EP1204408A2 - An improved form of form i celiprolol hydrochloride - Google Patents
An improved form of form i celiprolol hydrochlorideInfo
- Publication number
- EP1204408A2 EP1204408A2 EP00944158A EP00944158A EP1204408A2 EP 1204408 A2 EP1204408 A2 EP 1204408A2 EP 00944158 A EP00944158 A EP 00944158A EP 00944158 A EP00944158 A EP 00944158A EP 1204408 A2 EP1204408 A2 EP 1204408A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- celiprolol
- hydrochloride
- celiprolol hydrochloride
- base
- water
- 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.)
- Withdrawn
Links
- VKJHTUVLJYWAEY-UHFFFAOYSA-N Celiprolol hydrochloride Chemical compound Cl.CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 VKJHTUVLJYWAEY-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 229960000384 celiprolol hydrochloride Drugs 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 39
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- JOATXPAWOHTVSZ-UHFFFAOYSA-N Celiprolol Chemical compound CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 JOATXPAWOHTVSZ-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000008240 homogeneous mixture Substances 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 229960002320 celiprolol Drugs 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- -1 e.g. Chemical compound 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to an improved form of Form I celiprolol hydrochloride and a process for the production thereof.
- Chemically celiprolol is N'-[3-Acetyl-4-[(1 ,1 -dimethylethyl)amino]-2- hydroxypropoxy]phenyl]-N,N-diethyl urea and belongs to the ⁇ -blocker class of antihypertensive agents.
- celiprolol hydrochloride exists in several polymorphic modifications and that these can be distinguished by their infrared spectral characteristics and x-ray diffraction patterns (Burger et al Acta. Pharm. Technol., 34(3), 147-151 (1988); Sugiyama et al., lyakuhin Kenkyu, 21 (1 ), 27-39, (1990).
- Celiprolol hydrochloride has been prepared by treating celiprolol base in acetone with aqueous hydrochloric acid rArzneim. Forsch., 33(1), 2-4 (1983)]. However, this method generally gave mixtures of Form I and Form II celiprolol hydrochloride, or Form II celiprolol hydrochloride exclusively.
- this method suffers from difficulties in work-up such as difficulties in stirring and slow filtration.
- An object of this invention is to produce an improved form of Form I celiprolol hydrochloride which has highly desirable handling properties such as filtration, drying characteristics and flowability.
- Form I celiprolol hydrochloride having improved filtration and drying characteristics is provided.
- the process comprises dissolving celiprolol base or Form II celiprolol hydrochloride in a water-miscible organic solvent or a homogeneous mixture of the aforesaid solvents and water, adding hydrochloric acid and subsequently recovering improved form of Form I celiprolol hydrochloride from the solution thereof.
- the water-miscible organic solvent or solvents has the characteristic that it solubilizes celiprolol base and hydrochloric acid and precipitates the desired form of Form I celiprolol hydrochloride, slowly and uniformly.
- the process is carried out at a temperature ranging from about ambient to the reflux temperature of the solvent used. More preferably, it is carried out at ambient temperature.
- Suitable water-miscible organic solvents include the group consisting of ketones, e.g., acetone; alcohols, e.g., ethanol, isopropyl alcohol, n-propanol or n-butanol; acetonitrile; tetrahydrofuran; dioxan; and mixtures thereof.
- the solution containing celiprolol base may be seeded with crystals of Form I celiprolol hydrochloride prior to the addition of hydrochloric acid or the slurry may be cooled prior to filtration.
- the product can be recovered by any standard method known in the art such as by filtration, filtration under vacuum, centrifugation or decantation and drying.
- a new process for consistently producing an improved form of Form I celiprolol hydrochloride is provided.
- celiprolol base having melting point 110- 117 Q C for the preparation of celiprolol hydrochloride does not give Form I consistently.
- celiprolol base which has been dried at a temperature below 70 Q C, more preferably below 55 9 C with a moisture content of less than 5% w/w and having melting point 80-100 e C, leads to consistency in achieving Form I celiprolol hydrochloride.
- Such a base is characterized by its distinct infared spectrum, melting point and x-ray powder diffraction pattern differing from the celiprolol base melting above 1 10 Q C.
- the moisture content in the celiprolol base may vary from 2-5% w/w but it generally remains as a monohydrate (4.5% w/w water content).
- the present invention also provides a process for the conversion of celiprolol hyrochloride Form II to Form I celiprolol hydrochloride using similar conditions for crystallization as those described above which give Form I celiprolol hydrochloride.
- Form I celiprolol hydrochloride prepared by the process of the present invention is characterized by its infrared spectral data which matches with the infrared spectrum given in the Analytical profiles of Drug substances. DETAILED DESCRIPTION OF THE INVENTION
- Celiprolol free base 25gm, moisture content 4.71 % w/w was dissolved in a mixture of acetone (395ml) and water (8ml) at 25-30-C.
- Activated carbon 2.5gm was added to the clear solution and stirred for 15 minutes. Filtered it through hyflo bed, cooled the filtrate to about 20 Q C and seeded the clear filtrate with celiprolol hydrochloride Form 1 crystals. Added cone. Hydrochloric acid (5.4 ml) slowly till crystallization was complete. The precipitated celiprolol hydrochloride was filtered off, washed with acetone and dried under reduced pressure to give 22.15gm of celiprolol hydrochloride
- Celiprolol free base (12.5 gm, moisture content 4.71 % w/w) was dissolved in aqueous tetrahydrofuran (205ml) at 25-30 9 C. Added activated carbon and stirred for 30 minutes. Carbon was removed by filtration through hyflo-bed, seeded the clear filtrate with Form I celiprolol hydrochloride crystals. Added cone. Hydrochloric acid (2.7ml) slowly till crystallization was complete. The precipitated celiprolol hydrochloride was filtered off, washed with aqueous tetrahydrofuran and dried under reduced pressure to give
- Celiprolol free base (12.5gm, moisture content 4.71 % w/w) was dissolved in acetone (196ml) at 25-30 Q C.
- Activated carbon (1.25gm) was added to the clear solution and stirred for 15 minutes. Filtered off the carbon through hyflo-bed, cooled the filtrate to about 20 9 C and seaded the clear solution with Form I celiprolol hydrochloride crystals. Added cone. Hydrochloric acid slowly till the pH was about 6. The resulting suspension was stirred for about 10 minutes at about 20 9 C, filtered the solid, washed with acetone and dried under vacuum to give 12.4 gm of dry Form I celiprolol hydrochloride. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.
- Form I celiprolol hydrochloride (10gm) was suspended in absolute ethanol (50ml) at 55-60 9 C overnight and the resulting suspension was refluxed to get a clear solution. Seeded the clear solution with Form I celiprolol hydrochloride crystals. Cooled it to about 10 9 C and stirred at this temperature for about 30 minutes. The separated solid was filtered and dried under vacuum to afford 9.5gm of Form I celiprolol hydrochloride. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A novel process for the production of an improved form of Form I celiprolol hydrochloride, N'-[3-Acetyl-4-[(1,1-dimethylethyl)amino]-2-hydroxy-propoxy]phenyl]-N,N-diethyl urea hydrochloride, is described.
Description
AN IMPROVED FORM OF
FORM I CELIPROLOL HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to an improved form of Form I celiprolol hydrochloride and a process for the production thereof.
BACKGROUND OF THE INVENTION
Chemically celiprolol is N'-[3-Acetyl-4-[(1 ,1 -dimethylethyl)amino]-2- hydroxypropoxy]phenyl]-N,N-diethyl urea and belongs to the β-blocker class of antihypertensive agents. A literature search revealed that celiprolol hydrochloride exists in several polymorphic modifications and that these can be distinguished by their infrared spectral characteristics and x-ray diffraction patterns (Burger et al Acta. Pharm. Technol., 34(3), 147-151 (1988); Sugiyama et al., lyakuhin Kenkyu, 21 (1 ), 27-39, (1990). However, there exist conflicting reports in the literature regarding identification of Form I celiprolol hydrochloride. For example, the infrared spectral data of Form I celiprolol hydrochloride given in Acta. Pharm. Technol., 34(3), 147-151 (1988), differs from the one given in Drug Development and Industrial Pharmacy, 14 (4), 465-474 (1988). They also differ in their melting points. While there are a few instances where celiprolol hydrochloride has been synthesized, none of them mention which polymorph has been obtained. The only example of a method for preparation of Form I celiprolol hydrochloride that we came across was
one where Form 1 celiprolol hydrochloride is prepared by recrystallization from methanol-diethyl ether. However, this method did not give us Form I celiprolol hydrochloride. It has been mentioned in 'Analytical Profiles of Drug Substances', Vol. 20 that Form I celiprolol hydrochloride can be obtained from organic solvents under a wide variety of conditions but no method has been described which results in Form I celiprolol hydrochloride.
Celiprolol hydrochloride has been prepared by treating celiprolol base in acetone with aqueous hydrochloric acid rArzneim. Forsch., 33(1), 2-4 (1983)]. However, this method generally gave mixtures of Form I and Form II celiprolol hydrochloride, or Form II celiprolol hydrochloride exclusively.
Further, this method suffers from difficulties in work-up such as difficulties in stirring and slow filtration.
SUMMARY OF THE INVENTION
An object of this invention is to produce an improved form of Form I celiprolol hydrochloride which has highly desirable handling properties such as filtration, drying characteristics and flowability.
It is a further object of this invention to provide a process which produces an improved form of Form I celiprolol hydrochloride consistently and with good yields.
According to one aspect of the invention, a new process for producing
Form I celiprolol hydrochloride having improved filtration and drying characteristics is provided. The process comprises dissolving celiprolol base or Form II
celiprolol hydrochloride in a water-miscible organic solvent or a homogeneous mixture of the aforesaid solvents and water, adding hydrochloric acid and subsequently recovering improved form of Form I celiprolol hydrochloride from the solution thereof. The water-miscible organic solvent or solvents has the characteristic that it solubilizes celiprolol base and hydrochloric acid and precipitates the desired form of Form I celiprolol hydrochloride, slowly and uniformly.
Generally, the process is carried out at a temperature ranging from about ambient to the reflux temperature of the solvent used. More preferably, it is carried out at ambient temperature.
Suitable water-miscible organic solvents include the group consisting of ketones, e.g., acetone; alcohols, e.g., ethanol, isopropyl alcohol, n-propanol or n-butanol; acetonitrile; tetrahydrofuran; dioxan; and mixtures thereof.
Methods known in the art can be used with the process of this inven- tion to enhance any aspect of this process. For example, the solution containing celiprolol base may be seeded with crystals of Form I celiprolol hydrochloride prior to the addition of hydrochloric acid or the slurry may be cooled prior to filtration.
Generally, the product can be recovered by any standard method known in the art such as by filtration, filtration under vacuum, centrifugation or decantation and drying.
According to another aspect of the invention, a new process for consistently producing an improved form of Form I celiprolol hydrochloride is provided.
It has been found that use of celiprolol base having melting point 110- 117QC for the preparation of celiprolol hydrochloride does not give Form I consistently. Surprisingly, we have found that the use of celiprolol base which has been dried at a temperature below 70QC, more preferably below 559C with a moisture content of less than 5% w/w and having melting point 80-100eC, leads to consistency in achieving Form I celiprolol hydrochloride. Such a base is characterized by its distinct infared spectrum, melting point and x-ray powder diffraction pattern differing from the celiprolol base melting above 1 10QC. Depending on the drying time and technique for drying, the moisture content in the celiprolol base may vary from 2-5% w/w but it generally remains as a monohydrate (4.5% w/w water content).
The present invention also provides a process for the conversion of celiprolol hyrochloride Form II to Form I celiprolol hydrochloride using similar conditions for crystallization as those described above which give Form I celiprolol hydrochloride.
Form I celiprolol hydrochloride prepared by the process of the present invention is characterized by its infrared spectral data which matches with the infrared spectrum given in the Analytical profiles of Drug substances.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is illustrated by, but not limited to, the following examples:
EXAMPLE 1
PREPARATION OF FORM I CELIPROLOL HYDROCHLORIDE USING CELIPROLOL FREE BASE
Celiprolol free base (25gm, moisture content 4.71 % w/w) was dissolved in a mixture of acetone (395ml) and water (8ml) at 25-30-C. Activated carbon (2.5gm) was added to the clear solution and stirred for 15 minutes. Filtered it through hyflo bed, cooled the filtrate to about 20QC and seeded the clear filtrate with celiprolol hydrochloride Form 1 crystals. Added cone. Hydrochloric acid (5.4 ml) slowly till crystallization was complete. The precipitated celiprolol hydrochloride was filtered off, washed with acetone and dried under reduced pressure to give 22.15gm of celiprolol hydrochloride
Form 1. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.
EXAMPLE 2
Celiprolol free base (12.5gm, moisture content 4.71 % w/w) was dissolved in aqueous isopropanol (198ml) at 25-309C. Actiivated carbon
(1.25gm) was added to the clear solution and stirred for about 30 minutes.
Filtered off the carbon through hyflo bed, cooled the filtrate to about 20-C and seeded the clear solution with Form I celiprolol hydrochloride crystals. Added cone. Hydrochloric acid (2.7ml) slowly till crystallization was complete. The precipitated celiprolol hydrochloride was filtered off, washed with aqueous isopropanol and dried under vacuum to afford 12.5gm of dry Form I celiprolol hydrochloride. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.
EXAMPLE 3
Celiprolol free base (12.5 gm, moisture content 4.71 % w/w) was dissolved in aqueous tetrahydrofuran (205ml) at 25-309C. Added activated carbon and stirred for 30 minutes. Carbon was removed by filtration through hyflo-bed, seeded the clear filtrate with Form I celiprolol hydrochloride crystals. Added cone. Hydrochloric acid (2.7ml) slowly till crystallization was complete. The precipitated celiprolol hydrochloride was filtered off, washed with aqueous tetrahydrofuran and dried under reduced pressure to give
10.8gm of Form I celiprolol hydrochloride, IR (KBr) spectrum confirmed that material was Form I celiprolol hydrochloride.
EXAMPLE 4
PREPARATION OF FORM I CELIPROLOL HYDROCHLORIDE USING CELIPROLOL FREE BASE.
Celiprolol free base (12.5gm, moisture content 4.71 % w/w) was dissolved in acetone (196ml) at 25-30QC. Activated carbon (1.25gm) was
added to the clear solution and stirred for 15 minutes. Filtered off the carbon through hyflo-bed, cooled the filtrate to about 209C and seaded the clear solution with Form I celiprolol hydrochloride crystals. Added cone. Hydrochloric acid slowly till the pH was about 6. The resulting suspension was stirred for about 10 minutes at about 209C, filtered the solid, washed with acetone and dried under vacuum to give 12.4 gm of dry Form I celiprolol hydrochloride. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.
EXAMPLE 5
PREPARATION OF FORM I CELIPROLOL HYDROCHLORIDE
USING FORM I CELIPROLOL HYDROCHLORIDE.
Form I celiprolol hydrochloride (10gm) was suspended in absolute ethanol (50ml) at 55-609C overnight and the resulting suspension was refluxed to get a clear solution. Seeded the clear solution with Form I celiprolol hydrochloride crystals. Cooled it to about 109C and stirred at this temperature for about 30 minutes. The separated solid was filtered and dried under vacuum to afford 9.5gm of Form I celiprolol hydrochloride. IR (KBr) spectrum confirmed that the material was Form I celiprolol hydrochloride.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims
1. An improved form of Form I celiprolol hydrochloride having improved filtration and drying characteristics, produced by a process comprising dissolving celiprolol base or Form II celiprolol hydrochloride in a water- miscible organic solvent or a homogeneous mixture of the aforesaid solvents and water, adding hydrochloric acid and subsequently recovering improved form of Form I celiprolol hydrochloride from the solution thereof.
2. The process of claim 1 wherein seeds of Form I celiprolol hydrochloride are added to crystallize the improved form of Form I celiprolol hydrochloride.
3. The process of claim 1 wherein said water-miscible organic solvent is selected from the group consisting of ketones, alcohols, acetonitriles, tetrahydrofuran dioxan and mixtures thereof.
4. The process of claim 3 wherein said water-miscible organic solvent is selected from the group consisting of acetone, ethanol, isopropyl alcohol, n-propanol, n-butanol and mixtures thereof.
5. The process of claim 1 , 3 and 4 wherein said solvent is acetone or a homogeneous mixture of acetone and water.
6. The process of claim 1 wherein said improved form of Form I celiprolol hydrochloride is recovered by filtration or centrifuging.
7. The process of claim 1 wherein celiprolol base has a moisture content of less than 5% w/w.
8. The process of claim 6 wherein celiprolol base has a moisture content between 2-5% w/w.
9. The process of claim 1 wherein celiprolol base is obtained by drying at a temperature less than 709C.
10. The process of claim 9 wherein celiprolol base is obtained by drying at a temperature less than 559C.
11 . A process for the production of an improved form of Form I celiprolol hydrochloride having improved filtration and drying characteristics, said process comprising dissolving celiprolol base or Form II celiprolol hydrochloride in a water-miscible organic solvent or a homogeneous mixture of the aforesaid solvents and water, adding hydrochloric acid and subsequently recovering improved form of Form I celiprolol hydrochloride from the solution thereof.
12. The process of claim 11 wherein seeds of Form I celiprolol hydrochloride are added to crystallize the improved form of Form I celiprolol hydrochloride.
13. The process of claim 11 wherein said water-miscible organic solvent is selected from the group consisting of ketones, alcohols, acetonitriles, tetrahydrofuran dioxan and mixtures thereof.
14. The process of claim 13 wherein said water-miscible organic solvent is selected from the group consisting of acetone, ethanol, isopropyl alcohol, n-propanol, n-butanol and mixtures thereof.
15. The process of claim 11 , 13 and 14 wherein said solvent is acetone or a homogeneous mixture of acetone and water.
16. The process of claim 11 wherein said improved form of Form I celiprolol hydrochloride is recovered by filtration or centrifuging.
17. The process of claim 11 wherein celiprolol base has a moisture content of less than 5% w/w.
18. The process of claim 16 wherein celiprolol base has a moisture content between 2-5% w/w.
19. The process of claim 11 wherein celiprolol base is obtained by drying at a temperature less than 709C.
20. The process of claim 19 wherein celiprolol base is obtained by drying at a temperature less than 559C.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| INDE103599 | 1999-07-30 | ||
| IN1035DE1999 | 1999-07-30 | ||
| PCT/IB2000/001023 WO2001008633A2 (en) | 1999-07-30 | 2000-07-24 | An improved form of form i celiprolol hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1204408A2 true EP1204408A2 (en) | 2002-05-15 |
Family
ID=11092063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00944158A Withdrawn EP1204408A2 (en) | 1999-07-30 | 2000-07-24 | An improved form of form i celiprolol hydrochloride |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1204408A2 (en) |
| JP (1) | JP2003505485A (en) |
| AU (1) | AU5839000A (en) |
| BR (1) | BR0012864A (en) |
| PL (1) | PL353243A1 (en) |
| WO (1) | WO2001008633A2 (en) |
| ZA (1) | ZA200200693B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030135041A1 (en) | 2002-01-04 | 2003-07-17 | Orchid Chemicals & Pharmaceuticals Limited, India | Synthesis of ceftiofur intermediate |
| JP4547245B2 (en) * | 2004-12-16 | 2010-09-22 | 株式会社パーマケム・アジア | Perindopril erbumine type I crystal and its manufacturing method |
| WO2007029155A2 (en) * | 2005-09-05 | 2007-03-15 | Ranbaxy Laboratories Limited | An improved process for preparation of pure celiprolol base |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3544172A1 (en) * | 1985-12-13 | 1987-06-19 | Lentia Gmbh | NEW CRYSTALLINE SALTS OF ARYLOXY PROPANOLAMINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| US5980882A (en) * | 1997-04-16 | 1999-11-09 | Medeva Pharmaceuticals Manufacturing | Drug-resin complexes stabilized by chelating agents |
-
2000
- 2000-07-24 PL PL00353243A patent/PL353243A1/en not_active Application Discontinuation
- 2000-07-24 EP EP00944158A patent/EP1204408A2/en not_active Withdrawn
- 2000-07-24 WO PCT/IB2000/001023 patent/WO2001008633A2/en not_active Ceased
- 2000-07-24 AU AU58390/00A patent/AU5839000A/en not_active Abandoned
- 2000-07-24 BR BR0012864-3A patent/BR0012864A/en not_active Application Discontinuation
- 2000-07-24 JP JP2001513366A patent/JP2003505485A/en active Pending
-
2002
- 2002-01-25 ZA ZA200200693A patent/ZA200200693B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0108633A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001008633A2 (en) | 2001-02-08 |
| WO2001008633A3 (en) | 2001-08-23 |
| JP2003505485A (en) | 2003-02-12 |
| BR0012864A (en) | 2002-06-04 |
| PL353243A1 (en) | 2003-11-03 |
| ZA200200693B (en) | 2002-10-30 |
| AU5839000A (en) | 2001-02-19 |
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