WO2008082250A1 - Improved process for the preparation of non-crystalline atorvastatin calcium - Google Patents
Improved process for the preparation of non-crystalline atorvastatin calcium Download PDFInfo
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- WO2008082250A1 WO2008082250A1 PCT/KR2008/000009 KR2008000009W WO2008082250A1 WO 2008082250 A1 WO2008082250 A1 WO 2008082250A1 KR 2008000009 W KR2008000009 W KR 2008000009W WO 2008082250 A1 WO2008082250 A1 WO 2008082250A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
- C07B63/04—Use of additives
Definitions
- the present invention relates to an improved process for the preparation of non-crystalline atorvastatin calcium salt.
- Atorvastatin is known as
- Atorvastatin is generally known as an inhibitor of HMG-CoA reductase, and used as an antihypercholesterolemic agent. [Formula 1]
- Atorvastatin is usually prepared as its calcium salt, which can be conveniently formulated into the pharmaceutical formulations for oral administration such as tablets, capsules, and powders.
- Atorvastatin calcium may exist in an amorphous form or in one of the crystalline forms (Form I, Form II, Form III and Form IV) , which are disclosed in WO 97/3958 and WO 97/3959. It is known that the amorphous forms in a number of pharmaceutical substances exhibit different solubility characteristics and bioavailability patterns, as compared to the crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38: 2003-2007). For some therapeutic indications, the bioavailability is one of the key parameters determining the form of the drug substance to be used in a pharmaceutical formulation. Atorvastatin calcium is a drug substance which is very slightly water soluble.
- the crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin in the body. Further, it is difficult to separately perform crystallization and preparation processes of the amorphous substance, and as a product, amorphous-crystalline mixtures are produced. Therefore, there is a need to develop a method for preparing the amorphous atorvastatin calcium without producing the crystalline form, or a method for converting the crystalline form to the amorphous form.
- WO 97/3960 discloses a process comprising the steps of dissolving the crystalline form of atorvastatin calcium in a non-hydroxylic solvent, and then removing the solvent to give the amorphous atorvastatin calcium.
- the preferred non-hydroxylic solvent is selected from the group consisting of tetrahydrofuran and a mixture of tetrahydrofuran and toluene.
- the above process has a disadvantage of using non-environmentally-friendly solvents .
- the amorphous atorvastatin calcium is obtained by dissolving the crystalline form in the solvent and then concentrating it, not by filtering the precipitate formed through crystallization that is typically used at an industrial scale. Therefore, the process requires much energy during the concentration process of removing a large amount of solvent. Further, even after drying the obtained atorvastatin calcium under vacuum for 72 hrs, the resultant still includes the non-hydroxylic solvent. Therefore, a series of the processes are inefficient at a large scale.
- Korean Patent Publication No. 10-2002-73137 discloses a preparation method of amorphous atorvastatin calcium, in which atorvastatin calcium is dissolved in a polar hydroxylic solvent such as methanol, ethanol and acetone, and then a nonpolar solvent diethyl ether is added thereto to form a precipitate.
- a polar hydroxylic solvent such as methanol, ethanol and acetone
- diethyl ether is a crystallization solvent being not suitable for industrial scale production, since it is extremely flammable.
- the method may employ any solvent selected from the group consisting of diisopropyl ether, pentane, hexane and other solvents, in addition to diethyl ether.
- Korean Patent Publication No. 10-2002-63166 discloses a preparation method of amorphous atorvastatin calcium, comprising the steps of dissolving atorvastatin calcium (Crystalline Form I) in lower alkanol having 2 to A carbon atoms (e.g., ethanol, propanol, isopropanol, butanol or branched butanol) or dissolving crude amorphous atorvastatin calcium in a mixture of such alkanols under heating, and isolating the amorphous atorvastatin calcium precipitated after cooling.
- atorvastatin calcium Crystalstalline Form I
- lower alkanol having 2 to A carbon atoms e.g., ethanol, propanol, isopropanol, butanol or branched butanol
- dissolving crude amorphous atorvastatin calcium in a mixture of such alkanols under heating, and isolating the amorphous atorvastat
- the used lower alkanol having 2 to 4 carbon atoms should be heated to a boiling point, and used in a large amount.
- the ideal conditions for industrial scale production of amorphous atorvastatin calcium are as follows: 1) the filtration speed should be fast during the filtration process of the produced precipitate, 2) the solvent to be used for mass production should be safe and environmentally-friendly, 3) the solvent should be removed without remaining in the product according to a conventional drying method, and 4) its crystalline form should not exist in the product. Accordingly, the present inventors have conducted studies on the preparation method for amorphous atorvastatin calcium, which is easily performed for mass production and does not produce its crystalline form to exist in the product, so as to prepare atorvastatin calcium by completely dissolving in an organic solvent, and then by using t-butylmethylether instead of diethyl ether as a crystallization solvent.
- the produced atorvastatin calcium is amorphous, the crystalline atorvastatin calcium does not exist in the product, and the amorphous atorvastatin calcium is very rapidly filtered during filtration process to have excellent characteristics, thereby completing the present invention.
- FIG. 1 shows the powder X-ray diffractogram of non-crystalline atorvastatin calcium according to Example 1 of the present invention
- Fig. 2 shows the powder X-ray diffractogram of non-crystalline atorvastatin calcium according to Example 2 of the present invention
- Fig. 3 shows the powder X-ray diffractogram of non-crystalline atorvastatin calcium according to Example 3 of the present invention.
- Fig. 4 shows the powder X-ray diffractogram of crystalline atorvastatin calcium (Form I).
- the present invention provides an improved process for the preparation of non-crystalline atorvastatin calcium, comprising the steps of
- the atorvastatin calcium used in the preparation process of the present invention may be known crystalline atorvastatin calcium of Form I, Form II, Form III, or Form IV, non-crystalline atorvastatin calcium, amixture of crystalline forms, andamixture of crystalline and non-crystalline forms. Any crystalline form of atorvastatin calcium may be used to produce non-crystalline atorvastatin calcium.
- Methanol may be used as the organic solvent capable of dissolving atorvastatin calcium at room temperature in step 1) of the preparation process.
- Ethyl acetate or tetrahydrofuran is preferably used as the organic solvent capable of dissolving atorvastatin calcium at elevated temperature.
- the organic solvent is preferably used in an amount of 1 - 100 ml (volume) , and more preferably in an amount of 3 ⁇ 10 ml, based on 1 g of atorvastatin calcium (weight) .
- temperature may be in a range from room temperature to reflux temperature of the used solvent, preferably in a range of 20 ⁇ 70 ° C.
- the step of precipitating atorvastatin calcium may be performed by adding the atorvastatin calcium solution that is prepared in step 1) to a nonpolar organic solvent t-butylmethylether .
- the nonpolar organic solvent t-butylmethylether may be used in an amount of 1 ⁇ 100 fold (ml), preferably 2 - 15 fold (ml) of the organic solvent used in step 1) (volume ratio) .
- the precipitation may be performed in a range from room temperature to reflux temperature of the used solvent, preferably in a temperature range of 10 ⁇ 30 ° C.
- t-Butylmethylether is used to obtain a white solid form of non-crystalline atorvastatin calcium, which is more uniform than the case of using diethylether .
- t-butylmethylether is not explosive because it is peroxide-free, thereby being useful for mass production.
- t-butylmethylether is a very safe solvent that is classified into Class El according to ICH guidelines and its residual limit is 5000 ppm.
- atorvastatin calcium is added to an organic solvent, which is not capable of dissolving atorvastatin calcium at room temperature, and made into a slurry. Then, atorvastatin calcium is completely dissolved at elevated temperature, the atorvastatin calcium solution is cooled to room temperature and precipitated.
- step3 of the preparation process of thepresent invention the precipitate is filtered, washed with the organic solvent used in step 1) , and then dried under vacuum to prepare non-crystalline atorvastatin calcium.
- the preparation process according to the present invention comprises a step of completely dissolving atorvastatin calcium, whereby any known crystalline atorvastatin calcium can be converted to the non-crystalline form. Accordingly, the process is very useful to convert the crystalline atorvastatin calcium to the non-crystalline form.
- the preparation process according to the present invention has an excellent filterability, and is very economical and suitable for mass production, thereby producing highly pure non-crystalline atorvastatin calcium.
- Example 1 Preparation process of non-crystalline atorvastatin calcium
- X-ray diffraction measurement is based on the diffraction and interference of lattice atom (or electron) .
- the lattice structure that determines the characteristic of crystalline material is identified by reflection of X-ray pattern (interference maximum) . Due to their disordered structure, non-crystalline materials display no peak in diffraction patterns, and they are characterized only by flattened curves . Accordingly, X-ray diffraction may be used to clarify the crystalline or non-crystalline state of materials.
- the powder X-ray diffractogram of the product is shown in Fig. 1.
- Example 2 Preparation process of non-crystalline atorvastatin calcium 100 ml of ethyl acetate was added to 10 g of atorvastatin calcium (Form I) and stirred at room temperature (20 ⁇ 25°C).
- the temperature was raised to 40 ⁇ 60 ° C to completely dissolve atorvastatin calcium.
- the solution was cooled to 30 ⁇ 35°C, and 1300 ml of t-butylmethylether was slowly added to the solution under stirring.
- the solution was stirred for 4 hrs at room temperature (20 ⁇ 25 ° C), filtered, and then washed with t-butylmethylether.
- the resultant was dried under vacuum for 24 hrs at 90 ° C to give 7.5 g of non-crystalline atorvastatin calcium in a uniform white solid form.
- the powder X-ray diffractogram of the product is shown in Fig. 2.
- Example 3 Preparation process of non-crystalline atorvastatin calcium
- atorvastatin calcium (Form I) 100 ml of ethyl acetate was added to 10 g of atorvastatin calcium (Form I) and stirred at room temperature (20 ⁇ 25 ° C). The temperature was raised to 40 ⁇ 60 ° C to completely dissolve atorvastatin calcium. Next, the solution was cooled to 20 ⁇ 25 ° C, and stirred for 48 hrs. The precipitated crystal was filtered, and then washed with 10 ml of ethyl acetate. The resultant was dried under vacuum for24hrsat90 ° C togive7.4gof non-crystalline atorvastatin calcium in a uniform white solid form.
- the preparation process according to the present invention first comprises a step of completely dissolving atorvastatin calcium, thereby converting any known crystalline atorvastatin calcium to the non-crystalline form. Accordingly, the process is very useful to convert the crystalline atorvastatin calcium to the non-crystalline form. Further, the preparation process according to the present invention has an excellent filterability, and is very economical and suitable for mass production, thereby producing highly pure non-crystalline atorvastatin calcium.
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Abstract
The present invention relates to an improved process for the preparation of non-crystalline atorvastatin calcium salt. The preparation process according to the present invention first comprises a step of completely dissolving atorvastatin calcium, thereby converting any known crystalline atorvastatin calcium to the non-crystalline form. Accordingly, the process is very useful to convert the crystalline atorvastatin calcium to the non-crystalline form.
Description
[DESCRIPTION]
[invention Title]
IMPROVED PROCESS FOR THE PREPARATION OF NON-CRYSTALLINE ATORVASTATIN CALCIUM
[Technical Field]
The present invention relates to an improved process for the preparation of non-crystalline atorvastatin calcium salt.
[Background Art]
Atorvastatin is known as
{R- (R*, R*) }-2- (4-fluorophenyl) -β, δ-dihydroxy-5- ( 1-methylethy 1) -3-phenyl-4- { (phenylamino) carbonyl } -lH-pyrrole-1-heptanoic acid hemicalcium salt, and represented by the following Formula 1. Atorvastatin is generally known as an inhibitor of HMG-CoA reductase, and used as an antihypercholesterolemic agent. [Formula 1]
Ca 2+
The preparation process of atorvastatin and key intermediates are disclosed in US patent NOs.5,003,080, 5,097,045, 5,103,024, 5,124,482, 5,149,837, 5,155,251, 5,126,174, 5,245,047, 5,248,793, 5,280,126, 5,342,952 and 5,397,792. Atorvastatin is usually prepared as its calcium salt, which can be conveniently formulated into the pharmaceutical formulations for oral administration such as tablets, capsules, and powders.
Atorvastatin calcium may exist in an amorphous form or in one of the crystalline forms (Form I, Form II, Form III and Form IV) , which are disclosed in WO 97/3958 and WO 97/3959. It is known that the amorphous forms in a number of pharmaceutical substances exhibit different solubility characteristics and bioavailability patterns, as compared to the crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38: 2003-2007). For some therapeutic indications, the bioavailability is one of the key parameters determining the form of the drug substance to be used in a pharmaceutical formulation. Atorvastatin calcium is a drug substance which is very slightly water soluble. In particular, the crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin in the body. Further, it is difficult to separately perform crystallization and preparation processes of the amorphous substance, and as a product, amorphous-crystalline mixtures are produced. Therefore, there is a need to develop a
method for preparing the amorphous atorvastatin calcium without producing the crystalline form, or a method for converting the crystalline form to the amorphous form.
WO 97/3960 discloses a process comprising the steps of dissolving the crystalline form of atorvastatin calcium in a non-hydroxylic solvent, and then removing the solvent to give the amorphous atorvastatin calcium. The preferred non-hydroxylic solvent is selected from the group consisting of tetrahydrofuran and a mixture of tetrahydrofuran and toluene. However, the above process has a disadvantage of using non-environmentally-friendly solvents .
In addition, in the above process, the amorphous atorvastatin calcium is obtained by dissolving the crystalline form in the solvent and then concentrating it, not by filtering the precipitate formed through crystallization that is typically used at an industrial scale. Therefore, the process requires much energy during the concentration process of removing a large amount of solvent. Further, even after drying the obtained atorvastatin calcium under vacuum for 72 hrs, the resultant still includes the non-hydroxylic solvent. Therefore, a series of the processes are inefficient at a large scale.
Korean Patent Publication No. 10-2002-73137 discloses a preparation method of amorphous atorvastatin calcium, in which atorvastatin calcium is dissolved in a polar hydroxylic solvent such as methanol, ethanol and acetone, and then a nonpolar solvent
diethyl ether is added thereto to form a precipitate. However, the used diethyl ether is a crystallization solvent being not suitable for industrial scale production, since it is extremely flammable. Further, the above publication describes that the method may employ any solvent selected from the group consisting of diisopropyl ether, pentane, hexane and other solvents, in addition to diethyl ether. However, there is no mention of filtration speed of the precipitate, crystallinity or the like after crystallization. Korean Patent Publication No. 10-2002-63166 discloses a preparation method of amorphous atorvastatin calcium, comprising the steps of dissolving atorvastatin calcium (Crystalline Form I) in lower alkanol having 2 to A carbon atoms (e.g., ethanol, propanol, isopropanol, butanol or branched butanol) or dissolving crude amorphous atorvastatin calcium in a mixture of such alkanols under heating, and isolating the amorphous atorvastatin calcium precipitated after cooling. However, the used lower alkanol having 2 to 4 carbon atoms should be heated to a boiling point, and used in a large amount. Thus, there is a drawback in that much time is needed during filtration of the precipitate due to a small particle size of the produced atorvastatin calcium.
Therefore, the ideal conditions for industrial scale production of amorphous atorvastatin calcium are as follows: 1) the filtration speed should be fast during the filtration process of the produced precipitate, 2) the solvent to be used for mass
production should be safe and environmentally-friendly, 3) the solvent should be removed without remaining in the product according to a conventional drying method, and 4) its crystalline form should not exist in the product. Accordingly, the present inventors have conducted studies on the preparation method for amorphous atorvastatin calcium, which is easily performed for mass production and does not produce its crystalline form to exist in the product, so as to prepare atorvastatin calcium by completely dissolving in an organic solvent, and then by using t-butylmethylether instead of diethyl ether as a crystallization solvent. They found that the produced atorvastatin calcium is amorphous, the crystalline atorvastatin calcium does not exist in the product, and the amorphous atorvastatin calcium is very rapidly filtered during filtration process to have excellent characteristics, thereby completing the present invention.
[Disclosure]
[Technical Problem] It is an obj ect of the present invention to provide an improved process for the preparation of non-crystalline atorvastatin calcium.
[Description of Drawings] Fig. 1 shows the powder X-ray diffractogram of
non-crystalline atorvastatin calcium according to Example 1 of the present invention;
Fig. 2 shows the powder X-ray diffractogram of non-crystalline atorvastatin calcium according to Example 2 of the present invention;
Fig. 3 shows the powder X-ray diffractogram of non-crystalline atorvastatin calcium according to Example 3 of the present invention; and
Fig. 4 shows the powder X-ray diffractogram of crystalline atorvastatin calcium (Form I).
[Best Mode]
The present invention provides an improved process for the preparation of non-crystalline atorvastatin calcium, comprising the steps of
1) adding an organic solvent that is capable of dissolving atorvastatin calcium at room temperature or at elevated temperature to prepare an atorvastatin calcium solution,
2) adding the atorvastatin calcium solution to a t-butylmethylether solvent to precipitate atorvastatin calcium, and
3) isolating the precipitated atorvastatin calcium.
Hereinafter, the present invention will be described in
detail .
The atorvastatin calcium used in the preparation process of the present invention may be known crystalline atorvastatin calcium of Form I, Form II, Form III, or Form IV, non-crystalline atorvastatin calcium, amixture of crystalline forms, andamixture of crystalline and non-crystalline forms. Any crystalline form of atorvastatin calcium may be used to produce non-crystalline atorvastatin calcium.
Methanol may be used as the organic solvent capable of dissolving atorvastatin calcium at room temperature in step 1) of the preparation process. Ethyl acetate or tetrahydrofuran is preferably used as the organic solvent capable of dissolving atorvastatin calcium at elevated temperature. The organic solvent is preferably used in an amount of 1 - 100 ml (volume) , and more preferably in an amount of 3 ~ 10 ml, based on 1 g of atorvastatin calcium (weight) .
In step 1 ) of the preparation process of the present invention, temperature may be in a range from room temperature to reflux temperature of the used solvent, preferably in a range of 20 ~ 70 °C.
Instep2) of the preparation process of the present invention, the step of precipitating atorvastatin calcium may be performed by adding the atorvastatin calcium solution that is prepared in step 1) to a nonpolar organic solvent t-butylmethylether . The nonpolar organic solvent t-butylmethylether may be used in an
amount of 1 ~ 100 fold (ml), preferably 2 - 15 fold (ml) of the organic solvent used in step 1) (volume ratio) . The precipitation may be performed in a range from room temperature to reflux temperature of the used solvent, preferably in a temperature range of 10 ~ 30°C. t-Butylmethylether is used to obtain a white solid form of non-crystalline atorvastatin calcium, which is more uniform than the case of using diethylether . Unlike diethylether, t-butylmethylether is not explosive because it is peroxide-free, thereby being useful for mass production. Further, t-butylmethylether is a very safe solvent that is classified into Class El according to ICH guidelines and its residual limit is 5000 ppm.
Further, in the preparation process with omitting step 2) , atorvastatin calcium is added to an organic solvent, which is not capable of dissolving atorvastatin calcium at room temperature, and made into a slurry. Then, atorvastatin calcium is completely dissolved at elevated temperature, the atorvastatin calcium solution is cooled to room temperature and precipitated. Instep3) of the preparation process of thepresent invention, the precipitate is filtered, washed with the organic solvent used in step 1) , and then dried under vacuum to prepare non-crystalline atorvastatin calcium.
As described above, the preparation process according to the present invention comprises a step of completely dissolving
atorvastatin calcium, whereby any known crystalline atorvastatin calcium can be converted to the non-crystalline form. Accordingly, the process is very useful to convert the crystalline atorvastatin calcium to the non-crystalline form. The preparation process according to the present invention has an excellent filterability, and is very economical and suitable for mass production, thereby producing highly pure non-crystalline atorvastatin calcium.
[Mode for Invention]
Hereinafter, the preferred Examples are provided for better understanding. However, these Examples are for the illustrative purpose only, and the invention is not intended to be limited by these Examples.
Example 1 : Preparation process of non-crystalline atorvastatin calcium
30 ml of methanol was added to 10 g of atorvastatin calcium (Form I) and completely dissolved at room temperature (20~25°C). 1300 ml of t-butylmethylether was slowly added to the solution under stirring. The solution was stirred for 4 hrs at room temperature (20 ~ 25°C), filtered, and then washed with t-butylmethylether. The resultant was dried under vacuum for 24 hrs at 90°C to give 7.3 g of non-crystalline atorvastatin calcium in a uniform white solid form.
In order to confirm whether the product is a non-crystalline form, X-ray diffraction was measured under the following experimental conditions.
<X-ray diffraction measurement> -Instrument: Bruker Powder Diffractometer,
-Radiation: Cu-Kα(λ: 1.54190 A),
-Monochromator: graphite,
-Exciting voltage: 4OkV,
-Anode current: 30 mA, -sample: smooth surface, thickness 0.5 mm
X-ray diffraction measurement is based on the diffraction and interference of lattice atom (or electron) . The lattice structure that determines the characteristic of crystalline material is identified by reflection of X-ray pattern (interference maximum) . Due to their disordered structure, non-crystalline materials display no peak in diffraction patterns, and they are characterized only by flattened curves . Accordingly, X-ray diffraction may be used to clarify the crystalline or non-crystalline state of materials.
The powder X-ray diffractogram of the product is shown in Fig. 1.
Example 2 : Preparation process of non-crystalline atorvastatin calcium
100 ml of ethyl acetate was added to 10 g of atorvastatin calcium (Form I) and stirred at room temperature (20 ~ 25°C).
The temperature was raised to 40 ~ 60°C to completely dissolve atorvastatin calcium. Next, the solution was cooled to 30 ~ 35°C, and 1300 ml of t-butylmethylether was slowly added to the solution under stirring. The solution was stirred for 4 hrs at room temperature (20 ~ 25°C), filtered, and then washed with t-butylmethylether. The resultant was dried under vacuum for 24 hrs at 90°C to give 7.5 g of non-crystalline atorvastatin calcium in a uniform white solid form.
The powder X-ray diffractogram of the product is shown in Fig. 2.
Example 3 : Preparation process of non-crystalline atorvastatin calcium
100 ml of ethyl acetate was added to 10 g of atorvastatin calcium (Form I) and stirred at room temperature (20 ~ 25°C). The temperature was raised to 40 ~ 60°C to completely dissolve atorvastatin calcium. Next, the solution was cooled to 20 ~ 25°C, and stirred for 48 hrs. The precipitated crystal was filtered, and then washed with 10 ml of ethyl acetate. The resultant was dried under vacuum for24hrsat90°C togive7.4gof non-crystalline atorvastatin calcium in a uniform white solid form.
The powder X-ray diffractogram of the product is shown in Fig. 3.
[industrial Applicability]
The preparation process according to the present invention first comprises a step of completely dissolving atorvastatin calcium, thereby converting any known crystalline atorvastatin calcium to the non-crystalline form. Accordingly, the process is very useful to convert the crystalline atorvastatin calcium to the non-crystalline form. Further, the preparation process according to the present invention has an excellent filterability, and is very economical and suitable for mass production, thereby producing highly pure non-crystalline atorvastatin calcium.
Claims
1. A preparation process of non-crystalline atorvastatin calcium, comprising the steps of 1) adding an organic solvent that is capable of dissolving atorvastatin calcium at room temperature or at elevated temperature to prepare an atorvastatin calcium solution,
2) adding the atorvastatin calcium solution to a t-butylmethylether solvent to precipitate atorvastatin calcium, and
3) isolating the precipitated atorvastatin calcium.
2. The preparation process of non-crystalline atorvastatin calcium according to claim 1, wherein in step 1), the organic solvent that is capable of dissolving atorvastatin calcium at room temperature is methanol.
3. The preparation process of non-crystalline atorvastatin calcium according to claim 1, wherein in step 1), the organic solvent that is capable of dissolving atorvastatin calcium at elevated temperature is ethyl acetate or tetrahydrofuran.
4. The preparation process of non-crystalline atorvastatin calcium according to claim 1, wherein in step 1), the organic solvent is used in an amount of 1 ~ 100 ml (volume) , based on 1 g of atorvastatin calcium (weight) .
5. The preparation process of non-crystalline atorvastatin calcium according to claim 1, wherein in step 2), the t-butylmethylether solvent is used in an amount of 1 ~ 100 fold (ml) of the organic solvent used in step 1) (volume ratio).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2007-0000072 | 2007-01-02 | ||
| KR1020070000072A KR100833439B1 (en) | 2007-01-02 | 2007-01-02 | Improved process for the preparation of non-crystalline atorvastatin calcium |
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| WO2008082250A1 true WO2008082250A1 (en) | 2008-07-10 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432033A (en) * | 2016-10-21 | 2017-02-22 | 江苏阿尔法药业有限公司 | Preparation method of amorphous atorvastatin calcium |
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| WO2002059087A1 (en) * | 2001-01-23 | 2002-08-01 | Lek Pharmaceutical And Chemical Company D.D. | Preparation of non-crystalline atorvastatin calcium |
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| CZ296967B6 (en) * | 2002-02-01 | 2006-08-16 | Zentiva, A.S. | Process for preparing amorphous form of hemicalcium salt of (3R,5R)7-[3-phenyl-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropylpyrrol-l-yl]-3,5-dihydroxyheptanoic acid (atorvastatin) |
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Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001028999A1 (en) * | 1999-10-18 | 2001-04-26 | EGIS Gyógyszergyár Rt. | Process for the preparation of amorphous atorvastatin calcium |
| WO2001042209A1 (en) * | 1999-12-10 | 2001-06-14 | Lek Pharmaceutical And Chemical Company D.D. | Process for the preparation of amorphous atorvastatin |
| WO2002059087A1 (en) * | 2001-01-23 | 2002-08-01 | Lek Pharmaceutical And Chemical Company D.D. | Preparation of non-crystalline atorvastatin calcium |
| WO2003093233A1 (en) * | 2002-04-29 | 2003-11-13 | Chemi S.P.A. | Process for the preparation of the amorphous form of atorvastatin calcium salt |
| WO2004089895A1 (en) * | 2003-04-11 | 2004-10-21 | Lek Pharmaceuticals D.D. | Process for the preparation of amorphous calcium salt of atorvastatin |
| WO2005100313A1 (en) * | 2004-04-16 | 2005-10-27 | Pfizer Products Inc. | Process for forming amorphous atorvastatin calcium |
| WO2006045018A1 (en) * | 2004-10-18 | 2006-04-27 | Teva Pharmaceutical Industries Ltd. | Process for preparing amorphous atorvastatin hemi-calcium by dissolving the salt in an organic solvent which is a mixture of an alcohol and a ketone and/or an ester and removing the solvent |
| WO2006046109A1 (en) * | 2004-10-28 | 2006-05-04 | Warner-Lambert Company Llc | Process for forming amorphous atorvastatin |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432033A (en) * | 2016-10-21 | 2017-02-22 | 江苏阿尔法药业有限公司 | Preparation method of amorphous atorvastatin calcium |
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| KR100833439B1 (en) | 2008-05-29 |
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