WO2014063752A1 - Procédé de production de la forme cristalline alpha du bromhydrure d'élétriptan - Google Patents

Procédé de production de la forme cristalline alpha du bromhydrure d'élétriptan Download PDF

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Publication number
WO2014063752A1
WO2014063752A1 PCT/EP2012/071262 EP2012071262W WO2014063752A1 WO 2014063752 A1 WO2014063752 A1 WO 2014063752A1 EP 2012071262 W EP2012071262 W EP 2012071262W WO 2014063752 A1 WO2014063752 A1 WO 2014063752A1
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WO
WIPO (PCT)
Prior art keywords
eletriptan
solution
eletriptan hydrobromide
ethanol
hydrobromide
Prior art date
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PCT/EP2012/071262
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English (en)
Inventor
Raymond Jozef Hubertus Westheim
Original Assignee
Synthon Bv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Synthon Bv filed Critical Synthon Bv
Priority to PCT/EP2012/071262 priority Critical patent/WO2014063752A1/fr
Publication of WO2014063752A1 publication Critical patent/WO2014063752A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to an improved process for making the compound eletriptan hydrobromide in its crystalline Form a.
  • Eletriptan is a pharmaceutically active compound useful for the acute treatment of migraine with or without aura in adults. It is represented by formula (I).
  • Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water.
  • Eletriptan was disclosed in WO 92/06973. Hydrobromide salts were disclosed in WO 96/06842. Eletriptan hydrobromide in crystalline state is polymorphic. Various solid state forms of eletriptan hydrobromide have been disclosed in the prior art: e.g., crystalline Forms a and ⁇ (WO 96/06842), a monohydrate form (WO 00/32589), and an amorphous form
  • WO 96/06842 discloses two processes for the conversion of eletriptan free base to the cc- polymorph of eletriptan hydrobromide.
  • a solution of eletriptan base in acetone is treated with an aqueous solution of hydrogen bromide at room temperature, the reaction mixture is evaporated, residual water is azeotropically removed using isopropanol and the resulting oil is crystallized from isopropanol.
  • a solution of eletriptan base in acetone is treated with an aqueous solution of hydrogen bromide, and the reaction mixture is slurried, heated at reflux, cooled, and slurried a second time.
  • US 2005/0020663 discloses a process for the preparation of the cc-polymorphic Form of eletriptan hydrobromide by reaction of eletriptan base with hydrobromic acid in 2-butanone followed by removing water by distillation.
  • the cc-polymorphic Form prepared by this process may require an additional polymorph annealing step to increase resistance to subsequent hydration.
  • WO 2011/004391 discloses a process for the preparation of the -polymorphic Form of eletriptan hydrobromide by reaction of eletriptan base with hydrobromic acid in methanol followed by crystallization in methanol with diisopropyl ether as an antisolvent or from isopropanol.
  • Eletriptan base is prepared from eletriptan methanesulfonate. Also crystallisation from acetone has been disclosed.
  • WO 2012/004811 discloses a process for the preparation of eletriptan hydrobromide comprising reacting eletriptan base with aqueous hydrobromic acid, removal of the solvent (and water) by distillation and crystallizing the obtained oil to Form a from a suitable solvent, such as a Ci-8 alcohol (e.g., isopropanol, ethanol, methanol, ieri.-butanol or isobutanol), nitriles (e.g., acetonitrile), a C 4-1 o ether (e.g., tetrahydrofuran, 2-methyl tetrehydrofuran, dioxane, or dimethoxy ethane), an ester (e.g., ethyl acetate), a ketone (e.g., acetone, methyl ethyl ketone, or methyl isobutyl kentone), or an aliphatic or aromatic hydrocarbon such as
  • Example 11 isopropanol is used in six out of seven recrystallizations.
  • the prior art also discloses preparation of the Form a from other forms of eletriptan hydrobromide.
  • Form a may be prepared from Form ⁇ by slurring in e.g., isobutanol at 80°C and cooling, or dissolving in ethanol at room temperature and cooling to -19°C for 3 days.
  • the process in ethanol takes 3 days at a low temperature, which makes the process unsuitable from an industrial point of view.
  • eletriptan hydrobromide monohydrate is refluxed in toluene or isopropanol, the reaction mixture is distilled and the obtained solid is filtered to yield the Form a.
  • the present invention relates to the discovery of a new process for making the crystalline Form a of eletriptan hydrobromide using only ethanol as a solvent, avoiding the need to change solvents during the various steps of the preparation process, as is the case in the prior art.
  • hydrobromide in ethanol in the absence of any other organic solvent, from an elevated temperature to ambient or a lower than ambient temperature.
  • the solution of eletriptan hydrobromide is provided by dissolving eletriptan hydrobromide in ethanol at elevated temperature, wherein the eletriptan hydrobromide starting material useful for making the solution can be in any physical form of the eletriptan hydrobromide, e.g., any polymorphic and/or solvated or hydrated form of eletriptan
  • the solution of eletriptan hydrobromide in ethanol is provided by contacting eletriptan base in ethanol with a solution of hydrogen bromide, preferably with a solution of hydrogen bromide in ethanol.
  • the "Form a" of eletriptan hydrobromide is a crystalline form of eletriptan hydrobromide that is characterized by an XRPD pattern comprising, inter alia, principal peaks at about 9.5, 10.5, 12.1, 15.6, 18.0, 18.2, 19.2, 19.6, 19.9, 20.4, 21.0, 22.3, 25.2, 25.5, 26.2 and 26.4 degrees 2 theta ( + 0.2 degrees 2 theta).
  • the XRPD pattern of the Form a obtained by the process of the present invention substantially corresponds to that as disclosed for Form a in WO 96/06842. "Substantially corresponds" is meant to cover variations/differences in the pattern that would be understood by a worker skilled in the art not to represent a difference in the crystal structure, but rather differences in the technique, sample preparation, impurities, etc.
  • the known processes of making crystalline eletriptan hydrobromide Form a are at least three-step processes, i.e., eletriptan base is dissolved in a first solvent and treated with aqueous hydrobromic acid, the product is (partly) isolated after removal of water and is treated with a second solvent to initialize crystallization, whereby the second solvent is usually different from the first solvent.
  • Many different solvents have been used in these processes.
  • Some processes need intermediate purification steps, effected by adding a solvent to the isolated product followed by complete distillation. In the next step a further solvent is added and if necessary also distilled off.
  • Some of the processes need seeding to ensure that Form a is crystallized, and not e.g., the monohydrate or amorphous eletriptan hydrobromide.
  • the process of the present invention is based on the finding that eletriptan hydrobromide in the Form a can be prepared from a solution in ethanol at elevated temperature, wherein eletriptan hydrobromide Form a is directly obtained after cooling the reaction mixture. No solvent switch is necessary after the solution of eletriptan hydrobromide in ethanol has been provided.
  • a process for making eletriptan hydrobromide in the crystalline Form a comprising cooling a solution of eletriptan hydrobromide in ethanol, in the absence of any other organic solvent, from an elevated temperature to ambient or a lower than ambient temperature.
  • Eletriptan hydrobromide Form a obtained by the process of the present invention is substantially free from other crystalline forms of eletriptan hydrobromide, particularly from the monohydrate form of eletriptan hydrobromide, which can otherwise be very easily formed in other solvents in the presence of water.
  • the "substantially free” means that less than 5%, and advantageously less than 0.5% of other crystalline forms are present in the Form a of eletriptan hydrobromide.
  • the Form a of eletriptan hydrobromide obtained by the process of the present invention exhibits an excellent batch-to-batch uniformity in the size and shape of the formed crystals.
  • the process provides for crystals of excellent flowability, which is an advantageous and very suitable property for its formulation into pharmaceutical compositions.
  • eletriptan hydrobromide is dissolved in ethanol at an elevated temperature.
  • the solution may be pre-filtered hot to remove undesired solid particles, optionally in the presence of a surface active material, e.g. activated carbon, to improve the colour and clarity of the solution.
  • a surface active material e.g. activated carbon
  • the crude eletriptan hydrobromide starting material useful for making the solution can be in any physical form of the eletriptan hydrobromide, e.g., any polymorphic and/or solvated or hydrated form of eletriptan hydrobromide or a mixture of different polymorphic and/or solvated or hydrated forms, including a mixture comprising the cc-polymorphic Form itself.
  • the ethanol used may be pharmaceutical grade "absolute” ethanol comprising about 4% of water or specifically dried ethanol comprising a lower quantity of water than the "absolute” one.
  • the suitable concentration of eletriptan hydrobromide in ethanol is so selected that the solution can be kept at the chosen temperature without nucleation at said temperature.
  • the advantageous concentration is in the range of between 50-150 g/1, preferably 100-120 g/1.
  • the elevated temperature is a temperature from 30°C to reflux temperature and it preferably ranges of from 45 to 60°C.
  • a solution of eletriptan base in ethanol is provided at the elevated temperature defined above.
  • the solution may be pre-filtered hot to remove undesired solid particles, optionally in the presence of a surface active material, e.g. activated carbon, to improve the colour and clarity of the solution.
  • a surface active material e.g. activated carbon
  • the eletriptan base starting material useful for making the solution can be present in any physical form of the eletriptan base.
  • the starting eletriptan can also be crude eletriptan base that is present in the reaction mixture obtained after a chemical synthesis of eletriptan or after liberation of the eletriptan base from an eletriptan salt. Processes for obtaining eletriptan are well known in the art.
  • the ethanol used may be pharmaceutical grade "absolute” ethanol comprising about 4% of water or specifically dried ethanol comprising a lower quantity of water than the "absolute” one.
  • the suitable concentration of eletriptan in ethanol is so selected that the solution can be kept at the chosen temperature without nucleation at said temperature.
  • the advantageous concentration is in the range of between 50-150 g/1, preferably 100-120 g/1.
  • hydrogen bromide is contacted with the solution of eletriptan base upon maintaining the elevated temperature disclosed above.
  • Hydrogen bromide may be used in gaseous form or, advantageously, it may be used in a solution, which may be aqueous or non-aqueous, e.g. a solution of hydrogen bromide in ethanol.
  • a solution which may be aqueous or non-aqueous, e.g. a solution of hydrogen bromide in ethanol.
  • concentration is not specifically limited.
  • 10-20 wt.% solution in ethanol is used.
  • the overall amount of hydrogen bromide in the solution is at least 1 molar equivalent to eletriptan base and preferably is lower than 1.5 molar equivalents to eletriptan base.
  • Hydrogen bromide may be added to the solution comprising eletriptan base or, vice versa, eletriptan base may be added to the solution comprising hydrogen bromide.
  • the average rate of cooling should advantageously be l°C/min or less to avoid nucleation of undesired forms as form ⁇ or the monohydrated form.
  • the crystallization medium may be seeded with seeds of the desired Form a of eletriptan hydrobromide.
  • the original ethanol may be partly distilled out to increase the concentration.
  • an antisolvent is added to the hot eletriptan hydrobromide solution before or during cooling.
  • the "antisolvent” is a liquid, in which the eletriptan hydrobromide is essentially insoluble.
  • the antisolvent comprises at least one aliphatic and/or alicyclic hydrocarbon, having a boiling point of at least 80°C, preferably at least 90°C.
  • the antisolvent is a heptane such as n-heptane.
  • the antisolvent is free from traces of water.
  • the mutual ratio between the antisolvent and the solvent is from 1: 1 to 10: 1 (v/v), advantageously from 2: 1 to 5: 1 (v/v).
  • the solid material is isolated from the cooled mixture by conventional techniques, e.g. filtering or centrifugation, and can be washed, preferably by fresh ethanol, and dried.
  • the obtained Form a is essentially free from eletriptan hydrobromide monohydrate or any other form of eletriptan hydrobromide.
  • eletriptan hydrobromide Form a prepared by the above processes of the present invention can be formulated and used in pharmaceutical compositions.
  • a suitable pharmaceutical composition may comprise the eletriptan hydrobromide Form a and at least one pharmaceutically acceptable excipient.
  • excipients are known in the art and include carriers, diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste masking agents, sweeteners, flavorants, plasticizers, and any acceptable auxiliary substances such as absorption enhancers, penetration enhancers, surfactants, co- surfactants, and specialized oils.
  • the proper excipient(s) are selected based in part on the dosage form, the intended mode of administration, the intended release rate, and manufacturing reliability. Examples of common types of excipients include various polymers, waxes, calcium phosphates, sugars, etc.
  • Polymers include cellulose and cellulose derivatives such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and ethylcellulose; polyvinylpyrrolidones; polyethylenoxides;
  • polyalkylene glycols such as polyethylene glycol and polypropylene glycol
  • polyacrylic acids including their copolymers and crosslinked polymers thereof, e.g., Carbopol (B.F.
  • Waxes include white beeswax, microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl behenate, glycerylpalmito stearate, and saturated polyglycolyzed glycerate.
  • Calcium phosphates include dibasic calcium phosphate, anhydrous dibasic calcium phosphate, and tribasic calcium phosphate.
  • Sugars include simple sugars, such as lactose, maltose, mannitol, fructose, sorbitol, saccharose, xylitol, isomaltose, and glucose, as well as complex sugars (polysaccharides), such as maltodextrin, amylodextrin, starches, and modified starches.
  • the compositions may be formulated into various types of dosage forms, for instance as solutions or suspensions for parenteral or oral administration, as tablets or capsules for oral administration, ointments or lotions for transdermal administration etc. The above lists of excipients and forms are not exhaustive.
  • the eletriptan hydrobromide Form a prepared or purified by the process of the present invention is useful as an agent for the acute treatment of migraine with or without aura in adults, by administering an effective amount thereof to a patient in need of such treatment.
  • the effective amounts range from 20 mg to 80 mg, expressed as the amount of eletriptan base, per day.
  • Eletriptan base 1.0 g Eletriptan base was dissolved in 8 ml ethanol at RT, while stirring. To the solution, heated up to 45-50°C, 440 mg 48% HBr solution in water, mixed with 2 ml ethanol was added slowly and the solution was slowly cooled back to RT in about 1 hr. A solid was formed. The suspension was filtered over a P3-glass filter (reduced pressure). The solid was washed with little ethanol and vacuum-dried overnight at 40°C. XRPD showed all peaks characteristic of Form a.
  • Eletriptan base was dissolved in 7 ml ethanol at RT, while stirring. To the solution, heated up to 45°C, 3-3.5 ml 10-20% HBr solution in ethanol was added. After 10-15 min stirring >40°C, the solution was slowly cooled to RT. A solid was formed. The suspension was stirred at RT for an additional 1 hr. The suspension was filtered over a P3-glass filter (reduced pressure). The solid was vacuum-dried overnight at 40°C. XRPD showed all peaks characteristic of Form a.
  • Eletriptan hydrobromide was suspended in 200 ml ethanol, stirred and heated to reflux until dissolution of all API. The solution was stirred at reflux for about 1 hr. Then, 100 ml was distilled off. The concentrated solution was slowly cooled to RT under nitrogen and stirred for an additional 30 minutes. A solid was formed. The suspension was filtered over a P3-glass filter. The solid was vacuum-dried overnight at 40°C. XRPD showed all peaks characteristic of Form a.
  • Eletriptan hydrobromide monohydrate was dissolved in 10 ml ethanol at reflux. The solution was slowly cooled to RT in about 2.5 hrs and stirred at RT for about 30 minutes. A solid was formed. A part of the mixture was filtered over a P3-glass filter (reduced pressure). The solid was vacuum-dried overnight at 40°C. The remainder was stirred overnight at RT. The mixture was filtered over a P3-glass filter (reduced pressure). The solid was vacuum-dried overnight at 40°C. For both portions, XRPD showed all peaks characteristic of Form a.
  • Eletriptan hydrobromide monohydrate was dissolved in 900 ml ethanol at reflux, while stirring. Reflux was maintained for 15-30 min. Then, the solution was slowly cooled to about 30°C taking 3-3.5 hr. Crystals started to form ⁇ 35°C and crystal growth proceeded during additional cooling to RT for 1-1.5 hr. A part of the mixture was filtered over a P3-glass filter (reduced pressure). The solid was vacuum-dried overnight at RT. The remaining suspension was stirred overnight at RT. The mixture was filtered over a P3-glass filter (reduced pressure). The solid was vacuum-dried at RT for about 1 day. For both portions, XRPD showed all peaks characteristic of Form a.
  • Eletriptan hydrobromide was dissolved in 30 ml ethanol at reflux. To the hot solution was drop wise added 24 ml n-heptane (while cooling down, 5 min period). As a result, an opalescent oil was formed. The mixture was seeded with a spatula tip of form a and stirred at RT for 15-20 min under nitrogen. A solid was formed. The suspension was filtered over a P3- glass filter (reduced pressure). The solid was washed with n-heptane and vacuum-dried overnight at 40°C. XRPD showed all peaks characteristic of Form a.
  • Scan step time between 0.7-1 1.0 seconds
  • Antiscatter slit 11.8 mm

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé de production de la forme cristalline A du bromhydrure d'élétriptan comprenant le refroidissement d'une solution de bromhydrure d'élétriptan dans l'éthanol, en l'absence de tout autre solvant organique, d'une température élevée à la température ambiante ou à une température inférieure à la température ambiante.
PCT/EP2012/071262 2012-10-26 2012-10-26 Procédé de production de la forme cristalline alpha du bromhydrure d'élétriptan WO2014063752A1 (fr)

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PCT/EP2012/071262 WO2014063752A1 (fr) 2012-10-26 2012-10-26 Procédé de production de la forme cristalline alpha du bromhydrure d'élétriptan

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PCT/EP2012/071262 WO2014063752A1 (fr) 2012-10-26 2012-10-26 Procédé de production de la forme cristalline alpha du bromhydrure d'élétriptan

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006973A1 (fr) 1990-10-15 1992-04-30 Pfizer Inc. Derives d'indole
WO1996006842A1 (fr) 1994-08-27 1996-03-07 Pfizer Limited Sels de derive d'indole antimigraineux
WO2000032589A1 (fr) 1998-11-27 2000-06-08 Pfizer Limited Monohydrate de bromhydrate d'eletriptan
US20050020663A1 (en) 2003-07-23 2005-01-27 Furlong Patrick Joseph Process
WO2008137134A2 (fr) 2007-05-01 2008-11-13 Teva Pharmaceuticals Usa, Inc. Bromhydrate d'élétriptan amorphe et son procédé de préparation, et autres formes de bromhydrate d'élétriptan
WO2011004391A2 (fr) 2009-06-25 2011-01-13 Matrix Laboratories Ltd Procédé amélioré d'élaboration d'élétriptane et son sel correspondant
WO2011089614A1 (fr) 2010-01-19 2011-07-28 Sms Pharmaceuticals Limited Procédé de préparation de bromhydrate d'élétriptan ayant une forme α
WO2012004811A1 (fr) 2010-07-06 2012-01-12 Ind-Swift Laboratories Limited Procédé pour la préparation de dérivé d'indole substitué en position 5

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006973A1 (fr) 1990-10-15 1992-04-30 Pfizer Inc. Derives d'indole
WO1996006842A1 (fr) 1994-08-27 1996-03-07 Pfizer Limited Sels de derive d'indole antimigraineux
WO2000032589A1 (fr) 1998-11-27 2000-06-08 Pfizer Limited Monohydrate de bromhydrate d'eletriptan
US20050020663A1 (en) 2003-07-23 2005-01-27 Furlong Patrick Joseph Process
WO2008137134A2 (fr) 2007-05-01 2008-11-13 Teva Pharmaceuticals Usa, Inc. Bromhydrate d'élétriptan amorphe et son procédé de préparation, et autres formes de bromhydrate d'élétriptan
WO2011004391A2 (fr) 2009-06-25 2011-01-13 Matrix Laboratories Ltd Procédé amélioré d'élaboration d'élétriptane et son sel correspondant
WO2011089614A1 (fr) 2010-01-19 2011-07-28 Sms Pharmaceuticals Limited Procédé de préparation de bromhydrate d'élétriptan ayant une forme α
WO2012004811A1 (fr) 2010-07-06 2012-01-12 Ind-Swift Laboratories Limited Procédé pour la préparation de dérivé d'indole substitué en position 5

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