising them.
  • Bilastine of formula I with its chemical name 2- [4 (2- ⁇ 4 [1 - (2-ethoxy - ethyl) -1H-- benzimidazol-2-yl ] - piperidin-l-yl ⁇ ethyl) - phenyl]-2-methyl - propionic acid is marketed under the trade name Bilaxten by FAES and has been indicated for the treatment of allergic rhinitis and chronic idiopathic urticaria.
  • EP 1 505 066 discloses three different crystalline polymorphic forms of bilastine, form I, II and form III, and is directed to the preparation the new polymorph form I of bilastine, its pharmaceutical formulations and its use for the treatment of allergic reactions and pathological processes mediated by histamine in mammals such as humans.
  • Polymorph I of bilastine was reported to have a melting point at 200.3 °C and was prepared, in high yield, by recrystallization of bilastine as synthetized according to US Patent 5,877,187. According to EP 1 505 066, the procedure described in US patent no. 5,877,187 generates a mixture of polymorphs II and III.
  • polymorph II While it was found by EP 1 505 066 that polymorphic forms I and II are stable, polymorph III turned out not to be very stable and to be difficult to obtain in the pure form. Both polymorph II and polymorph III eventually converted into polymorph I. Polymorph II of bilastine was reported to have a melting point of 205.2 °C and polymorph III a melting point of 197.0 °C. In selected experimental conditions, the mixture of polymorphic forms II and III, obtained according to US patent no. 5,877,187; the pure polymorphic form II as well as the pure polymorphic form III, transformed into polymorph I under the same conditions, e.g. using short chained alcohols, preferably isopropylic alcohol and n-butanol and their mixtures.
  • WO 2014/026657 discloses a process for the preparation of bilastine and its isolation in polymorphic form I or II.
  • CN 103214454 discloses a crystalline form of bilastine, with an X-ray powder diffraction pattern of about: 9.2717 °, 10.9004 °, 12.7461 °, 15.6617 °, 17.6890 °, 18.3202 °, 20.0376 ° , 21.9021 °, 27.3518 ° ( ⁇ 0.2) 2 ⁇ , which is presumably identical to form III of EP 1 505 066.
  • the crystallization solvents used were methanol, ethyl acetate, toluene and n-hexane, or mixtures thereof, preferably toluene.
  • the melting point ranges reported in the examples varied between 197.5-199.8 °C and 197-200 °C.
  • CN 103214455A describes a method for preparing a bilastine crystalline form, using dichloromethane as the isolation solvent, with a reported melting interval between 199°C and 20FC.
  • CN 103613579A discloses a bilastine crystallization purifying method using methyl acetate, ethyl acetate, propyl acetate; acetone, methyl ethyl ketone, benzophenone; methanol, ethanol, isopropanol, n-butanol, ethylene glycol; dichloromethane, chloroform, carbon tetrachloride; acetonitrile, propionitrile; diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran or their mixtures as solvents. No data regarding the polymorphic form(s) obtained is disclosed.
  • CN 103755683 A describes the isolation of bilastine from reaction mother liquors by using isopropanol, n-butanol, acetone, methylene chloride, ethylene glycol, methanol, acetone, ethyl acetate, methylene chloride, water or mixtures thereof. No data regarding the polymorphic form(s) obtained is disclosed.
  • CN 103788062 discloses and claims a bilastine crystal comprising the following peaks in X- ray powder diffraction data: 11.30 °, 12.50 °, 17.18 °, 18.94 °, 19.80 °, 21.14 °, 22.68 °, 24.92 ° 2 ⁇ ( ⁇ 0.2).
  • the process described consists of dissolving bilastine in isopropyl alcohol under nitrogen atmosphere, heating the mixture to reflux until a clear solution was obtained. The solution was filtered while hot and the filtrate was cooled to 20 °C. Crystallization was achieved while stirring the solution for 10 - 12h. The crystals obtained were filtered, washed with cold isopropanol at 10 °C or less and vacuum dried to constant weight at 50-60 °C.
  • CN 104447682 provides crystalline bilastine with a moisture content of less than 1 %o.
  • the crystals were isolated from solutions comprising mixtures of DMF and water and/or acetonitrile and methyl ethyl ketone in a ratio of 7: 5 (V/V).
  • CN 104447683 describes and claims a process for the preparation of bilastine monohydrate crystal form.
  • the process comprises recrystallization of bilastine from a mixture comprising ethanol, acetic acid and water, in the ratios of 7-4: 1.5-2: 4-8 (V/V/V).
  • the reported X-ray powder diffraction characteristic absorption peaks (2 ⁇ ), d values and relative intensities for bilastine monohydrate are as follows: Line number 2 ⁇ Spacing (d) I / I 0
  • Polymorphism the occurrence of different crystalline forms, is the property of some molecules and molecular complexes. It is generally known that various salts or polymorphs of pharmaceutically active substances may have different physico-chemical, and consequently pharmacological properties. Then, such salts and their polymorphs can be used to obtain an ideal composition of pharmaceutical formulations containing the given active substance or its salt. This means that it is very important to keep looking for suitable salts or polymorphic forms of pharmaceutically active substances.
  • crystalline forms of bilastine and their use in pharmaceutical dosage forms.
  • processes for preparing crystalline forms of bilastine comprising contacting bilastine with moisture, drying the wet bilastine and isolating the solid state forms of bilastine.
  • composition comprising a crystalline form of bilastine as disclosed herein, and one or more pharmaceutically acceptable excipients.
  • a process for preparing a pharmaceutical formulation comprising combining any one of the crystalline forms of bilastine disclosed herein with one or more pharmaceutically acceptable excipients.
  • the crystalline forms of bilastine are disclosed herein for use in the pharmaceutical compositions having particle size determined by microscopic method, measured as the longest dimension under a scanning electron microscope in the range of 1 to 350 ⁇ , preferably 10 to 250 ⁇ , most preferably 50 to 190 ⁇ .
  • FIG. 1 is a characteristic Powder X-ray Diffraction (XRD) pattern of crystalline form Kl of bilastine.
  • Fig. 2 is a characteristic FT-IR spectrum of crystalline Form Kl of bilastine.
  • Fig. 3 is a characteristic DSC thermogram of crystalline Form Kl of bilastine.
  • Fig. 4 is a photograph of bilastine form Kl crystals at a magnification of 200x.
  • FIG. 5 is a photograph of bilastine form Kl crystals at a magnification of lOOOx.
  • FIG. 6 is a characteristic Powder X-ray Diffraction (XRD) pattern of crystalline form K2 of bilastine.
  • Fig.7 is a characteristic FT-IR spectrum of crystalline Form K2 of bilastine.
  • Fig. 8 is a characteristic DSC thermogram of crystalline Form K2 of bilastine.
  • Fig. 9 is a photograph of bilastine form K2 crystals at a magnification of 200x.
  • Fig. 10 is a photograph of bilastine form K2 crystals at a magnification of lOOOx.
  • Crystalline bilastine polymorphic form Kl and crystalline bilastine polymorphic form K2 as well as processes for their preparation, will be described below.
  • Crystalline bilastine polymorphic form K2 forms from bilastine having a water content of more than 20 wt% when being dried to comprise a water content of between 15 wt% to less or equal to 20 wt%.
  • Bilastine having a water content of more than 20 wt% may be isolated from aqueous mixtures which optionally comprise one or more organic solvents, such as for example diisopropyl ether, methyl tert-butyl ether and/or methanol.
  • Drying bilastine with a water content of more than 20 wt% can be performed for example by drying in a vacuum drier or at ambient conditions, until a bilastine form K2 can be isolated, having a water content of between 15 wt% to less or equal to 20 wt%.
  • the content of water in bilastine is preferably monitored by using Karl Fisher titration or with non-destructive, online measurements using FT-NIR spectroscopy.
  • bilastine form K2 preferably takes places at temperatures from 10°C to 45 °C and at pressures from below 50 mbar to 6000 mbar.
  • the relative humidity is preferably from 20 to 80% when wet bilastine is dried at ambient conditions to form bilastine form K2.
  • Bilastine form Kl is isolated when either wet bilastine with a water content of above 20 wt% or bilastine form K2 having a water content of between 15 wt% to less or equal to 20 wt% is dried to comprise a water content of between 3 wt% to 5 wt%.
  • bilastine form Kl preferably takes places at temperatures from 10°C to 45 °C and at pressures from below 50 mbar to 6000 mbar.
  • the relative humidity is preferably from 30 to 80% when wet bilastine or bilastine form K2 is dried at ambient conditions to form bilastine form Kl .
  • bilastine polymorphic form Kl is very stable and is not transformed into any of the other polymorphs or hydrates, even when bilastine is dried to a water content of below 3 wt% and left to absorb moisture at ambient conditions until a water content of between 3 wt% to 5 wt% is again reached.
  • Bilastine staring material solid form, oily form or solution in solvents, in a reaction mixture or in a diluted reaction mixture
  • a suitable method e.g. comprises conversion of methyl bilastine into in a salt form of bilastine, and its consequent conversion to the free acid form of bilastine, as described by WO 2014/026657.
  • the preparation of bilastine forms K2 and Kl may also comprise organic extractions as a purification step, wherein the bilastine thus purified is converted to bilastine forms K2 and/or Kl in the last step, by drying the wet bilastine comprising a water content of above 20 wt%.
  • a suitable method comprises the purification of bilastine acid form by converting it into a salt form, and extracting the aqueous solution with an organic solvent.
  • the purified material containing bilastine is dried in a state of the art dryer such as a fluid bed dryer, a tray dryer with or without vacuum, or a rotating dryer (application of air flow).
  • a fluid bed dryer where the inlet air has water content in the range of 0.5 to 10 g per kg of air. In some cases higher humidity of inlet air is desired in order to prevent the fast drying of the surface of the material in the dryer resulting in forming a strongly impermeable layer on the surface of the particles causing slow and incomplete removal of solvent(s) from the interior of the particles.
  • the as-prepared material can be left to stand in air (or applied air-flow over the solid product bilastine), with water content between 0,01 to 10 g per kg of air, until anhydrous forms present in the material are spontaneously transformed to the stable bilastine form Kl .
  • the particle size of primary particles of bilastine forms Kl and K2 is between 1- 350 ⁇ , preferably 10 - 250 ⁇ , more preferably 50 to 190 ⁇ , measured as the longest dimension under a scanning electron microscope.
  • the particle size of bilastine forms Kl and K2 can be reduced and the particle size distribution can be narrowed, if advantageous for the manufacturing of solid dosage forms, e.g. by conventional milling or grinding methods and equipment such as jet mills and/or hammer mills.
  • the new polymorphic form Kl of bilastine is characterized by the following 2-theta degrees: 12.1, 19.1, 20.1, and 23.2 ⁇ 0.2.
  • the new polymorphic form Kl of bilastine is characterized by the following 2-theta degrees: 9.5, 12.1, 14.9, 18.1, 19.1, 20.1, 21.4, 23.2, and 27.8 ⁇ 0.2 (Table 1).
  • Polymorphic form Kl of bilastine is further characterized by a Powder X-ray Diffraction (XRD) pattern substantially in accordance with Fig. 1.
  • XRD Powder X-ray Diffraction
  • the new polymorphic form K2 of bilastine is characterized by the following 2-theta degrees: 10.4, 14.5, 20.3, and 22.2 ⁇ 0.2.
  • the new polymorphic form K2 of bilastine is characterized by the following 2-theta degrees: 7.7, 10.4, 12.9, 14.5, 16.2, 18.1, 20.3, 22.2 and 29.1 ⁇ 0.2. (Table 2).
  • Polymorphic form K2 of bilastine is further characterized by a Powder X-ray Diffraction (XRD) pattern substantially in accordance with Fig. 6.
  • Bilastine form Kl of the invention can be used as the drug substance in production of pharmaceutical preparations by combining it with conventional pharmaceutical carriers or diluents employed in this field.
  • the pharmaceutical preparations may be produced by a method usually employed in this field.
  • Bilastine form K2 may be used to prepare other crystalline forms of bilastine, e.g. form Kl of bilastine, as described below.
  • compositions of this invention can contain, as well as an effective quantity of polymorph Kl of bilastine as an active ingredient as an antiallergic or antihistaminic agent, several pharmaceutically acceptable excipients that can be solid or liquid.
  • the solid pharmaceutical preparations include powders, tablets, dispersible granules, capsules, stamps and suppositories.
  • a solid excipient can be one of several substances that act as diluents, aromatising agents, agglutinants or disintegrating agents and an encapsulation material.
  • the powders and tablets preferentially contain from approximately 5 to approximately 80 per cent of the active ingredient.
  • Appropriate solid excipients are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, waxes with low melting point, cocoa butter and similar products.
  • preparation includes the formulation of the active ingredient with an excipient for encapsulation to produce a capsule in which the active ingredient (with or without other excipients) is surrounded with the excipient by an encapsulation material. Tablets, powders, stamps and capsules can be used as suitable forms for oral administration.
  • the active ingredient can also be incorporated into a chewing gum that can contain sweeteners, flavorings and colorings as appropriate.
  • the prepared reaction mixture was transferred to a 150 mL glass reactor equipped with a pitched blade turbine (4 blades at a 45 ° angle) and a distillation column.
  • the reactor jacket was heated to 120 °C and methanol was removed by vacuum distillation (approx. 51 mL of distillate was removed; and the temperature of the reaction mixture was maintained at 85 - 95 °C during the vacuum distillation step).
  • the reaction mixture was cooled to room temperature.
  • diisopropyl ether was added (3 x 24 mL), mixed and the phases were left to separate.
  • the prepared reaction mixture was transferred to a 150 mL glass reactor equipped with a pitched blade turbine (4 blades at a 45 ° angle) and a distillation column.
  • the reactor jacket was heated to 120 °C and methanol was removed by vacuum distillation (approx. 51 mL of distillate was removed; the temperature of the reaction mixture was maintained at 85 - 95 °C during the vacuum distillation step).
  • the reaction mixture was cooled to room temperature.
  • diisopropyl ether was added (3 x 24 mL), mixed and the phases were left to separate.
  • methyl tert-butyl ether was added (3 x 70 mL), mixed and the phases were left to separate.
  • methyl tert-butyl ether was added (1 x 840 mL, 2 x 500 mL), mixed and the phases were left to separate.
  • a solution of 1 M HC1 was added drop wise until pH 6.8 was reached. During this step a suspension was formed.
  • the obtain suspension was further mixed for the next 30 min.
  • the formed product was isolated using filtration with a Buchner funnel and washed with water (120 mL). 152 g of the product were obtained, having a water content of 22.6 wt.% as determined by using KF titration.
  • the sample was left at room temperature and atmospheric pressure for 2 h to obtain 144 g of the product in polymorphic form K2. Its water content was determined to be 19.6 wt. % by using KF titration.
  • methyl tert-butyl ether was added (1 x 840 mL, 2 x 500 mL), mixed and the phases were left to separate.
  • a solution of 1 M HC1 was added drop wise until pH 6.8 was reached. During this step a suspension was formed.
  • the obtain suspension was further mixed for the next 30 min.
  • the formed product was isolated using filtration with a Buchner funnel and washed with water (120 mL). 154 g of the product were obtained, with a water content of 22.1 wt. % as determined by KF titration.
  • the water content of obtained product was determined to be 16.2 wt. % using KF titration.
  • the product was further dried in a vacuum drier for 22 h at 40 °C, p ⁇ 50 mbar to obtain 120 g of the product in polymorphic form Kl . Its water content was determined to be 3,8 wt. % using KF titration.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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Abstract

La présente invention concerne de nouvelles formes solides de bilastine, des procédés de préparation de celles-ci et des compositions pharmaceutiques les comprenant.
PCT/EP2017/057656 2016-04-01 2017-03-31 Formes cristallines de bilastine Ceased WO2017167949A1 (fr)

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SI201600093 2016-04-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3470062A1 (fr) 2017-12-18 2019-04-17 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition de comprimé pharmaceutique comprenant de la bilastine et de l'aluminométasilicate de magnésium
WO2019097091A1 (fr) 2017-12-18 2019-05-23 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition de comprimé pharmaceutique comprenant une forme de bilastine 3 et une charge soluble dans l'eau

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US5877187A (en) 1996-06-04 1999-03-02 Fabrica Espanola De Productos Quimicos Y Farmaceuticos S.A. (Faes) Benzimidazole derivatives with antihistaminic activity
EP1505066A1 (fr) 2002-04-19 2005-02-09 Faes Farma, S.A. Polymorphe de l'acide 4-[2-[4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-il]-1-piperidinyl]ethyl]-alpha, alpha-dimethyl-benzenoacetique
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CN103613579A (zh) 2013-11-13 2014-03-05 江苏万特制药有限公司 一种纯化bilastine的方法
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CN103788062A (zh) 2014-02-17 2014-05-14 北京博泽德润医药科技开发有限公司 一种比拉斯汀晶型及其制备方法
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CN105017211A (zh) * 2014-04-30 2015-11-04 重庆华邦制药有限公司 一种2-苯基丙酸酯衍生物及其制备方法和用途

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3470062A1 (fr) 2017-12-18 2019-04-17 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition de comprimé pharmaceutique comprenant de la bilastine et de l'aluminométasilicate de magnésium
WO2019097091A1 (fr) 2017-12-18 2019-05-23 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition de comprimé pharmaceutique comprenant une forme de bilastine 3 et une charge soluble dans l'eau
WO2019097090A1 (fr) 2017-12-18 2019-05-23 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition de comprimé pharmaceutique comprenant de la bilastine et de l'aluminométasilicate de magnésium

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