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WO1997035853A1 - Procede de preparation de chlorhydrate de ranitidine de forme 1 - Google Patents

Procede de preparation de chlorhydrate de ranitidine de forme 1 Download PDF

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Publication number
WO1997035853A1
WO1997035853A1 PCT/US1997/002867 US9702867W WO9735853A1 WO 1997035853 A1 WO1997035853 A1 WO 1997035853A1 US 9702867 W US9702867 W US 9702867W WO 9735853 A1 WO9735853 A1 WO 9735853A1
Authority
WO
WIPO (PCT)
Prior art keywords
ranitidine hydrochloride
solution
isopropanol
ranitidine
alkanol
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1997/002867
Other languages
English (en)
Inventor
Wen J. Cheng
Roger L. Briggs
Lee V. Mccoy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Hoechst Marion Roussel Inc
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.)
Filing date
Publication date
Application filed by Hoechst Marion Roussel Inc filed Critical Hoechst Marion Roussel Inc
Priority to AU19720/97A priority Critical patent/AU1972097A/en
Publication of WO1997035853A1 publication Critical patent/WO1997035853A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • Ranitidine hydrochloride is reported to exist in two polymorphic crystalline forms, designated Form 1 and Form 2.
  • the preparation of Form 1 ranitidine hydrochloride is reported in U.S. Patent No. 4,128,658. According to that preparation ranitidine hydrochloride is formed in a volume of industrial methylated spirits and the Form 1 polymorph is obtained upon precipitation or crystallization induced by the addition of an equal volume of ethyl acetate.
  • Form 1 ranitidine hydrochloride prepared in this manner is reported to possess unsuitable filtration and drying characteristics, see U.S. Patent No. 4,672,133.
  • the preparation of Form 1 ranitidine hydrochloride is also reported in U.S. Patent No.5, 338, 871.
  • Form 1 ranitidine hydrochloride is prepared by crystallization, in the presence of seed crystals of pure Form 1 ranitidine hydrochloride, in a mixed solvent system comprising at least one C1-C4 alkanol and a C 6 -C 10 aromatic hydrocarbon, "the volume ratio of alkanol (s) to hydrocarbon being from about 1:1 to 1:2.
  • Form 2 ranitidine hydrochloride The preparation of Form 2 ranitidine hydrochloride is reported in U.S. Patent No. 4,672,133. Accordingly, the Form 2 polymorph is prepared by crystallization from a solvent, in general, the solvent used is a lower alkanol. In a preferred preparation, a solution of ranitidine in propan-2-ol is treated with aqueous hydrochloric acid, followed by crystallization at elevated temperature at up to 70°C by the addition of further quantities of isopropanol. Also, U.S. Patent IO.
  • Form 2 polymorph is obtained by crystallization when the starting material is Form 1 or Form 2 ranitidine hydrochloride by dissolving the salt in a solvent, such as methane1 or ethanol, by warming, followed by cooling of the resulting solution, e.g., to 10° to 40°C and stirring.
  • a solvent such as methane1 or ethanol
  • Form 1 ranitidine hydrochloride is prepared by crystallization of ranitidine hydrochloride from at least one Ci-C ⁇ alkanol.
  • the art teaches that Form 1 ranitidine hydrochloride is prepared in mixed solvent systems containing alkanols and antisolvents, such as ethyl acetate or a C 6 -C 10 aromatic hydrocarbon, and that Form 2 ranitidine hydrochloride is formed upon crystallization from lower alkanols, it has been found according to the present invention that Form 1 ranitidine hydrochloride is obtained in pure polymorphic form by crystallizing ranitidine hydrochloride from at least one Ci-Cg alkanol without a substantial amount of an antisolvent.
  • the present invention provides a process for preparing Form 1 ranitidine hydrochloride, comprising crystallization of ranitidine hydrochloride in at least one Ci-Ce alkanol.
  • Ci-Ce alkanol refers to straight or branch chained alkanols containing from 1 to 6 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, i-butanol, s-butanol, n-pentanol, i- amyl alcohol, t-amyl alcohol, hexanol, and the like.
  • Ci-Cg alkanols are ethanol, isopropanol, mixtures of ethanol and isopropanol, mixtures of methanol and isopropanol, and t- amyl alcohol, with ethanol and isopropanol being more preferred and isopropanol being most preferred.
  • the present process does not require the use of a substantial amount of an antisolvent.
  • one aspect of the present invention is that it is generally carried out using at least one Ci-C ⁇ alkanol without an antisolvent.
  • antisolvent refers to organic solvents in which ranitidine hydrochloride is not appreciably soluble and generally are of lower polarity than the alkanol (s) used to effect solution.
  • Polymorphs of ranitidine hydrochloride can be characterized by a variety of techniques, including differential scanning calorimetry, infra-red spectrometry, and x-ray diffraction, with varying sensitivity.
  • differential scanning calorimetry infra-red spectrometry
  • x-ray diffraction with varying sensitivity.
  • the present process can be carried out using ranitidine hydrochloride which is formed from a solution of ranitidine base in at least one Ci-Cs alkanol by the addition of ar. appropriate amount of hydrogen chloride.
  • An appropriate amount of hydrogen chloride is from about 0.8 to 1.2 molar equivalents, preferably 0.9 to 1.1 molar equivalents, more preferably 0.95 to 1.0 molar equivalents, and most preferably 1.0 molar equivalents.
  • An appropriate amount of hydrogen chloride can be added as a gas or more conveniently as a solution in a Ci-C ⁇ alkanol.
  • the present process can be carried out using preformed ranitidine hydrochloride.
  • Form 1 ranitidine hydrochloride may be obtained when the temperature of the initial solution is as low as 0°C.
  • temperatures above 70°C are not well tolerated by ranitidine hydrochloride in solution.
  • the present process is carried out at temperatures of from about 0°C to about 70°C, with temperatures of from about 0°C to about 60°C being preferred and temperatures of from about 10°C to about 40°C being more preferred.
  • Form 1 ranitidine hydrochloride may be obtained when the water content of the initial solution before nucleation is less than about 0.7%.
  • the water content cf the initial crystallization solution is less than about 0.7%, preferably less than about 0.4% and more preferably less than about 0.3%.
  • the rate of nucleation is most greatly affected by the concentration of ranitidine hydrochloride in che initial solution.
  • concentration of ranitidine hydrochloride in solution before nucleation is more important than temperature and water content in determining the polymorphic purity of Form 1 ranitidine hydrochloride obtained by the present invention, i.e., the formation of Form 1 ranitidine hydrochloride from less concentrated solutions is more sensitive to water content and temperature than it is from more concentrated solutions.
  • Seeding the initial solution with Form 1 ranitidine hydrochloride crystals is effective in insuring rapid nucleation to give Form 1 ranitidine hydrochloride.
  • the crystallization solution should be seeded with pure Form 1 ranitidine hydrochloride before nucleation. Seeding the crystallization solution with Form 1 ranitidine hydrochloride crystals is a preferred embodiment of the present invention.
  • Form 1 ranitidine hydrochloride continues to crystallize. Unlike the initial solution, it has been found that after nucleation, Form 1 ranitidine hydrochloride continues to form even though water is added, the temperature is lowered below 0°C, or both water is added and the temperature is lowered below 0°C.
  • the filtering and drying characteristics of the Form 1 ranitidine hydrochloride obtained from the present process are affected by the size of the crystals formed. Smaller crystals have less desirable filtering and drying characteristics . It has been ound that the size of the Form 1 ranitidine hydrochloride crystals obtained by the present invention can be increased by digestion techniques giving Form 1 ranitidine hydrochloride possessing good filtration and drying characteristics.
  • the crystals of Form 1 ranitidine hydrochloride formed may be very small. Digestion of the crystals formed upon nucleation allows larger crystals to grow at the expense of smaller crystals. J. W. Mullin, Crystallization (1961) . Digestion can be achieved, as is known in the art, by reducing the population of crystals in the crystallization solution, either by elevating the temperature of the solution or by the addition of a digestion solvent. In a preferred embodiment of the present invention the crystals formed upon nucleation are digested. It is preferred that the digestion is carried out by the addition of a digestion solvent, such as water, methanol, or ethanol, with water being preferred.
  • a digestion solvent such as water, methanol, or ethanol
  • ranitidine base 1.0 g, 3.2 mmol
  • isopropanol 6.2 g
  • Add a solution of hydrogen chloride in isopropanol 3.2 g, 4% by weight, 3.5 mmol
  • ranitidine base (66 g, 210 mmol) and t-amyl alcohol (251 g) . Warm to 51°C. Slowly, add a solution of hydrogen chloride in isopropanol (20.5 g, 15% by weight, 84 mmol) and stir to give a solid. After 18 hours, collect the solid by filtration and dry in ⁇ acuo to give the title compound.
  • EXAMPLE 4 Preparation of Form 1 ranitidine hydrochloride Combine ranitidine base (30.0 g, 95.4 mmol), isopropanol (256.5 g) , and methanol (13.5 g) at 30°C. Add seed crystals of Form 1 ranitidine hydrochloride (0.065 g) .
  • ranitidine base 2.0 g, 6.36 mmol
  • isopropanol 14.05 g
  • warm to about 30°C With stirring, add a solution of hydrogen chloride in isopropanol (5% by weight) at a rate of about 0.15 g per minute until about one fourth the solution is added.
  • Add seed crystals of Form 1 ranitidine hydrochloride Continue adding the solution of hydrogen chloride in isopropanol at a rate of 0.15 g per minute until 4.95 g (total) of the solution is added. Collect the solid by filtration and dry in vacuo to give the title compound. Karl Fisher determination of the mother liquor gives 0.31% water.
  • ranitidine base 1.0 g, 3.18 mmol
  • isopropanol 7.40 g
  • warm to about 50°C With stirring, add a solution of hydrogen chloride in isopropanol (5% by weight) at a rate of about 0.15 g per minute until about one fourth the solution is added.
  • Add seed crystals of Form 1 ranitidine hydrochloride Continue adding the solution of hydrogen chloride in isopropanol at a rate of 0.15 g per minute until 2.50 g (total) of the solution is added. Collect the solid by filtration and dry in vacuo to give the title compound.
  • EXAMPLE 8 Preparation of Form 1 ranitidine hydrochloride Combine ranitidine base (1.0 g, 3.18 mmol), isopropanol (7.40 g) and warm to about 60°C. With stirring, add a solution of hydrogen chloride in isopropanol (5% by weight) at a rate of about 0.15 g per minute until about one fourth the solution is added. Ad seed crystals of Form 1 ranitidine hydrochloride. Continue adding the solution of hydrogen chloride in isopropanol at a rate of 0.15 g per minute until 2.50 g (total) of the solution is added. Cool to about 25°C, collect the solid by filtration, and dry in vacuo to give the title compound.
  • ranitidine base (20.0 g, 63.6 mmol) and isopropanol (146.3 g) .
  • Warm to 40°C. With stirring, add a solution of hydrogen chloride in isopropanol (4.9% by weight) at a rate of 0.74 g per minute.
  • After about 8 g of solution of hydrogen chloride in isopropanol is added add seed crystals of Form 1 ranitidine hydrochloride.
  • the solution of hydrogen chloride in isopropanol until about 14 g of the solution is added. Stir until nucleation is complete and then add water (11.8 g) .
  • EXAMPLE 10 Preparation of Form 1 ranitidine hydrochloride Combine ranitidine base (800 g, 2.54 mol) and isopropanol (5.86 kg) . Warm to 44°C. With stirring, add a solution of hydrogen chloride in isopropanol (5% by weight) at a rate of 8 g per minute until about 150 g of the solution is added. Add seed crystals of Form 1 ranitidir.e hydrochloride (0.095 g) . Continue adding the solution of hydrogen chloride in isopropanol at a rate of 8 g per minute until 406 g (total) of the solution is added. After nucleation is complete (about 4 hours), add water (210.5 g) to the slurry.
  • ranitidine base (2.9 kg, 9.22 mol) and isopropanol (8.25 kg) at 37°C. Filter thorough a 1 micron filter and rinse the filter with isopropanol (0.45 kg) .
  • ranitidine base (30.2 g, 96 mmol) and isopropanol (210.5 g) . Filter thorough a 1 micron filter and rinse the filter with isopropanol (60 g) . Cool to about 14 C C.
  • Add seed crystals of Form i ranitidine hydrochloride (0.044 g) .
  • ranitidine base 100 g, 318 mmol
  • isopropanol 358.6 g
  • Cool to about 15°C. Add seed crystals of Form 1 ranitidine hydrochloride. With stirring, add a solution of hydrogen chloride in isopropanol (15% by weight) at a rate of 1.13 g per minute until about 38.6 g of the solution is added. After nucleation is complete (about 2 hours) , warm to about 35°C and add water (22.2 g) . After about 30 minutes, continue adding the solution of hydrogen chloride in isopropanol at a rate of 0.079 g per minute until an additional 38.6 g of the solution is added. Cool the slurry obtained to about 5°C, collect the solid by filtration, and dry in vacuo to give the title compound.

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

Abstract

Cette invention porte sur un nouveau procédé de préparation de chlorhydrate de ranitidine de forme 1 par cristallisation à partir d'au moins un alcanol en C1-C6.
PCT/US1997/002867 1996-03-25 1997-02-25 Procede de preparation de chlorhydrate de ranitidine de forme 1 Ceased WO1997035853A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19720/97A AU1972097A (en) 1996-03-25 1997-02-25 Process for the preparation of form 1 ranitidine hydrochloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62082296A 1996-03-25 1996-03-25
US08/620,822 1996-03-25

Publications (1)

Publication Number Publication Date
WO1997035853A1 true WO1997035853A1 (fr) 1997-10-02

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/002867 Ceased WO1997035853A1 (fr) 1996-03-25 1997-02-25 Procede de preparation de chlorhydrate de ranitidine de forme 1

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AU (1) AU1972097A (fr)
TW (1) TW350842B (fr)
WO (1) WO1997035853A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999065890A1 (fr) * 1998-06-17 1999-12-23 Russinsky Limited Compose d'addition a base de ranitidine
CN106432148A (zh) * 2015-05-26 2017-02-22 烟台市华文欣欣医药科技有限公司 一种治疗胃病的药物盐酸雷尼替丁化合物的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1565966A (en) * 1976-08-04 1980-04-23 Allen & Hanburys Ltd Aminoalkyl furan derivatives
US4521431A (en) * 1980-10-01 1985-06-04 Glaxo Group Limited Aminoalkyl furan derivative
WO1995027709A1 (fr) * 1994-04-08 1995-10-19 Acic (Canada) Inc. Hydrochlorure de ranitidine de forme 1 a densite accrue
EP0694540A1 (fr) * 1994-06-24 1996-01-31 Ranbaxy Laboratories Limited Procédé pour la préparation de l'hydrochlorure de ranitidine de forme 1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1565966A (en) * 1976-08-04 1980-04-23 Allen & Hanburys Ltd Aminoalkyl furan derivatives
US4521431A (en) * 1980-10-01 1985-06-04 Glaxo Group Limited Aminoalkyl furan derivative
WO1995027709A1 (fr) * 1994-04-08 1995-10-19 Acic (Canada) Inc. Hydrochlorure de ranitidine de forme 1 a densite accrue
EP0694540A1 (fr) * 1994-06-24 1996-01-31 Ranbaxy Laboratories Limited Procédé pour la préparation de l'hydrochlorure de ranitidine de forme 1

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999065890A1 (fr) * 1998-06-17 1999-12-23 Russinsky Limited Compose d'addition a base de ranitidine
CN106432148A (zh) * 2015-05-26 2017-02-22 烟台市华文欣欣医药科技有限公司 一种治疗胃病的药物盐酸雷尼替丁化合物的制备方法
CN106432148B (zh) * 2015-05-26 2018-04-17 烟台市华文欣欣医药科技有限公司 一种治疗胃病的药物盐酸雷尼替丁化合物的制备方法

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TW350842B (en) 1999-01-21
AU1972097A (en) 1997-10-17

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