CN105111123A - Atorvastatin calcium and composition - Google Patents

Atorvastatin calcium and composition Download PDF

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CN105111123A
CN105111123A CN201510589013.1A CN201510589013A CN105111123A CN 105111123 A CN105111123 A CN 105111123A CN 201510589013 A CN201510589013 A CN 201510589013A CN 105111123 A CN105111123 A CN 105111123A
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impurity
atorvastatincalcuim
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李兴惠
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

The invention relates to atorvastatin calcium and composition, in particular to a medical bulk drug. The active ingredient of the bulk drug is shown in the formula I compound or hydrate such as rihydrate. Further, the invention relates to a pharmaceutical composition which comprises the bulk drug and an optional pharmaceutical acceptable carrier or accessory. The bulk drug and the pharmaceutical composition can be taken as an antilipemic agent and can be used for curing or preventing hypercholesterolemia or coronary heart disease in clinical practice (img file=' DDA0000804520800000011. TIF' wi=' 1358' he=' 742'/).

Description

Atorvastatincalcuim and composition
Technical field
The invention belongs to medical art, relate to a kind of pharmaceutical composition as lipid regulating agent, particularly relate to a kind of pharmaceutical composition comprising atorvastatincalcuim as lipid regulating agent.
Background technology
Atorvastatincalcuim; English name AtorvastatinCalcium; chemistry is by name: (3R; 5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrroles-1-base]-3; 5-dihydroxyl enanthic acid calcium (2:1) trihydrate; molecular formula: C66H68CaF2N4O103H2O, molecular weight: 1209.4 (trihydrates, anhydride is 1155.3).The chemical structural formula of atorvastatincalcuim is as follows:
Atorvastatincalcuim is selectivity, the competitive inhibitor of HMG-CoA reductase.The effect of HMG-CoA is that Hydroxymethylglutaryl list acyl coenzyme A is changed into mevalonic acid, namely comprises the steroid precursor of cholesterol.Clinical study, pathological study and epidemiological study display, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) blood plasma level raise and promote that human atherosclerosis is formed, be the Hazard Factor that cardiovascular disorder occurs, High-density Lipoprotein-cholesterol raises then relevant to the reduction of risk of cardiovascular diseases.
In animal model, atorvastatincalcuim reduces plasma cholesterol and lipoprotein levels by suppressing the synthesis of HMG-CoA reductase and cholesterol in liver, and by the ldl receptor number that increases liver cell surface to strengthen the picked-up Sum decomposition metabolism of low-density lipoprotein; Atorvastatincalcuim also reduces low-density lipoprotein and generates and low-density lipoprotein particle number.Atorvastatincalcuim can reduce the low-density lipoprotein cholesterol level of some homozygous familial hypercholesterolemia (FH) patient, and other falls lipid drug usually seldom has clinical efficacy to this kind of patient.Atorvastatincalcuim reduces total cholesterol, low density lipoprotein cholesterol and the Level of Apolipoprotein B that homozygous and heterozygosis give type familial hypercholesterolemia, non-familial hypercholesterolemia and mixed dyslipidemia patient.Atorvastatincalcuim also reduces C-VLDL and triglyceride levels, and high density lipoprotein cholesterol and aPoA-I level can be made to raise to some extent.Atorvastatincalcuim reduces the total cholesterol of simple primary hypertriglyceridemiapatients patients, low density lipoprotein cholesterol, C-VLDL, apolipoprotein B, triglyceride level, and Non-high-density Lipoprotein Cholesterol, and increase High-density Lipoprotein-cholesterol.Atorvastatincalcuim can reduce the intermediated-density lipoprotein cholesterol of B lipoprotein abnormalities mass formed by blood stasis patient.
The atorvastatincalcuim applied clinically has the tablet sold with trade(brand)name Lipitor, and specification is 10mg, 20mg, 40mg etc., is used for the treatment of hypercholesterolemia, coronary heart disease etc.For primary hypercholesterolemia patient, comprise familial hypercholesterolemia (heterozygosis subtype) or combined hyperlipidemia (being equivalent to IIa and the IIb type of Fredrickson classification) patient, if dietetic treatment and other non-drug therapy curative effect are unsatisfied with, application this product can treat the rising of its total cholesterol, low density lipoprotein cholesterol raises, apolipoprotein B raises and triglyceride level raises.For homozygote Familial HypercholesterolemicPatients Patients, atorvastatincalcuim can share or be used alone (when without other treatment means), to reduce total cholesterol and low density lipoprotein cholesterol with other Comprehensive Therapy for Correcting Lipidemia (as LDL plasma dialysis method).For the danger such as coronary heart disease or coronary heart disease disease (as: diabetes, symptomatic atherosclerotic disease etc.) merge the patient of hypercholesterolemia or mixed dyslipidemia, this product is applicable to: reduce the risk of non-fatal myocardial infarction, reduce the risk of lethality and non-lethality palsy, reduce the risk of reconstructive vascular operation, reduce be in hospital because of congestive heart failure risk, reduce anginal risk.
There is plurality of impurities in known atorvastatin or its medicinal calcium salt, such as enantiomeric impurity, diastereomer impurity, remove fluorochemical, Difluoride, epoxide etc.In view of atorvastatin (i.e. free acid (3R; 5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrroles-1-base]-3; 5-dihydroxyl enanthic acid) the 3-position of enanthic acid side chain and 5-position there are 2 chiral carbon atoms; its steric configuration is (3R; 5R); can be described as (3R, 5R)-atorvastatin.Other steric isomer as impurity comprises (3S, 5S)-atorvastatin, (3R, 5S)-atorvastatin and (3S, 5R)-atorvastatin.Exist with its calcium salt (free acid: calcium=2:1) as medicinal atorvastatin due to current, and atorvastatin is when forming calcium salt, these are as (the 3S of impurity, 5S)-atorvastatin, (3R, 5S)-atorvastatin and (3S, 5R)-atorvastatin also preferably form its calcium salt (free acid: calcium=2:1) simultaneously.
The synthesis of atorvastatin is first public in US4681893, and wherein embodiment 1 has prepared the lactone compound comprising pyranoid ring.In the embodiment 10 of US5273995, disclose and first form sodium salt from above-mentioned lactone compound, then this sodium salt and calcium chloride react the process generating atorvastatin calcium salt.In the reactions steps that this is many, there is the possibility of introducing such as impurity mentioned above.
In view of there is the expectation using high-quality medicine clinically, therefore those skilled in the art still expect to provide and have the low atorvastatincalcuim of better quality such as foreign matter content.
Summary of the invention
The present inventor has been found that, specific treatment process is used can effectively to reduce in atorvastatincalcuim the content removing fluorine impurity, and low levels remove fluorine impurity can make (the 3S of enantiomeric impurity in atorvastatincalcuim, in Long-term Storage process, content maintains lower level to 5S)-atorvastatin (or can be its calcium salt), so also contributes to improving Drug safety.Therefore the present invention finds and is able to and completes.
In the present invention, term " atorvastatincalcuim " is compounds of Formula I:
Or its hydrate such as trihydrate.
In the present invention, term " atorvastatin " is following formula: compound:
It is the free acid form of atorvastatincalcuim in essence.
In the present invention, term " impurity A " is following formula: compound:
or its calcium salt.
Impurity A be in essence atorvastatin remove fluorine cpd, be namely the fluorine do not had on phenyl ring with the difference of atorvastatin.This goes fluorine cpd or its calcium salt to be optionally present in bulk drug of the present invention or preparation as impurity.These go fluorine cpd or its calcium salt also to can be described as in the present invention: remove fluorine cpd, remove fluorine atorvastatin, impurity A, A impurity or other similar appellation.As do not illustrated especially in addition, these appellations include impurity A free acid or its calcium salt.Chemistry (3R, 5R) by name-3,5-dihydroxyl-7-[5-(1-methylethyl)-2,3-phenylbenzene-4-(the phenylcarbamoyl)-1H-pyrroles-1-base] enanthic acid removing fluorine cpd of free acid form.
In the present invention, term " impurity B " is following formula: compound:
and enantiomorph,
Or its calcium salt.
Chemistry (the 3RS by name of the impurity B of free acid form; 5SR)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrroles-1-base]-3; 5-dihydroxyl enanthic acid; it is the diastereomer pair of atorvastatin in essence; i.e. described (3R above; 5S)-atorvastatin and (3S, 5R)-both atorvastatins.This impurity B or its calcium salt are optionally present in bulk drug of the present invention or preparation as impurity.These impurity Bs or its calcium salt also can be described as in the present invention: diastereomer impurity, diastereomer isomer to, (3RS, 5SR)-atorvastatin, go fluorine atorvastatin, impurity B, B impurity or other similar appellation.As do not illustrated especially in addition, these appellations include impurity B free acid or its calcium salt.
In the present invention, term " impurity E " is following formula: compound:
or its calcium salt.
Chemistry (the 3S by name of the impurity E of free acid form; 5S)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrroles-1-base]-3; 5-dihydroxyl enanthic acid; it is the enantiomer of atorvastatin in essence; i.e. described (3S, 5S)-atorvastatin above.This impurity E or its calcium salt, they can be used as impurity and are optionally present in bulk drug of the present invention or preparation.Above-mentioned impurity E or its calcium salt also can be described as in the present invention: enantiomeric impurity, (3S, 5S)-atorvastatin, impurity E, E impurity or other similar appellation.As do not illustrated especially in addition, these appellations include impurity E free acid or its calcium salt.
Specifically, first aspect present invention provides a kind of preparation method of bulk drug of hyoscine, and the activeconstituents of this bulk drug is atorvastatincalcuim, and the method comprises the step using solvent to refine the raw material comprising atorvastatincalcuim.
The preparation method of arbitrary embodiment according to a first aspect of the present invention, the method comprises the following steps:
Step 1: at the temperature of 40 ~ 70 DEG C, makes the material dissolution comprising atorvastatincalcuim of 1 weight part in the methyl alcohol of 10 ~ 50 weight parts, then adds trolamine wherein and makes its concentration in the solution reach 0.1 ~ 1.0%, stir;
Step 2: at temperature described in maintenance step 1, under agitation, slowly add the water of 5 ~ 50 weight parts in step 1 gained solution, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, 55 DEG C of vacuum-dryings; According to product purity, the operation of repeating step 1 and step 2 if desired; Optionally
Step 3: at the temperature of 50 ~ 60 DEG C (such as at the temperature of 55 DEG C), the step 2 gained atorvastatincalcuim product of 1 weight part is made to be dissolved in the methyl alcohol of 15 ~ 40 weight parts (such as 25 weight parts), under agitation slowly add the water of 10 ~ 30 weight parts (such as 20 weight parts), leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, wash with water, then vacuum-drying at the temperature of 55 DEG C, obtain atorvastatin calcium raw material drug.
The preparation method of arbitrary embodiment according to a first aspect of the present invention, wherein in step 1, described temperature is the temperature within the scope of 45 ~ 65 DEG C, such as, be the temperature within the scope of 50 ~ 60 DEG C.
The preparation method of arbitrary embodiment according to a first aspect of the present invention, wherein in step 1, makes the atorvastatincalcuim of 1 weight part be dissolved in the methyl alcohol of 15 ~ 45 weight parts, such as, makes the atorvastatincalcuim of 1 weight part be dissolved in the methyl alcohol of 15 ~ 40 weight parts.
The preparation method of arbitrary embodiment according to a first aspect of the present invention, wherein in step 1, adds trolamine and makes its concentration in the solution reach 0.2 ~ 0.8%, such as, add trolamine and make its concentration in the solution reach 0.2 ~ 0.6%.
The preparation method of arbitrary embodiment according to a first aspect of the present invention, wherein in step 2, slowly adds the water of 10 ~ 40 weight parts, such as, in step 1 gained solution, slowly adds the water of 10 ~ 30 weight parts in step 1 gained solution.
In the method for the invention, phrase described in step 1 " comprises the raw material of atorvastatincalcuim ", it can be crude starting material or the crude product of atorvastatincalcuim, it can be such as the conventionally bulk drug for preparing of method, although the bulk drug that art methods prepares may be used for the preparation of formulation example as tablet equally, but processed further by the bulk drug of the inventive method to the prior art, more excellent performance is given, such as better stability, better security with the preparation making it and be prepared into by it.
" bulk drug of hyoscine " of the present invention or " bulk drug " its can be used as the bulk drug of pharmaceutical composition such as pharmaceutical preparation production, therefore it also can be regarded as the bulk drug of formula I or its hydrate such as trihydrate and atorvastatincalcuim.Well-known, as the bulk drug of the hyoscine of useful in preparing drug formulations, they comprise formula I as main ingredient or its hydrate such as trihydrate, can also comprise the trace impurity of the limit that conforms with the regulations.
Method according to a first aspect of the present invention, wherein said recrystallization carries out according to the general operation method of those skilled in the art, particularly in the temperature range of comparatively high temps such as more than 40 ° until below solvent reflux temperature (such as at the temperature of 40 ~ 70 DEG C) by solute dissolves in solvent, then such as within the scope of 0 ~ 15 DEG C, such as in 10 ~ 15 DEG C of temperature ranges, material crystallization is made at a lower temperature, then crystallization is leached, drying, to obtain bulk drug of the present invention.Particularly repeatedly recrystallization can be carried out according to product purity as required.
Have been found that and use preparation method of the present invention can effectively remove the impurity A existed in atorvastatincalcuim raw material, namely remove fluorine cpd shown in following formula:
or its calcium salt.
Method according to a first aspect of the present invention, bulk drug obtained by it comprises the atorvastatincalcuim as main ingredient, and the optional impurity A as impurity, the content of impurity A for atorvastatincalcuim lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%), such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope).
Method according to a first aspect of the present invention, bulk drug obtained by it comprises the atorvastatincalcuim as main ingredient, and the optional impurity B as impurity, impurity B for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%), such as impurity B content (relative to atorvastatincalcuim meter) (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope) in 0.003% ~ 0.500% scope.
Method according to a first aspect of the present invention, bulk drug obtained by it comprises the atorvastatincalcuim as main ingredient, and the optional impurity E as impurity, impurity E for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.28%), such as impurity E content (relative to atorvastatincalcuim meter) in 0.002% ~ 0.500% scope (such as in 0.002% ~ 0.400% scope, such as in 0.002% ~ 0.300% scope, such as in 0.002% ~ 0.280% scope).
In the present invention, phrase " content of impurity A for atorvastatincalcuim " represents in any material, such as in atorvastatincalcuim crude product, atorvastatin calcium raw material drug of the present invention or the pharmaceutical composition such as pharmaceutical preparation that prepared by atorvastatin calcium raw material drug of the present invention, the percentage composition that impurity A calculates for atorvastatincalcuim, it also can referred to as " Impurity A content ".In the present invention, " content of impurity E for atorvastatincalcuim " mentioned below or " impurity E content " also have similar meaning.The content of such definition impurity phase for atorvastatincalcuim, no matter can make which kind of material, no matter wherein whether be added with other material such as pharmaceutical excipient, impurity and the two relative ratios of atorvastatincalcuim are constant.This expression method goes for the material of above-mentioned any kind.
In the present invention, the content of phrase impurity A for atorvastatincalcuim or Impurity A content are measured by the present invention [HPLC-A] method and obtain.In the present invention, the content of phrase impurity B for atorvastatincalcuim or impurity B content are measured by the present invention [HPLC-A] method and obtain.
In the present invention, the content of phrase impurity E for atorvastatincalcuim or impurity E content are measured by the present invention [HPLC-B] method and obtain.
According to the present invention, the method for described [HPLC-A] is as follows:
(i) dosing:
Damping fluid: 3.9g/L ammonium acetate solution, is adjusted to pH5.0 with glacial acetic acid, to obtain final product,
Test liquid: 50.0mg trial-product dimethyl formamide is dissolved and is diluted to 50.0mL, to obtain final product,
Reference liquid: 1.0mL test liquid dimethyl formamide is diluted to 100.0mL, then this solution dimethyl formamide of 1.0mL is diluted to 10.0mL, to obtain final product,
System suitability solution: 2.5mg impurity A, 2.5mg impurity B and 2.5mg trial-product dimethyl formamide are dissolved and be diluted to 50.0mL, to obtain final product;
(ii) chromatographic condition:
Carry out according to Chinese Pharmacopoeia version in 2010 two contained high performance liquid chromatography of annex V D,
Chromatographic column: column length 25cm, internal diameter 4.6mm, stationary phase is eight alkyl silane bonded silica gels, [this chromatographic column is typical C8 chromatographic column to granularity 5 μm, it can easily be buied from commercial channels, and the brand of such as buying from Agilent company is the chromatographic column of ZORBAXC8, ZorbaxSBC8, ZorbaxXDBC8 etc., in the present invention specifically tests, brand is used to be the pillar of ZORBAXC8]
Column temperature: 35 DEG C,
Moving phase:
Mobile phase A: tetrahydrofuran (THF): acetonitrile: damping fluid=12:21:67 (V/V/V),
Mobile phase B: tetrahydrofuran (THF): damping fluid: acetonitrile=12:27:61 (V/V/V),
Elution program:
Time (min) Mobile phase A (%, v/v) Mobile phase B (%, v/v)
0—>40 100 0
40—>70 100—>20 0—>80
70—>85 20—>0 80—>100
Flow velocity: 1.5mL/min,
Detector: UV-detector, determined wavelength 244nm;
(iii) mensuration and result calculate:
By test liquid, reference liquid, each 20 μ L of system suitability solution injection liquid chromatography respectively, record color atlas respectively,
Impurity is differentiated: by the retention time of main peak determination atorvastatincalcuim in test liquid color atlas, determine that the peak of each impurity belongs to by system suitability solution gained color atlas according to following relative retention time (RRT) again: the RRT of impurity A is about 0.8 (test result of the present invention is all in 0.77 ~ 0.83 scope) for atorvastatincalcuim (its usual retention time is in 32 ~ 34min) in system suitability solution color atlas, the RRT of impurity B is about 0.9 (test result of the present invention is all in 0.87 ~ 0.93 scope) [if desired by increasing or reducing the per-cent of acetonitrile or the pH of ammonium acetate solution, to make the retention time of atorvastatin in 32 ~ 34min, such as raise the retention time that pH can reduce atorvastatin],
System suitability: use system suitability solution testing, the resolution between impurity B and atorvastatincalcuim is at least 1.5,
The content of various impurity is calculated by following calculating formula:
In addition, by above [HPLC-A] method, can also by the atorvastatincalcuim reference substance solution of the suitable concentration of preparation, by the atorvastatin calcium contents (absolute content in external standard method trial-product, the i.e. quality of atorvastatincalcuim or its hydrate such as trihydrate in every gram of trial-product, %, w/w)." trial-product " of above-mentioned [HPLC-A] method and the test of following [HPLC-B] method
According to the present invention, the method for described [HPLC-B] is as follows:
(i) dosing:
Mixed solvent: dehydrated alcohol/methyl alcohol=50/50 (V/V);
Testing liquid: 10mg trial-product is dissolved in 4mL mixed solvent, then be diluted to 10.0mL (C=1000 μ g/ml) with hexane;
Reference solution (a): 2mg atorvastatin impurity E reference substance dissolve with methanol is diluted to 20.0mL (solution A); 10mg trial-product is dissolved in 1.25mL methyl alcohol, adds 0.75mL solution A and 2mL dehydrated alcohol, then be diluted to 10.0mL with hexane;
Reference solution (b): add 40.0mL mixed solvent in 2.0mL testing liquid, then be diluted to 100.0mL with hexane; In this solution of 3.0mL, add 5mL mixed solvent, then be diluted to 20.0mL with hexane;
(ii) chromatographic condition:
Carry out according to Chinese Pharmacopoeia version in 2010 two contained high performance liquid chromatography of annex V D,
Chromatographic column: column length 25cm, internal diameter 4.6mm, stationary phase is that surface application has amylose starch-three (3,5-xylyl carbamate) silica gel, granularity 10 μm [typically can easily buy from commercial channels by this chromatographic column, the brand of such as buying from ChiralTechnologies company is the chromatographic column of ChiralpakAD and ChiralpakAD-H, in the present invention specifically tests, uses brand to be the pillar of ChiralpakAD];
Moving phase: trifluoroacetic acid: dehydrated alcohol: hexane=1:60:940 (V/V/V);
Flow velocity: 1.0mL/min;
Detector: UV-detector, determined wavelength 244nm;
(iii) mensuration and result calculate:
By testing liquid, reference solution (a), each 20 μ L of reference solution (b) injection liquid chromatography respectively, record color atlas is to more than 1.5 times of atorvastatin retention time respectively,
Peak ownership and relative retention time: in reference solution (a) color atlas, main peak is atorvastatincalcuim peak, for atorvastatincalcuim, relative retention time (RRT) is about 0.8 (test result of the present invention is all in 0.77 ~ 0.83 scope, the retention time of atorvastatincalcuim is within the scope of 42 ~ 46min) chromatographic peak at place is impurity E chromatographic peak, determines retention time and the relative retention time of atorvastatincalcuim and impurity E thus;
System suitability: with reference solution (a) test, the resolution between impurity E and atorvastatin is at least 2.0;
The content of impurity E is calculated by following calculating formula:
According to above-mentioned [HPLC-A] method and [HPLC-B] method, wherein tested " trial-product ", this material both can be take atorvastatincalcuim or its hydrate such as trihydrate as the bulk drug of main composition, can also be added with the pharmaceutical composition of other pharmaceutical excipient with atorvastatincalcuim or its hydrate such as trihydrate for activeconstituents, such as pharmaceutical preparation, such as tablet etc.Thus, the calculating of Impurity A content can not be affected because of the existence of other composition such as pharmaceutical excipient.
In the present invention, the method for mensuration impurity A, impurity B, impurity E content can have many, such as, according to well known to a person skilled in the art the measuring method that mode is determined.Typical method is high performance liquid chromatography.In addition, can be separated by preparative high performance liquid chromatography and obtain various impurity reference substances (such as impurity A, the impurity B that highly purified such as chromatographic purity reaches more than 98%, and the impurity E such as mentioned herein), with this impurity reference substance for contrast, measured the relative content of those impurity in the bulk drug that the present invention comprises atorvastatincalcuim or its hydrate such as trihydrate and the pharmaceutical preparation prepared by them by the known feasible method of those skilled in the art.The impurity that the present invention relates to comprises impurity A, impurity B, impurity E etc., and they are all that prior art is known or prepare by art methods, and can buy from commercial channels.Such as following impurity or atorvastatincalcuim buy from American Pharmacopeia council standard substance providing gear (http://www.usp.org) and use as detection reference substance or biology reagent process of the test of the present invention: impurity A, calcium salt, (3R, 5R)-7-[3-(phenylcarbamoyl)-2-sec.-propyl-4,5-phenylbenzene-1H-pyrroles-1-base]-3,5-dihydroxyl enanthic acid calcium, CAS 433289-83-9, article No. 1044527, lot number H0L181 (it measures according to the present invention [HPLC-A], and chromatographic purity is greater than 99.8%); Impurity B, calcium salt, (3SR, 5RS)-7-[3-(phenylcarbamoyl)-5-(4-fluorophenyl)-2-sec.-propyl-4-phenyl-1H-pyrroles-1-base]-3,5-dihydroxyl enanthic acid calcium, CAS 887196-25-0, article No. 1044538, lot number H0L297 (it measures according to the present invention [HPLC-A], and chromatographic purity is greater than 99.9%); Impurity E, calcium salt, i.e. 3S, 5S-atorvastatincalcuim, CAS 1105067-88-6, article No. 1044571, lot number G0J426 (it measures according to the present invention [HPLC-B], and chromatographic purity is greater than 99.8%); Atorvastatincalcuim reference substance CAS 344423-98-9, article No. 1044516, (its chromatographic purity measured according to the present invention [HPLC-A] is greater than 99.9% to lot number G0J276, the chromatographic purity measured according to the present invention [HPLC-B] is greater than 99.9%, and impurity A, impurity B, impurity E all do not detect).
The typical high performance liquid chromatography of one measuring impurity A and/or impurity B is high performance liquid chromatography A as herein described (can be called for short [HPLC-A] in the present invention), its to can be used for measuring in the various material of the present invention (comprising bulk drug and preparation) various impurity particularly impurity A and/or impurity B in this material relative to the amount of atorvastatincalcuim.Certainly, it will be appreciated by those skilled in the art that analytical procedure is easily improved, anyly available all can be used for the present invention with the method for the various impurity in the potential various material of mensuration the present invention; In view of the content of the various impurity in the various material of the present invention can not change because of improving of analytical procedure, the foreign matter content therefore in the various material of the present invention or the measuring method of relative content can be not particularly limited.Certainly, in the present invention, if not otherwise indicated, particularly the content of impurity A and/or impurity B or the method for relative content are all adopt [HPLC-A] described herein to measure various impurity in various material (comprising bulk drug and preparation).
Measuring the typical high performance liquid chromatography of one of impurity E is high performance liquid chromatography B as herein described (can be called for short [HPLC-B] in the present invention), its to can be used for measuring in the various material of the present invention (comprising bulk drug and preparation) various impurity particularly impurity E in this material relative to the amount of atorvastatincalcuim.Certainly, it will be appreciated by those skilled in the art that analytical procedure is easily improved, anyly available all can be used for the present invention with the method for the various impurity in the potential various material of mensuration the present invention; In view of the content of the various impurity in the various material of the present invention can not change because of improving of analytical procedure, the foreign matter content therefore in the various material of the present invention or the measuring method of relative content can be not particularly limited.Certainly, in the present invention, if not otherwise indicated, particularly the content of impurity E or the method for relative content are all adopt [HPLC-B] described herein to measure various impurity in various material (comprising bulk drug and preparation).
Although the various chemical substances that the present invention relates to, such as atorvastatincalcuim or its hydrate such as trihydrate, impurity A, impurity B, impurity E etc., their chemical structure is known and can directly obtains with commercial sources from the market, but it is as well known to those skilled in the art, these impurity can also come qualitative by the high performance liquid chromatography of regulation or characterize, such as by the high performance liquid chromatography operation of regulation, this impurity is determined by measuring the retention behavior of impurity in this regulation high performance liquid chromatography (i.e. relative retention time, RRT).Particularly, the present invention has been found that, in [HPLC-A] of the present invention system, for atorvastatincalcuim, the relative retention time (usual RRT about 0.80) in 0.77 ~ 0.83 scope of impurity A, thus this impurity A also can be called RRT0.80 impurity, impurity RRT0.80 or RRT0.80 in [HPLC-A] method system by the present invention.Similarly, in [HPLC-A] of the present invention system, for atorvastatincalcuim, the relative retention time (usual RRT about 0.90) in 0.87 ~ 0.93 scope of impurity B, thus this impurity B also can be called RRT0.90 impurity, impurity RRT0.90 or RRT0.90 by the present invention.
And in [HPLC-B] of the present invention method system, for atorvastatincalcuim, the relative retention time (usual RRT about 0.80) in 0.77 ~ 0.83 scope of impurity E, thus this impurity E also can be called RRT0.80 impurity, impurity RRT0.80 or RRT0.80 in [HPLC-B] method system by the present invention.
The implication of relative retention time is well known in the art, such as, the relative retention time (being abbreviated as RRT) of impurity A refers in color atlas, the retention time of impurity A chromatographic peak is divided by the value of the retention time gained of atorvastatincalcuim chromatographic peak, the i.e. RRT=impurity A retention time ÷ atorvastatincalcuim retention time of impurity A, and the relative retention time of atorvastatincalcuim itself is 1 or 1.00, this algorithm well known to a person skilled in the art.
Have been found that along with the prolongation of storage time, impurity E content demonstrates the trend gradually increased for the bulk drug of the present invention comprising atorvastatincalcuim or its hydrate such as trihydrate or the pharmaceutical preparation be made up of them.Particularly when Impurity A content is higher, such as relative to atorvastatincalcuim meter Impurity A content higher than 0.30% (particularly higher than 0.40%, particularly higher than 0.50%, particularly higher than 1.0%) time, show the prolongation along with storage time of bulk drug of the present invention or the pharmaceutical preparation be made up of them, impurity E content demonstrates the trend gradually increased.In the present invention, have been surprisingly found that, the bulk drug of the present invention of atorvastatincalcuim or its hydrate such as trihydrate is comprised by purifying, the impurity A coming from technique wherein comprised is reduced to a certain degree, particularly make Impurity A content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%), such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope) time, these bulk drugs or pharmaceutical preparation gather way at long-time storage rear impurity E content and are significantly suppressed, this is completely beat all.This content can use high effective liquid chromatography for measuring and calculate, and particularly uses [HPLC-A] measure and calculate.
Method according to a first aspect of the present invention, comprise in the bulk drug of the present invention of atorvastatincalcuim obtained by it, impurity B for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%), such as impurity B content (relative to atorvastatincalcuim meter) (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope) in 0.003% ~ 0.500% scope.This content can use high effective liquid chromatography for measuring and calculate, and particularly uses [HPLC-A] measure and calculate.
Method according to a first aspect of the present invention, comprise in the bulk drug of the present invention of atorvastatincalcuim obtained by it, impurity E for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.28%), such as impurity E content (relative to atorvastatincalcuim meter) in 0.002% ~ 0.500% scope (such as in 0.002% ~ 0.400% scope, such as in 0.002% ~ 0.300% scope, such as in 0.002% ~ 0.280% scope).This content can use high effective liquid chromatography for measuring and calculate, and particularly uses [HPLC-B] measure and calculate.
Method according to a first aspect of the present invention, the bulk drug of the present invention comprising atorvastatincalcuim obtained by it measures according to the present invention [HPLC-A], wherein relative retention time (also can be described as the RRT0.80 impurity of [HPLC-A] at the impurity at 0.77 ~ 0.83 place in the present invention or is called RRT0.80, it is essentially impurity A) for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope).
Method according to a first aspect of the present invention, the bulk drug of the present invention comprising atorvastatincalcuim obtained by it measures according to the present invention [HPLC-A], wherein relative retention time (also can be described as the RRT0.90 impurity of [HPLC-A] at the impurity at 0.87 ~ 0.93 place in the present invention or is called RRT0.90, it is essentially impurity B) for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope).
Method according to a first aspect of the present invention, the bulk drug of the present invention comprising atorvastatincalcuim obtained by it measures according to the present invention [HPLC-B], wherein relative retention time (also can be described as the RRT0.80 impurity of [HPLC-B] at the impurity at 0.77 ~ 0.83 place in the present invention or is called RRT0.80, it is essentially impurity E) for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.28%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.002% ~ 0.500% scope (such as in 0.002% ~ 0.400% scope, such as in 0.002% ~ 0.300% scope, such as in 0.002% ~ 0.280% scope).
The present invention finds, make Impurity A content control lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope) time, impurity E in bulk drug of the present invention and the pharmaceutical composition for preparing thereof can be made not have significant increase along with the prolongation of storage time.The discovery of biological significance is had to be that impurity E is the material that a kind of toxicity is such as obviously strong than atorvastatincalcuim to mouse toxicity (with median lethal flow measurement) in the present invention.In the bulk drug of the present invention comprising atorvastatincalcuim that method is according to a first aspect of the present invention obtained in the present invention and the pharmaceutical composition such as pharmaceutical preparation be made up of this bulk drug, impurity E for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.28%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.002% ~ 0.500% scope (such as in 0.002% ~ 0.400% scope, such as in 0.002% ~ 0.300% scope, such as in 0.002% ~ 0.280% scope).
Method according to a first aspect of the present invention, the bulk drug of the present invention comprising atorvastatincalcuim obtained by it places 6 months 40 DEG C of condition lower seals, lucifuges, certain impurity phase after 6 months is disposed in calculating with this understanding increases percentage ratio for content when 0 month, wherein measure impurity (i.e. impurity E) content of relative retention time at 0.77 ~ 0.83 place according to [HPLC-B] and increase percentage ratio lower than 200%, such as lower than 150%, such as lower than 100%, such as lower than 75%, such as lower than 50%, such as, lower than 40%.This test method in the present invention can referred to as investigating 40 DEG C-June.Described term " foreign matter content increase percentage ratio " calculates according to following formula:
In above calculating formula, impurity 0 month content or impurity content in June refer to this impurity relative content relative to atorvastatincalcuim in material.
Further, second aspect present invention provides a kind of bulk drug of hyoscine, and the activeconstituents of this bulk drug is atorvastatincalcuim.
Or further, second aspect present invention provides a kind of bulk drug of hyoscine, the activeconstituents of this bulk drug is with compounds of Formula I:
Or its hydrate such as trihydrate.
That is, in the present invention, atorvastatincalcuim refers to above formula I or its hydrate such as trihydrate.
Bulk drug according to a second aspect of the present invention, comprising as the formula I of main ingredient or its hydrate such as trihydrate, and the optional impurity A as impurity.
Bulk drug according to a second aspect of the present invention, wherein the content of impurity A for atorvastatincalcuim lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%), such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope).
Bulk drug according to a second aspect of the present invention, comprising as the formula I of main ingredient or its hydrate such as trihydrate, and the optional impurity B as impurity.
Bulk drug according to a second aspect of the present invention, wherein impurity B for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%), such as impurity B content (relative to atorvastatincalcuim meter) (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope) in 0.003% ~ 0.500% scope.
Bulk drug according to a second aspect of the present invention, comprising as the formula I of main ingredient or its hydrate such as trihydrate, and the optional impurity E as impurity.
Bulk drug according to a second aspect of the present invention, wherein impurity E for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.28%), such as impurity E content (relative to atorvastatincalcuim meter) in 0.002% ~ 0.500% scope (such as in 0.002% ~ 0.400% scope, such as in 0.002% ~ 0.300% scope, such as in 0.002% ~ 0.280% scope).
Bulk drug according to a second aspect of the present invention, it measures according to the present invention [HPLC-A], wherein relative retention time (also can be described as the RRT0.80 impurity of [HPLC-A] at the impurity at 0.77 ~ 0.83 place in the present invention or is called RRT0.80, it is essentially impurity A) for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope).
Bulk drug according to a second aspect of the present invention, it measures according to the present invention [HPLC-A], wherein relative retention time (also can be described as the RRT0.90 impurity of [HPLC-A] at the impurity at 0.87 ~ 0.93 place in the present invention or is called RRT0.90, it is essentially impurity B) for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope).
Bulk drug according to a second aspect of the present invention, it measures according to the present invention [HPLC-B], wherein relative retention time (also can be described as the RRT0.80 impurity of [HPLC-B] at the impurity at 0.77 ~ 0.83 place in the present invention or is called RRT0.80, it is essentially impurity E) for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.28%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.002% ~ 0.500% scope (such as in 0.002% ~ 0.400% scope, such as in 0.002% ~ 0.300% scope, such as in 0.002% ~ 0.280% scope).
Bulk drug according to a second aspect of the present invention, it places 6 months 40 DEG C of condition lower seals, lucifuges, certain impurity phase after 6 months is disposed in calculating with this understanding increases percentage ratio for content when 0 month, wherein measure impurity (i.e. impurity E) content of relative retention time at 0.77 ~ 0.83 place according to [HPLC-B] and increase percentage ratio lower than 200%, such as lower than 150%, such as, lower than 100%, such as, lower than 75%, such as lower than 50%, such as, lower than 40%.
Bulk drug according to a second aspect of the present invention, it is by carrying out refining obtaining to the raw material comprising atorvastatincalcuim.
Bulk drug according to a second aspect of the present invention, wherein said refining method comprises the following steps:
Step 1: at the temperature of 40 ~ 70 DEG C, makes the material dissolution comprising atorvastatincalcuim of 1 weight part in the methyl alcohol of 10 ~ 50 weight parts, then adds trolamine wherein and makes its concentration in the solution reach 0.1 ~ 1.0%, stir;
Step 2: at temperature described in maintenance step 1, under agitation, slowly add the water of 5 ~ 50 weight parts in step 1 gained solution, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out; According to product purity, the operation of repeating step 1 and step 2 if desired;
Step 3: at the temperature of 50 ~ 60 DEG C, the step 2 gained atorvastatincalcuim product of 1 weight part is made to be dissolved in the methyl alcohol of 15 ~ 40 weight parts, under agitation slowly add the water of 10 ~ 30 weight parts, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, wash with water, then vacuum-drying at the temperature of 50 ~ 55 DEG C, obtain atorvastatin calcium raw material drug.
Bulk drug according to a second aspect of the present invention, in wherein said refining method, in step 1, described temperature is the temperature within the scope of 45 ~ 65 DEG C, such as, be the temperature within the scope of 50 ~ 60 DEG C.
Bulk drug according to a second aspect of the present invention, in wherein said refining method, in step 1, make the atorvastatincalcuim of 1 weight part be dissolved in the methyl alcohol of 15 ~ 45 weight parts, such as, make the atorvastatincalcuim of 1 weight part be dissolved in the methyl alcohol of 15 ~ 40 weight parts.
Bulk drug according to a second aspect of the present invention, in wherein said refining method, in step 1, adds trolamine and makes its concentration in the solution reach 0.2 ~ 0.8%, such as, add trolamine and make its concentration in the solution reach 0.2 ~ 0.6%.
Bulk drug according to a second aspect of the present invention, in wherein said refining method, in step 2, slowly adds the water of 10 ~ 40 weight parts, such as, in step 1 gained solution, slowly adds the water of 10 ~ 30 weight parts in step 1 gained solution.
Further, third aspect present invention provides a kind of pharmaceutical composition (such as pharmaceutical preparation), wherein comprises the bulk drug described in any one of second aspect present invention, and optional pharmaceutically acceptable carrier or auxiliary material.In one embodiment, pharmaceutical composition of the present invention uses the bulk drug described in any one of second aspect present invention to prepare through pharmaceutical composition (such as pharmaceutical preparation) preparation technology.
Pharmaceutical composition according to a third aspect of the present invention, it is oral preparations or injection formulations.
Pharmaceutical composition according to a third aspect of the present invention, it is tablet, capsule, granule, injection (comprising injection liquid and lyophilize powder injection), suspensoid, pill.
Pharmaceutical composition according to a third aspect of the present invention, it is tablet.
Pharmaceutical composition according to a third aspect of the present invention, it is tablet, wherein comprises atorvastatincalcuim or its hydrate such as trihydrate and be selected from following auxiliary material: calcium carbonate, croscarmellose sodium, hydroxypropylcellulose, Spherolac 100, Magnesium Stearate, Celluloasun Microcrystallisatum.These auxiliary materials add in described tablet with its conventional amount used.
Pharmaceutical composition according to a third aspect of the present invention, it is tablet, wherein comprises atorvastatincalcuim or its hydrate such as trihydrate and be selected from following auxiliary material: calcium carbonate, croscarmellose sodium, hydroxypropylcellulose, Spherolac 100, Magnesium Stearate, Celluloasun Microcrystallisatum, tween 80.These auxiliary materials add in described tablet with its conventional amount used.
Pharmaceutical composition according to a third aspect of the present invention, it is tablet, wherein comprises atorvastatincalcuim or its hydrate such as trihydrate and be selected from following auxiliary material: calcium carbonate, croscarmellose sodium, hydroxypropylcellulose, Spherolac 100, Magnesium Stearate, Celluloasun Microcrystallisatum, tween 80, Simethicone.These auxiliary materials add in described tablet with its conventional amount used.Such as calcium carbonate can be 10 ~ 80% of composition total weight as the addition of weighting agent, hydroxypropylcellulose can be 10 ~ 80% of composition total weight as the addition of weighting agent, Spherolac 100 can be 10 ~ 80% of composition total weight as the addition of weighting agent, Celluloasun Microcrystallisatum can be 10 ~ 80% of composition total weight as the addition of weighting agent, croscarmellose sodium can be 2 ~ 30% of composition total weight as the addition of disintegrating agent, Magnesium Stearate can be 0.5 ~ 5% of composition total weight as the addition of lubricant, the addition of tween 80 can be 0.2 ~ 5% of composition total weight, the addition of Simethicone can be 0.2 ~ 5% of composition total weight.The present invention provides in fact a kind of atorvastatin calcium raw material drug with premium properties and the pharmaceutical composition prepared by it, and the preparation method of pharmaceutical composition such as tablet well known to a person skilled in the art, the various auxiliary material therefore in the present composition and proportioning thereof can not be particularly limited.
Pharmaceutical composition according to a third aspect of the present invention, it is tablet, and the amount wherein comprising atorvastatincalcuim or its hydrate such as trihydrate in each tablet is 2 ~ 100mg, such as 3 ~ 100mg, such as 3 ~ 50mg.In one embodiment, the total tablet of described tablet is heavily 50 ~ 500mg, and such as total tablet is heavily 60 ~ 300mg.
Pharmaceutical composition according to a third aspect of the present invention, account for 3 ~ 30% of composition total weight as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, pharmaceutically acceptable carrier or auxiliary material account for 70 ~ 97% of composition total weight.
Pharmaceutical composition according to a third aspect of the present invention, comprising as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, and the optional impurity A as impurity.
Pharmaceutical composition according to a third aspect of the present invention, wherein the content of impurity A for atorvastatincalcuim is lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope).
Pharmaceutical composition according to a third aspect of the present invention, comprising as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, and the optional impurity B as impurity.
Pharmaceutical composition according to a third aspect of the present invention, wherein impurity B for atorvastatincalcuim content lower than 1.00% (such as lower than 0.80%, lower than 0.60%, lower than 0.50%), such as impurity B content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.800% scope, such as in 0.003% ~ 0.600% scope, such as in 0.003% ~ 0.500% scope).
Pharmaceutical composition according to a third aspect of the present invention, comprising as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, and the optional impurity E as impurity.
Pharmaceutical composition according to a third aspect of the present invention, wherein impurity E for atorvastatincalcuim content lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as impurity E content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope).
Pharmaceutical composition according to a third aspect of the present invention, it measures according to the present invention [HPLC-A], wherein relative retention time (also can be described as the RRT0.80 impurity of [HPLC-A] at the impurity at 0.77 ~ 0.83 place in the present invention or is called RRT0.80, it is essentially impurity A) for atorvastatincalcuim content lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope).
Pharmaceutical composition according to a third aspect of the present invention, it measures according to the present invention [HPLC-A], wherein relative retention time (also can be described as the RRT0.90 impurity of [HPLC-A] at the impurity at 0.87 ~ 0.93 place in the present invention or is called RRT0.90, it is essentially impurity B) for atorvastatincalcuim content lower than 1.00% (such as lower than 0.80%, lower than 0.60%, lower than 0.50%), such as impurity B content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.800% scope, such as in 0.003% ~ 0.600% scope, such as in 0.003% ~ 0.500% scope).
Pharmaceutical composition according to a third aspect of the present invention, it measures according to the present invention [HPLC-B], wherein relative retention time (also can be described as the RRT0.80 impurity of [HPLC-B] at the impurity at 0.77 ~ 0.83 place in the present invention or is called RRT0.80, it is essentially impurity E) for atorvastatincalcuim content lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as impurity E content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope).
Pharmaceutical composition according to a third aspect of the present invention, it places 5 months 40 DEG C of condition lower seals, lucifuges, certain impurity phase after 5 months is disposed in calculating with this understanding increases percentage ratio for content when 0 month, wherein measure impurity (i.e. impurity E) content of relative retention time at 0.77 ~ 0.83 place according to [HPLC-B] and increase percentage ratio lower than 200%, such as lower than 150%, such as, lower than 100%, such as, lower than 75%, such as lower than 50%, such as, lower than 40%.This test method in the present invention can referred to as investigating 40 DEG C-May.
Further, fourth aspect present invention provides the purposes of pharmaceutical composition described in bulk drug described in bulk drug that method described in first aspect present invention prepares, second aspect or the third aspect in the medicine of preparation treatment or prevention hypercholesterolemia or coronary heart disease.
Purposes according to a fourth aspect of the present invention, wherein said hypercholesterolemia includes but not limited to: primary hypercholesterolemia, familial hypercholesterolemia, combined hyperlipidemia, Fredrickson classification IIa hyperlipidaemia and Fredrickson classification IIb type hyperlipidaemia.
Purposes according to a fourth aspect of the present invention, wherein said hypercholesterolemia includes but not limited to following symptoms: total cholesterol raises, low density lipoprotein cholesterol raises, apolipoprotein B raises and triglyceride level raises.
Purposes according to a fourth aspect of the present invention, wherein said coronary heart disease includes but not limited to: danger disease such as coronary heart disease itself, coronary heart disease (as: diabetes, symptomatic atherosclerotic disease etc.) merge hypercholesterolemia or mixed dyslipidemia.
Purposes according to a fourth aspect of the present invention, wherein said treatment or prevention coronary heart disease include but not limited to: reduce the risk of non-fatal myocardial infarction, reduce the risk of lethality and non-lethality palsy, reduce the risk of reconstructive vascular operation, reduce be in hospital because of congestive heart failure risk, reduce anginal risk.
According to either side of the present invention, the content that in wherein said Medicinal crude drug, atorvastatincalcuim calculates with anhydride is greater than 98.0%, such as, in 98.0 ~ 102.0% scopes.This content can to use atorvastatincalcuim reference substance as reference, and use the method for the present invention [HPLC-A], external standard method routinely tests the content of wherein atorvastatincalcuim with peak area.In addition, the atorvastatincalcuim comprised in the pharmaceutical composition of bulk drug of the present invention also can be measured in the same method.
According to either side of the present invention, the chromatographic purity that wherein said Medicinal crude drug measures according to the present invention [HPLC-A] in 98.00% ~ 99.99% scope, such as, in 98.50% ~ 99.99% scope, such as, in 99.00% ~ 99.99% scope.Term " chromatographic purity " is the result of trial-product color atlas being carried out to area normalization method calculating, and deduction solvent, auxiliary material isochromatic spectrum peak and the result that obtains, it is different from content mentioned above.
According to either side of the present invention, the chromatographic purity that wherein said Medicinal crude drug measures according to the present invention [HPLC-B] in 98.00% ~ 99.99% scope, such as, in 98.50% ~ 99.99% scope, such as, in 99.00% ~ 99.99% scope.
Arbitrary embodiment of either side of the present invention, can combine, as long as they there will not be contradiction with other arbitrary embodiment of either side.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
In the present invention, the implication of " % " can be determined according to concrete environment for use, and particularly it has as implication as described in Article 28 (4) money under " metering " item in version Chinese Pharmacopoeia in 2010 two notes on the use.
In the present invention, when mentioning separately, " ethanol " refers to dehydrated alcohol.
In the present invention, each carbon atom of atorvastatincalcuim can number indicate as follows:
namely atorvastatincalcuim represents (3R, 5R)-atorvastatincalcuim.
Also document is had to indicate the numbering of each carbon atom in the following manner:
i.e. (β R, δ R)-atorvastatincalcuim.
In the present invention, although the particular chemical of RRT0.80 and RRT0.90 of the present inventor in clear [HPLC-A] system and RRT0.80 tri-specific impurities in [HPLC-B] system, but these impurity also carry out qualitative characterization by it in [HPLC-A] and [HPLC-B] of specific, concrete of the present invention, and the RRT parameter presented under being especially for use in specific HPLC condition characterizes.As well known to those skilled in the art, RRT can be completely independently used to characterize and its particular chemical need not be considered completely, reason is that RRT is the parameter of a substantially constant under regulation HPLC condition, and namely RRT characterizes and can use separate or in combination with one another with structural characterization.And this characterizing method is pharmaceutical field allowed bulk drug or preparation quality standard, possesses industrial applicability completely.
In the present invention, if not otherwise indicated, when determining the content of atorvastatincalcuim or other impurity in various material (such as various as pharmaceutical preparation bulk drug, pharmaceutical composition such as pharmaceutical preparation etc.), and when determining the chromatographic purity of these materials, can all adopt the method for [HPLC-A] mentioned above and [HPLC-B] to measure.
" pharmaceutically acceptable carrier " that use in pharmaceutical composition of the present invention can be the carrier of any routine in field of pharmaceutical preparations.The selection of specific support will depend on the administering mode or disease type and state that are used for the treatment of particular patient.For the preparation method of the said synthetic processes of specific administration pattern completely in the ken of pharmaceutical field technician.Such as, the thinner of pharmaceutical field routine, carrier, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and lubricant etc. can be comprised as pharmaceutically acceptable carrier.If desired, flavouring agent, preservative and sweetener etc. can also be added in pharmaceutical composition.
Pharmaceutical composition of the present invention can make the various ways such as tablet, pulvis, granule, capsule, oral liquid, paste, creme, injectable emulsion (aseptic powder needle for injection).The medicine of above-mentioned various formulation all can be prepared according to the ordinary method of pharmaceutical field.
The atorvastatincalcuim medicament (such as tablet etc.) of now list marketing, it is as a kind of hypolipidemic, can be used for treatment or prevents hypercholesterolemia or coronary heart disease.The invention provides a kind of new atorvastatin calcium raw material drug, it has excellent feature in such as stability in certain or some pharmacy, and/or demonstrate good biological safety, therefore material medicine of the present invention can be used for treatment or prevention hypercholesterolemia or coronary heart disease equally and expects to have low rate of side effects.
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.
embodiment 1: prepare atorvastatin calcium raw material drug
Step 1: synthesis atorvastatincalcuim
Embodiment 1 according to US4681893 has prepared the lactone compound comprising pyranoid ring, and the method then according to the embodiment 10 of US5273995 first forms sodium salt from above-mentioned lactone compound, and then this sodium salt and calcium chloride react and generates atorvastatincalcuim;
Measure each foreign matter content in products therefrom: impurity A=2.73%, impurity B=1.48%, impurity E=2.14%.
Step 2: at the temperature of 55 DEG C, makes the step 0 gained atorvastatincalcuim of 1 weight part be dissolved in the methyl alcohol of 25 weight parts, then adds trolamine wherein and makes its concentration in the solution reach 0.4%, stir; Under maintenance said temperature, under agitation, in gained mixed solution, slowly add the water of 20 weight parts, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, vacuum-drying at the temperature of 55 DEG C; Measure each foreign matter content in products therefrom: impurity A=0.38%, impurity B=0.44%, impurity E=0.34%.
Step 2a: at the temperature of 50 DEG C, makes the step 0 gained atorvastatincalcuim of 1 weight part be dissolved in the methyl alcohol of 40 weight parts, then adds trolamine wherein and makes its concentration in the solution reach 0.2%, stir; Under maintenance said temperature, under agitation, in gained mixed solution, slowly add the water of 10 weight parts, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, vacuum-drying at the temperature of 55 DEG C; Measure each foreign matter content in products therefrom: impurity A=0.046%, impurity B=0.141%, impurity E=0.061%.
Step 2b: at the temperature of 60 DEG C, makes the step 0 gained atorvastatincalcuim of 1 weight part be dissolved in the methyl alcohol of 15 weight parts, then adds trolamine wherein and makes its concentration in the solution reach 0.6%, stir; Under maintenance said temperature, under agitation, the water of 30 weight parts is slowly added in gained mixed solution, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, at the temperature of 55 DEG C, vacuum-drying measures each foreign matter content in products therefrom: impurity A=0.007%, impurity B=0.039%, impurity E=0.009%.
Step 2c: with step 2b products therefrom for initiator, repeating step 2 operates and again carries out purification process; Measure each foreign matter content in products therefrom: impurity A=0.001%, impurity B=0.012%, impurity E=0.001%.
Above, step 2 and step 2a, step 2b, step 2c, these use the purification step of trolamine, purifying each time, for impurity A, reduction amplitude reaches the degree of about 84 ~ 88%, for impurity B, reduction amplitude reaches the degree of about 67 ~ 82%, and for impurity E, reduction amplitude reaches the degree of about 81 ~ 86%.
Above step 2a, step 2b or step 2c products therefrom detect through vapor-phase chromatography, wherein containing the trolamine lower than 20ppm.
Step 3: at the temperature of 55 DEG C, the step 2a of 1 weight part, step 2b or step 2c gained atorvastatincalcuim product is made to be dissolved in the methyl alcohol of 25 weight parts, under agitation slowly add the water of 20 weight parts, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, wash with water, then vacuum-drying at the temperature of 55 DEG C, obtain atorvastatin calcium raw material drug three batches, be respectively Ex1S3a, Ex1S3b, Ex1S3c three.Detect through vapor-phase chromatography, in three batch samples, trolamine content is lower than detectability (<0.02ppm).In view of trolamine is a kind of conventional pharmaceutical excipient and its toxicity is lower, even if the concentration reaching 20ppm is also acceptable as the atorvastatincalcuim of Medicinal crude drug.Therefore in fact, step 2a, step 2b or step 2c gained three batches of atorvastatincalcuims, and step 3 gained three batches of atorvastatincalcuims all can as Medicinal crude drug.
In addition, in step 3, do not use trolamine to carry out purifying when carrying out purifying, gained three crowdes of products Ex1a, Ex1b, Ex1c, measure each foreign matter content in each product of gained:
Ex1S3a criticizes: impurity A=0.031%, impurity B=0.079%, impurity E=0.043%;
Ex1S3b criticizes: impurity A=0.005%, impurity B=0.023%, impurity E=0.006%;
Ex1S3c criticizes: impurity A <0.001%, impurity B=0.007%, impurity E <0.001%.
Above, in step 3, step 2a, step 2b, step 2c gained three batches of products are further purified (but not adding trolamine), in this purifying, for impurity A, reduction amplitude reaches the degree of about 30 ~ 33%, for impurity B, reduction amplitude reaches the degree of about 40 ~ 44%, and for impurity E, reduction amplitude reaches the degree of about 28 ~ 33%.When showing not add trolamine to the reduction amplitude of various impurity significantly lower than reduction amplitude when adding trolamine.
Above step 2a, step 2b or step 2c products therefrom, and step 3 gained Ex1S3a, Ex1S3b, Ex1S3c tri-batches of products, they are all the atorvastatincalcuim trihydrates with molecular formula C66H68CaF2N4O103H2O after measured.
embodiment 2: prepare atorvastatin calcium raw material drug
Step 1: synthesis atorvastatincalcuim
According to the method in CN100484920C (China Patent No. ZL200510060396.X, new Donggang City) embodiment 1, prepare atorvastatincalcuim raw material.Its method through the present invention [HPLC-A] and [HPLC-B] measures each foreign matter content in products therefrom: impurity A=0.51%, impurity B=0.27%, impurity E=0.39%.[this result is different from the contained result of CN100484920C, may HPLC method different such as chromatographic separation effect, determined wavelength etc. are different cause].This batch of atorvastatincalcuim because of impurity A, impurity E content is higher should not as Medicinal crude drug.
Step 2: above step 1 gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 2 once, measures each foreign matter content in products therefrom: impurity A=0.071%, impurity B=0.084%, impurity E=0.062%.This batch of atorvastatincalcuim can as Medicinal crude drug.
Step 3: above step 2 gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 3 once, measures each foreign matter content in products therefrom: impurity A=0.050%, impurity B=0.048%, impurity E=0.043%.This batch of atorvastatincalcuim can as Medicinal crude drug.
embodiment 3: prepare atorvastatin calcium raw material drug
Step 1: synthesis atorvastatincalcuim
According to the method in CN101560177A (Chinese Patent Application No. 200810104156.9, perfectly sound) embodiment 5, prepare atorvastatincalcuim raw material.Its method through the present invention [HPLC-A] and [HPLC-B] measures each foreign matter content in products therefrom: impurity A=1.86%, impurity B=1.04%, impurity E=1.76%.
Step 2: above step 1 gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 2 once, measures each foreign matter content in products therefrom: impurity A=0.259%, impurity B=0.291%, impurity E=0.277%.This batch of atorvastatincalcuim can as Medicinal crude drug.
Step 2a: above step 2 gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 2 once, measures each foreign matter content in products therefrom: impurity A=0.045%, impurity B=0.090%, impurity E=0.048%.This batch of atorvastatincalcuim can as Medicinal crude drug.
Step 3: above step 2 gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 3 once, measures each foreign matter content in products therefrom: impurity A=0.193%, impurity B=0.166%, impurity E=0.196%.This batch of atorvastatincalcuim can as Medicinal crude drug.
embodiment 4: prepare atorvastatin calcium raw material drug
Step 1: synthesis atorvastatincalcuim
To the method for [0106] section, atorvastatincalcuim raw material is prepared according to CN101805279A (Chinese Patent Application No. 201010100932.5, the people's livelihood) it [0034].Its method through the present invention [HPLC-A] and [HPLC-B] measures each foreign matter content in products therefrom: impurity A=0.907%, impurity B=0.114%, impurity E=0.469%.This batch of atorvastatincalcuim should not as Medicinal crude drug.
Step 2: above step 1 gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 2 once, measures each foreign matter content in products therefrom: impurity A=0.136%, impurity B=0.034%, impurity E=0.075%.This batch of atorvastatincalcuim can as Medicinal crude drug.
Step 2a: above step 2 gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 2 once, measures each foreign matter content in products therefrom: impurity A=0.019%, impurity B=0.010%, impurity E=0.012%.This batch of atorvastatincalcuim can as Medicinal crude drug.
Step 2b: above step 2a gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 2 once, measures each foreign matter content in products therefrom: impurity A=0.003%, impurity B=0.003%, impurity E=0.002%.This batch of atorvastatincalcuim can as Medicinal crude drug.
Step 3: above step 2a gained atorvastatincalcuim is shone the method process of the embodiment of the present invention 1 step 3 once, measures each foreign matter content in products therefrom: impurity A=0.013%, impurity B=0.006%, impurity E=0.008%.This batch of atorvastatincalcuim can as Medicinal crude drug.
To when each batch of sample is tested above, in [HPLC-A] method, the relative retention time of RRT0.80 impurity and impurity A is all in 0.77 ~ 0.83 scope, the relative retention time of RRT0.90 impurity and impurity B is all in 0.87 ~ 0.93 scope, and atorvastatincalcuim retention time is all in 32 ~ 34min; In [HPLC-B] method, the relative retention time of RRT0.80 impurity and impurity E is all in 0.77 ~ 0.83 scope, and atorvastatincalcuim retention time is all within the scope of 42 ~ 46min.
comparing embodiment 1: with reference to the operation of herein embodiment 1 step 2, different only wherein trolamine is replaced with equivalent: triethylamine, diethanolamine, Monoethanolamine MEA BASF, diisopropanolamine (DIPA), methyl alcohol, obtained 5 batches of products.Calculate these 5 batches of products and reduce degree through this purifying rear impurity A, impurity B, impurity E three content, the content of result impurity A reduces degree all in 25 ~ 46% scopes, the content of impurity B reduces degree all in 22 ~ 41% scopes, the content of impurity E reduces degree all in 29 ~ 49% scopes, and the degree more than content reduction at least 68% during use trolamine of the present invention is low.
comparing embodiment 2: with reference to the operation of herein embodiment 1 step 2, different is only by wherein trolamine consumption changes into and makes its concentration in the solution reach 0.05%, 0.1%, 0.85%, 1.2%, 2.5%, obtained 4 batches of products.Calculate these 4 batches of products and reduce degree through this purifying rear impurity content, the content of result impurity A reduces degree all in 17 ~ 36% scopes, the content of impurity B reduces degree all in 20 ~ 35% scopes, the content of impurity E reduces degree all in 13 ~ 32% scopes, and the degree more than content reduction at least 68% during use trolamine of the present invention is low.
test example 1: the study on the stability of bulk drug
Get the atorvastatincalcuim material of above each batch of embodiment 1 ~ embodiment 4 gained, and criticize atorvastatincalcuim by embodiment 1 step 3Ex1c and mix (with a little dissolve with methanol with impurity A, impurity B and/or impurity E with certain proportion, vacuum-drying immediately fully mixes to make them, measure wherein impurity A, impurity B and/or impurity E relative to the content of atorvastatincalcuim) make assembly thing.
These materials are sealed, places 6 months 40 DEG C of condition lower seals, lucifuges, calculate and dispose certain impurity phase after 6 months with this understanding percentage ratio is increased for the content of this impurity 0 month time.
Found that, in various content situation, impurity A and impurity B increased percentage ratio all lower than 45% relative to its content 0 month time 6 months time.Such as, impurity A in embodiment 1 step 1 sample, being 2.73% 0 month time, is 3.58% when June, and it is 31% [algorithm: (3.58%-2.73%)/2.73% × 100%=31%, lower same] that Impurity A content increases percentage ratio.Impurity B again in such as embodiment 1 step 2 sample, being 0.44% 0 month time, is 0.56% when June, and it is 27% that impurity B content increases percentage ratio.
But for impurity E, it increases percentage ratio at the content of high-temperature treatment after 6 months and but shows relevant with Impurity A content in sample: when Impurity A content lower than 0.260% time, impurity E content increases percentage ratio all lower than 43%; But when Impurity A content is greater than 0.330%, impurity E content increases percentage ratio display and is increased to more than 95%, and in sample, Impurity A content higher then impurity E content increase percentage ratio is larger.Such as, impurity A=0.38% in embodiment 1 step 2 sample, this sample June rear impurity E be increased to 0.76% by original 0.34%, impurity E content increase percentage ratio reach 124%; And impurity A=0.046% in embodiment 1 step 2a sample, this sample June rear impurity E be increased to 0.077% by original 0.061%, impurity E content increase percentage ratio be only 26%.Concrete outcome is in table 1, table 2, table 3.
Table 1: the study on the stability result of the atorvastatincalcuim that each test is obtained
No. Sample (source or assembly thing) Feature (0 month impurity A, B, E content, %) June, E increased percentage ratio
1 Ex1S1 A＝2.73、B＝1.48、E＝2.14 >400％
2 Ex1S2 A＝0.38、B＝0.44、E＝0.34 124％
3 Ex1S2a A＝0.046、B＝0.141、E＝0.061 26％
4 Ex1S2b A＝0.007、B＝0.039、E＝0.009 19％
5 Ex1S2c A＝0.001、B＝0.012、E＝0.001 23％
6 Ex1S3a A＝0.031、B＝0.079、E＝0.043 34％
7 Ex1S3b A＝0.005、B＝0.023、E＝0.006 28％
8 Ex1S3c A<0.001、B＝0.007、E<0.001 36％
9 Ex2S1 A＝0.51、B＝0.27、E＝0.39 218％
10 Ex2S2 A＝0.071、B＝0.084、E＝0.062 38％
11 Ex2S3 A＝0.050、B＝0.048、E＝0.043 34％
12 Ex3S1 A＝1.86、B＝1.04、E＝1.76 375％
13 Ex3S2 A＝0.259、B＝0.291、E＝0.277 42％
14 Ex3S2a A＝0.045、B＝0.090、E＝0.048 31％
15 Ex3S3 A＝0.193、B＝0.166、E＝0.196 27％
16 Ex4S1 A＝0.907、B＝0.114、E＝0.469 284％
17 Ex4S2 A＝0.136、B＝0.034、E＝0.075 32％
18 Ex4S2a A＝0.019、B＝0.010、E＝0.012 38％
19 Ex4S2b A＝0.003、B＝0.003、E＝0.002 31％
20 Ex4S3 A＝0.013、B＝0.006、E＝0.008 27％
In above table 1, secondary series Ex1S1 represents the embodiment of the present invention 1 step 1 products therefrom, this product is as sample, wherein each impurity phase is listed in the 3rd row " feature (0 month impurity A, B, E content; %) " for the content of atorvastatincalcuim, is specially A=2.73, B=1.48, E=2.14, represents in this material, relative to the content of atorvastatincalcuim, impurity A=2.73%, impurity B=1.48%, impurity E=2.14%.Other statement all has similar meaning.
Table 2: the study on the stability result of the atorvastatincalcuim of assembly
No. Sample (source or assembly thing) Feature (0 month impurity A, B, E content, %) June, E increased percentage ratio
1 Ex4S2b A＝0.003、B＝0.003、E＝0.002 31％
2 Ex4S2b+A A＝0.053、B＝0.003、E＝0.002 19％
3 Ex4S2b+A A＝0.103、B＝0.003、E＝0.002 24％
4 Ex4S2b+A A＝0.153、B＝0.003、E＝0.002 27％
5 Ex4S2b+A A＝0.205、B＝0.003、E＝0.002 18％
6 Ex4S2b+A A＝0.255、B＝0.003、E＝0.002 31％
7 Ex4S2b+A A＝0.263、B＝0.003、E＝0.002 42％
8 Ex4S2b+A A＝0.303、B＝0.003、E＝0.002 51％
9 Ex4S2b+A A＝0.331、B＝0.003、E＝0.002 96％
10 Ex4S2b+A A＝0.375、B＝0.003、E＝0.002 119％
11 Ex4S2b+A A＝0.402、B＝0.003、E＝0.002 186％
12 Ex4S2b+A A＝0.503、B＝0.003、E＝0.002 224％
13 Ex4S2b+A A＝0.753、B＝0.003、E＝0.002 258％
14 Ex4S2b+A A＝1.251、B＝0.003、E＝0.002 >300％
15 Ex4S2b+A A＝2.015、B＝0.003、E＝0.002 >400％
16 Ex4S2b+A A＝3.003、B＝0.003、E＝0.002 >500％
17 Ex4S2b+A A＝5.002、B＝0.003、E＝0.002 >500％
In above table 2, secondary series Ex4S2b+A represents that the embodiment of the present invention 4 step 2b products therefrom and impurity A carry out assembly, in assembly thing, each impurity phase is listed in the 3rd row " feature (0 month impurity A, B, E content; %) " for the content of atorvastatincalcuim, and other statement all has similar meaning.
Table 3: the study on the stability result of the atorvastatincalcuim of assembly
No. Sample (source or assembly thing) Feature (0 month impurity A, B, E content, %) June, E increased percentage ratio
1 Ex4S2 A＝0.136、B＝0.034、E＝0.075 32％
2 Ex4S2+A A＝0.205、B＝0.034、E＝0.075 27％
3 Ex4S2+A A＝0.255、B＝0.034、E＝0.075 22％
4 Ex4S2+A A＝0.335、B＝0.034、E＝0.075 101％
5 Ex4S2+A A＝0.405、B＝0.034、E＝0.075 183％
6 Ex4S2+A A＝0.552、B＝0.034、E＝0.075 238％
7 Ex4S2+A A＝0.725、B＝0.034、E＝0.075 287％
8 Ex4S2+A A＝1.250、B＝0.034、E＝0.075 >300％
9 Ex4S2+A A＝2.050、B＝0.034、E＝0.075 >400％
10 Ex4S2+A A＝3.510、B＝0.034、E＝0.075 >500％
11 Ex4S2+A A＝5.050、B＝0.034、E＝0.075 >500％
In above table 3, secondary series Ex4S2+A represents that the embodiment of the present invention 4 step 2 products therefrom and impurity A carry out assembly, in assembly thing, each impurity phase is listed in the 3rd row " feature (0 month impurity A, B, E content; %) " for the content of atorvastatincalcuim, and other statement all has similar meaning.
Table 4: the study on the stability result of the atorvastatincalcuim of assembly
No. Sample (source or assembly thing) Feature (0 month impurity A, B, E content, %) June, E increased percentage ratio
1 Ex4S3 A＝0.013、B＝0.006、E＝0.008 27％
2 Ex4S3+E A＝0.013、B＝0.006、E＝0.250 34％
3 Ex4S3+A+E A＝0.113、B＝0.006、E＝0.250 23％
4 Ex4S3+A+E A＝0.205、B＝0.006、E＝0.250 29％
5 Ex4S3+A+E A＝0.263、B＝0.006、E＝0.250 33％
6 Ex4S3+A+E A＝0.332、B＝0.006、E＝0.250 97％
7 Ex4S3+A+E A＝0.403、B＝0.006、E＝0.250 164％
8 Ex4S3+A+E A＝0.552、B＝0.006、E＝0.250 216％
9 Ex4S3+A+E A＝0.750、B＝0.006、E＝0.250 279％
10 Ex4S3+A+E A＝1.015、B＝0.006、E＝0.250 >300％
11 Ex4S3+A+E A＝1.525、B＝0.006、E＝0.250 >400％
In above table 4, secondary series Ex4S3+A+E represents the embodiment of the present invention 4 step 3 products therefrom and impurity A and/or impurity E assembly, in assembly thing, each impurity phase is listed in the 3rd row " feature (0 month impurity A, B, E content; %) " for the content of atorvastatincalcuim, and other statement all has similar meaning.In table, result is visible, even if the appropriate impurity E amount to 0.250% increased in sample body, it is still relevant with the impurity A in sample that its content increases trend.
In addition, with reference to the assembly thing of above table 4, for the amount of atorvastatincalcuim, reach 0.5% unlike adding certain amount of impurity B in each sample more in the composition to it.Obtain 11 assembly things and carry out 40 DEG C of disposal in 6 months equally, result impurity A and impurity B increased percentage ratio all lower than 35% relative to its content 0 month time 6 months time.Such as, but impurity E increased percentage ratio substantially identical with the assembly thing result of Impurity A content corresponding in table 4 (being all no more than 6 percentage points) relative to its content 0 month time 6 months time, and it is 167% that the Iz of corresponding to the sample of table 4 numbering 7 assembly thing increases percentage ratio.
After tested, the sample that wherein Impurity A content is minimum is 0.003% to the atorvastatincalcuim that can be used as bulk drug that these are prepared above, and the sample that impurity B content is minimum is 0.003%, and the sample that impurity E content is minimum is 0.002%.Obviously, with regard to bulk drug of the present invention, wherein impurity A for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%) be useful, such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope) be useful.After tested the above-mentioned atorvastatincalcuim that can be used as bulk drug for their impurity As for atorvastatincalcuim content lower than the sample equaling 0.26%, their impurity B for atorvastatincalcuim content all lower than 0.3%, their impurity E for atorvastatincalcuim content all lower than 0.28%.---namely for can be used as atorvastatin calcium raw material drug of the present invention, as one embodiment of the invention, in atorvastatin calcium raw material drug of the present invention, impurity A for atorvastatincalcuim content lower than 0.26% (being such as 0.003% ~ 0.260%), impurity B for atorvastatincalcuim content in 0.003% ~ 0.300% scope, content is in 0.002% ~ 0.280% scope for atorvastatincalcuim for impurity E, and the atorvastatin calcium raw material drug with these features is that the present invention is preferred.
composition example 1:
Use the embodiment of the present invention 1 step 1 gained atorvastatincalcuim as bulk drug, tablet (amount shown below is every sheet amount, and during preparation, every batch quantity is 10000) is prepared: atorvastatincalcuim 10mg, calcium carbonate 20mg, croscarmellose sodium 5mg, hydroxypropylcellulose 15mg, Spherolac 100 20mg, Magnesium Stearate 1mg, Celluloasun Microcrystallisatum 10mg, 0.2mg tween 80, Simethicone 1mg by following formula.Method for making: tween 80 and a little 85% dissolve with ethanol of Simethicone, this solution is evenly sprayed in the mixed powder of atorvastatincalcuim and calcium carbonate, then hydroxypropylcellulose, Spherolac 100 and Celluloasun Microcrystallisatum is added, mix, with 75% ethanol softwood, granulate, dry, dry particle mixes with rest materials, and compressing tablet to obtain final product.
In addition, with reference to the above-mentioned method preparing tablet, unlike part material sample bulk drug wherein used instead respectively in table 1 to table 4 above, obtain many batches of tablet samples, list in in following table 5.
These tablets are sealed in aluminum-plastic composite membrane bag and (impact of illumination, air, moisture can be avoided), these tablets are placed in 40 DEG C to place 5 months, calculate and dispose certain impurity phase after 5 months with this understanding percentage ratio is increased for the content of this impurity 0 month time.
Found that, in various content situation, impurity A and impurity B increased percentage ratio all lower than 54% relative to its content 0 month time 5 months time.Be such as the tablet of raw material for embodiment 1 step 2a products therefrom, impurity A was 0.048% 0 month time, was 0.066% when June, and it is 38% that Impurity A content increases percentage ratio; Impurity B was 0.140% 0 month time, was 0.169% when June, and it is 21% that impurity B content increases percentage ratio.
But for impurity E, it increases percentage ratio at the content of high-temperature treatment after 5 months and but shows relevant with Impurity A content in sample: when Impurity A content lower than 0.500% time, impurity E content increases percentage ratio all lower than 47%; But when Impurity A content is greater than 0.600%, impurity E content increases percentage ratio display and is increased to more than 95%, and in sample, Impurity A content higher then impurity E content increase percentage ratio is larger.Concrete outcome is in table 5.
Table 5
Sheet No. Raw material (source or assembly thing) Tablet characteristics (0 month impurity A, B, E content, %) May, E increased percentage ratio
1 Ex1S1 A＝2.70、B＝1.53、E＝2.18 >350％
2 Ex1S2 A＝0.39、B＝0.48、E＝0.33 41％
3 Ex1S2a A＝0.048、B＝0.140、E＝0.062 22％
4 Ex1S2b A＝0.009、B＝0.036、E＝0.010 15％
5 Ex1S3a A＝0.034、B＝0.073、E＝0.045 31％
6 Ex2S1 A＝0.500、B＝0.281、E＝0.442 43％
7 Ex2S2 A＝0.070、B＝0.086、E＝0.061 34％
8 Ex3S1 A＝1.81、B＝1.08、E＝1.79 305％
9 Ex3S2 A＝0.263、B＝0.290、E＝0.274 37％
10 Ex3S2a A＝0.047、B＝0.091、E＝0.043 21％
11 Ex3S3 A＝0.192、B＝0.165、E＝0.192 24％
12 Ex4S1 A＝0.901、B＝0.112、E＝0.472 193％
13 Ex4S2 A＝0.135、B＝0.033、E＝0.077 30％
14 Ex4S2a A＝0.022、B＝0.012、E＝0.014 24％
15 Table 2No.13 A＝0.757、B＝0.004、E＝0.003 118％
16 Table 2No.14 A＝1.255、B＝0.003、E＝0.002 254％
17 Table 2No.16 A＝3.009、B＝0.003、E＝0.002 >400％
18 Table 3No.7 A＝0.721、B＝0.037、E＝0.073 97％
19 Table 3No.9 A＝2.054、B＝0.033、E＝0.078 >300％
20 Table 3No.11 A＝5.051、B＝0.032、E＝0.073 >500％
21 Table 4No.9 A＝0.753、B＝0.005、E＝0.253 108％
22 Table 4No.11 A＝1.522、B＝0.006、E＝0.252 275％
In above table 5, secondary series " raw material (source or assembly thing) " represents active raw materials used when preparing tablet, such as " Ex1S1 " represents that raw material when preparing tablet is embodiment 1 step 1 products therefrom, and again such as " table 2No.13 " represents that use has table 2 No.13 raw material sample above; In prepared tablet, each impurity phase is listed in the 3rd row " feature (0 month impurity A, B, E content, %) " for the content of atorvastatincalcuim, and other statement all has similar meaning.
The atorvastatin calcium raw material drug with feature of the present invention prepared using foregoing embodiments 1 ~ embodiment 4 of the present invention to feed intake the tablet obtained as activeconstituents, after measured, their Impurity A content is all in 0.003% ~ 0.500% scope, impurity B content is all in 0.003% ~ 0.500% scope, and impurity E content is all in 0.003% ~ 0.450% scope.These tablet samples are after disposing 40 DEG C-May, and impurity E content increases percentage ratio all lower than 45%.Visible, with regard to the present composition such as tablet, wherein impurity A content for atorvastatincalcuim is useful lower than equaling 0.500%, and such as Impurity A content (relative to atorvastatincalcuim meter) is useful in 0.003% ~ 0.500% scope.
After tested above-mentioned can be used as preparation particularly tablet atorvastatin calcium compositions for their impurity As for atorvastatincalcuim content lower than the sample equaling 0.500%, their impurity B for atorvastatincalcuim content all lower than 0.5%, their impurity E for atorvastatincalcuim content all lower than 0.450%.---namely for can be used as atorvastatin calcium compositions of the present invention, as one embodiment of the invention, in atorvastatin calcium compositions of the present invention, impurity A for atorvastatincalcuim content in 0.003% ~ 0.500% scope, impurity B for atorvastatincalcuim content in 0.003% ~ 0.500% scope, content is in 0.003% ~ 0.450% scope for atorvastatincalcuim for impurity E, and the atorvastatin calcium compositions with these features is that the present invention is preferred.
test example 2: biological test (mensuration of LD50)
With reference to the document (Li Yinchao that Li Yin is superfine, Deng, the mensuration of rabdosia rubescens diterpene constituents medium lethal dose, Journal of Chinese Hospital Pharmacy, 2011,31 (2): 163) described method, use Bliss method design experiment, to mouse single oral gavage, observe toxic reaction and the death condition of mouse in 14d, with death of mice rate for index, mensuration atorvastatincalcuim or related impurities are to 95% fiducial limit of LD50 and LD50 of mouse.Result: the LD50 of atorvastatincalcuim (embodiment of the present invention 4 step 3 products therefrom, in C66H68CaF2N4O10) single oral gavage administration is 17.13g/kg body weight, 95% of LD50 is crediblely limited to 15.47 ~ 18.63g/kg body weight; Be measured in the same method impurity E and 3S, 5S-atorvastatincalcuim (in C66H68CaF2N4O10), the LD50 of single oral gavage administration is 2.12g/kg body weight, and 95% of LD50 is crediblely limited to 1.95 ~ 2.38g/kg body weight.Visible, from Drug safety angle, atorvastatincalcuim is obviously better than the security of 3S, 5S-atorvastatincalcuim.
industrial applicability
Atorvastatin calcium raw material drug provided by the invention or preparation, as a kind of hypolipidemic, can be used for treatment clinically or prevent hypercholesterolemia or coronary heart disease.The invention provides a kind of new atorvastatin calcium raw material drug, it has excellent feature in such as stability in certain or some pharmacy, and/or demonstrate good biological safety, therefore material medicine of the present invention can be used for treatment or prevention hypercholesterolemia or coronary heart disease equally and expects to have low rate of side effects.

Claims (10)

1. a preparation method for the bulk drug of hyoscine, the activeconstituents of this bulk drug is atorvastatincalcuim, and the method comprises the step using solvent to refine the raw material comprising atorvastatincalcuim; Or, further,
The method comprises the following steps:
Step 1: at the temperature of 40 ~ 70 DEG C, makes the material dissolution comprising atorvastatincalcuim of 1 weight part in the methyl alcohol of 10 ~ 50 weight parts, then adds trolamine wherein and makes its concentration in the solution reach 0.1 ~ 1.0%, stir;
Step 2: at temperature described in maintenance step 1, under agitation, slowly add the water of 5 ~ 50 weight parts in step 1 gained solution, leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, 55 DEG C of vacuum-dryings; According to product purity, the operation of repeating step 1 and step 2 if desired; Optionally
Step 3: at the temperature of 50 ~ 60 DEG C (such as at the temperature of 55 DEG C), the step 2 gained atorvastatincalcuim product of 1 weight part is made to be dissolved in the methyl alcohol of 15 ~ 40 weight parts (such as 25 weight parts), under agitation slowly add the water of 10 ~ 30 weight parts (such as 20 weight parts), leave standstill and make the temperature naturally cooling to 10 ~ 15 DEG C, leach throw out, wash with water, then vacuum-drying at the temperature of 55 DEG C, obtain atorvastatin calcium raw material drug;
Or, further,
The method has embodiment as described in any one of specification sheets first aspect.
2. a bulk drug for hyoscine, the activeconstituents of this bulk drug is with compounds of Formula I:
Or its hydrate such as trihydrate;
When this bulk drug measures according to the present invention [HPLC-A], wherein the impurity (i.e. impurity A) of relative retention time at 0.77 ~ 0.83 place for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.26%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.003% ~ 0.500% scope (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope, such as in 0.003% ~ 0.260% scope).
3. bulk drug according to claim 2, when this bulk drug measures according to the present invention [HPLC-A], wherein the impurity (i.e. impurity B) of relative retention time at 0.87 ~ 0.93 place for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%), such as this foreign matter content (relative to atorvastatincalcuim meter) (such as in 0.003% ~ 0.400% scope, such as in 0.003% ~ 0.300% scope) in 0.003% ~ 0.500% scope; And/or,
When this bulk drug measures according to the present invention [HPLC-B], wherein the impurity (i.e. impurity E) of relative retention time at 0.77 ~ 0.83 place for atorvastatincalcuim content lower than 0.5% (such as lower than 0.4%, such as lower than 0.3%, such as lower than 0.28%), such as this foreign matter content (relative to atorvastatincalcuim meter) in 0.002% ~ 0.500% scope (such as in 0.002% ~ 0.400% scope, such as in 0.002% ~ 0.300% scope, such as in 0.002% ~ 0.280% scope).
4. bulk drug according to claim 2, it places 6 months 40 DEG C of condition lower seals, lucifuges, certain impurity phase after 6 months is disposed in calculating with this understanding increases percentage ratio for content when 0 month, wherein measure impurity (i.e. impurity E) content of relative retention time at 0.77 ~ 0.83 place according to [HPLC-B] and increase percentage ratio lower than 200%, such as lower than 150%, such as, lower than 100%, such as, lower than 75%, such as lower than 50%, such as, lower than 40%.
5. a pharmaceutical composition, comprising as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, and the optional impurity A as impurity; Further, wherein the content of impurity A for atorvastatincalcuim is lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope).
6. pharmaceutical composition according to claim 5, comprising as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, and the optional impurity B as impurity; Further, wherein impurity B for atorvastatincalcuim content lower than 1.00% (such as lower than 0.80%, lower than 0.60%, lower than 0.50%), such as impurity B content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.800% scope, such as in 0.003% ~ 0.600% scope, such as in 0.003% ~ 0.500% scope).
7. pharmaceutical composition according to claim 5, comprising as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, and the optional impurity E as impurity; Further, wherein impurity E for atorvastatincalcuim content lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as impurity E content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope).
8., according to the pharmaceutical composition of any one of claim 5-7, it is characterized in that:
When it measures according to the present invention [HPLC-A], wherein the impurity (i.e. impurity A) of relative retention time at 0.77 ~ 0.83 place for atorvastatincalcuim content lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as Impurity A content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope);
When it measures according to the present invention [HPLC-A], wherein the impurity (i.e. impurity B) of relative retention time at 0.87 ~ 0.93 place for atorvastatincalcuim content lower than 1.00% (such as lower than 0.80%, lower than 0.60%, lower than 0.50%), such as impurity B content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.800% scope, such as in 0.003% ~ 0.600% scope, such as in 0.003% ~ 0.500% scope);
When it measures according to the present invention [HPLC-B], wherein the impurity (i.e. impurity E) of relative retention time at 0.77 ~ 0.83 place for atorvastatincalcuim content lower than 1.00% (such as lower than 0.75%, lower than 0.50%, lower than 0.45%), such as impurity E content (relative to atorvastatincalcuim meter) in 0.003% ~ 1.000% scope (such as in 0.003% ~ 0.750% scope, such as in 0.003% ~ 0.500% scope, such as in 0.003% ~ 0.450% scope);
It is when 40 DEG C of condition lower seals, lucifuges place 5 months, certain impurity phase after 5 months is disposed in calculating with this understanding increases percentage ratio for content when 0 month, wherein measure impurity (i.e. impurity E) content of relative retention time at 0.77 ~ 0.83 place according to [HPLC-B] and increase percentage ratio lower than 200%, such as lower than 150%, such as lower than 100%, such as lower than 75%, such as, lower than 50%, such as, lower than 40%.
9., according to the pharmaceutical composition of any one of claim 5-7, it is characterized in that:
Wherein comprise the bulk drug described in any one of claim 2-4, and optional pharmaceutically acceptable carrier or auxiliary material;
It uses the bulk drug described in any one of claim 2-4 to prepare through pharmaceutical composition (such as pharmaceutical preparation) preparation technology;
It is oral preparations or injection formulations;
It is tablet, capsule, granule, injection (comprising injection liquid and lyophilize powder injection), suspensoid, pill;
It is tablet, wherein comprises atorvastatincalcuim or its hydrate such as trihydrate and be selected from following auxiliary material: calcium carbonate, croscarmellose sodium, hydroxypropylcellulose, Spherolac 100, Magnesium Stearate, Celluloasun Microcrystallisatum;
It is tablet, wherein comprises atorvastatincalcuim or its hydrate such as trihydrate and be selected from following auxiliary material: calcium carbonate, croscarmellose sodium, hydroxypropylcellulose, Spherolac 100, Magnesium Stearate, Celluloasun Microcrystallisatum, tween 80;
It is tablet, wherein comprises atorvastatincalcuim or its hydrate such as trihydrate and be selected from following auxiliary material: calcium carbonate, croscarmellose sodium, hydroxypropylcellulose, Spherolac 100, Magnesium Stearate, Celluloasun Microcrystallisatum, tween 80, Simethicone;
It is tablet, and the amount wherein comprising atorvastatincalcuim or its hydrate such as trihydrate in each tablet is 2 ~ 100mg, such as 3 ~ 100mg, such as 3 ~ 50mg; In one embodiment, the total tablet of described tablet is heavily 50 ~ 500mg, and such as total tablet is heavily 60 ~ 300mg; And/or
Wherein account for 3 ~ 30% of composition total weight as the atorvastatincalcuim of active ingredient or its hydrate such as trihydrate, pharmaceutically acceptable carrier or auxiliary material account for 70 ~ 97% of composition total weight.
10. the purposes of pharmaceutical composition described in the bulk drug, bulk drug described in any one of claim 2-4 or any one of claim 5-9 that prepare of method described in claim 1 in the medicine of preparation treatment or prevention hypercholesterolemia or coronary heart disease; Further,
Wherein said hypercholesterolemia includes but not limited to: primary hypercholesterolemia, familial hypercholesterolemia, combined hyperlipidemia, Fredrickson classification IIa hyperlipidaemia and Fredrickson classification IIb type hyperlipidaemia;
Wherein said hypercholesterolemia includes but not limited to following symptoms: total cholesterol raises, low density lipoprotein cholesterol raises, apolipoprotein B raises and triglyceride level raises;
Wherein said coronary heart disease includes but not limited to: danger disease such as coronary heart disease itself, coronary heart disease (as: diabetes, symptomatic atherosclerotic disease etc.) merge hypercholesterolemia or mixed dyslipidemia;
Wherein said treatment or prevention coronary heart disease include but not limited to: reduce the risk of non-fatal myocardial infarction, reduce the risk of lethality and non-lethality palsy, reduce the risk of reconstructive vascular operation, reduce be in hospital because of congestive heart failure risk, reduce anginal risk;
The content that in wherein said Medicinal crude drug, atorvastatincalcuim calculates with anhydride is greater than 98.0%, such as, in 98.0 ~ 102.0% scopes;
The chromatographic purity that wherein said Medicinal crude drug measures according to the present invention [HPLC-A] in 98.00% ~ 99.99% scope, such as, in 98.50% ~ 99.99% scope, such as, in 99.00% ~ 99.99% scope; And/or
The chromatographic purity that wherein said Medicinal crude drug measures according to the present invention [HPLC-B] in 98.00% ~ 99.99% scope, such as, in 98.50% ~ 99.99% scope, such as, in 99.00% ~ 99.99% scope.
CN201510589013.1A 2013-11-25 2013-11-25 Atorvastatin calcium and composition Pending CN105111123A (en)

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