CN109824606A - A kind of Rosuvastatin calcium impurities and rosuvastain calcium method of quality control - Google Patents
A kind of Rosuvastatin calcium impurities and rosuvastain calcium method of quality control Download PDFInfo
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Abstract
The present invention provides a kind of rosuvastain calcium unknown impuritie with and preparation method thereof.The present invention also provides the methods of the content of control Rosuvastatin calcium impurities, control the content of foregoing impurities by controlling the content of R1 compound Chinese style (RC) compound.The present invention also provides the methods for controlling rosuvastain calcium quality by the content for controlling Rosuvastatin calcium impurities.
Description
Technical field
The present invention relates to organic synthetic pharmacochemistry fields, more specifically, it is unknown miscellaneous to be related to a kind of rosuvastain calcium
Matter formula RC-Ca compound with and preparation method thereof.
Background technique
Rosuvastatin (rosuvastatin) is developed by Astrazeneca AB, is ratified first in Holland in November, 2002
Listing, in August, 2003 obtain U.S. FDA approval, got the Green Light and listed in China in 2006, at present in numerous countries
City is one of widely used statins.
Impurity is a key factor for influencing drug quality, in drug quality research process, it is necessary to confirm impurity
The content of structure and control impurity.Declared in registration in drug, according to the requirement of FDA and CFDA must to the impurity in finished product into
The stringent control of row must carry out structural analysis to the impurity for appearing in final products and quality controls, and source and removal need
It to be described in registration file.
Impurity majority in general drug has potential source biomolecule activity, and some interacts with drug, can influence drug peace
Full property and efficiency, or even generate toxic effect.Such as the protein and peptide class of residual minim in beta-lactam antibiotic finished product
Impurity and its penicillin thiazole albumen produced with beta-lactam nucleus effect have immunity.Popularity caused by the U.S. in 1989
Muscle syndrome (EMS) caused by Eosinophilia is also in that caused by impurity in a left side-tryptophan production process.Again
Such as methanesulfonic acid Nai Feinafei (vilasette ingot) event of Roche Group in 2007, the impurity ethyl methane sulfonate in bulk pharmaceutical chemicals is exceeded
Cause the DNA sequence dna of 6 patients abnormal.Therefore Control of Impurities is to the safe important in inhibiting of drug in drug, following
It will reinforce the control and research to impurity during new drug development.
Rosuvastain calcium is prepared by the synthetic route that original grinds patent WO00/149014 offer, can generally there is impurity.
The basic demand that Structural Identification is drug registration is carried out to impurity to obtain due to the small impurity of comparision contents by enriching and purifying
The difficulty of the impurity is bigger.
Rosuvastain calcium quality standard mainly has USP draft, EP standard, CP standard, pharmacopoeia of India and import system at present
Agent standard；Mainly following impurity is controlled in these standards.
Summary of the invention
As previously mentioned, the basic demand that Structural Identification is drug registration is carried out to impurity, it is auspicious in order to further increase drug
It relaxes and cuts down the quality of statin calcium, control the impurity content of drug rosuvastain calcium, an object of the present invention is to provide one kind such as
The compound of following formula (RC-Ca) structure,
Formula (RC-Ca) compound can be used as the standard items in the analysis of rosuvastain calcium finished product detection, be conducive to add
By force to the security control of drug.
Inventors have found that formula (RC-Ca) compound be in rosuvastain calcium production at present still it is undiscovered it is a kind of not
It knows impurity, is generated in R1 compound and D7 compound reaction process.Since its structure and R1 compound structure compare
It is similar, reaction can be participated in subsequent reactions are crossed into, be eventually transferred in finished product influence product quality, therefore it provides a kind of
The preparation method of Rosuvastatin calcium impurities RC-Ca is of great significance for the control of impurity.
On this basis, it is an object of the present invention to provide the preparation method of formula (RC-Ca) compound, the method packets
Include following steps:
(1) formula (RC) compound reacts to obtain formula (RC-1) compound with acid；
(2) formula (RC-1) compound reacts to obtain formula (RC-2) compound with alkali；
(3) formula (RC-2) compound reacts to obtain formula (RC-Ca) compound with calcium salt；
A specific embodiment according to the present invention, in the preparation of formula (RC-Ca) compound, the acid selected from hydrochloric acid,
Sulfuric acid, acetic acid, formic acid, trifluoroacetic acid, preferably hydrochloric acid.
A specific embodiment according to the present invention, in the preparation of formula (RC-Ca) compound, the alkali is selected from hydroxide
Sodium, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, preferably sodium hydroxide.
A specific embodiment according to the present invention, in the preparation of formula (RC-Ca) compound, the calcium salt is selected from chlorination
Calcium, calcium oxalate, calcium acetate, calcium carbonate, calcium bromide, preferably calcium chloride.
Formula (RC) compound, formula (RC-1) compound, the structure difference of formula (RC-2) compound are as follows:
The present invention also provides a kind of following structural formula (RC) compounds represented
The present invention also provides the preparation methods of compound shown in formula (RC), which comprises
(1) it reacts to obtain formula (R1) compound by formula (DPPO) compound and formula (D7) compound；
(2) it reacts to obtain formula (RC) compound by formula (R1) compound and formula (D7) compound.
The structure of formula (DPPO) compound is as follows:
A specific embodiment according to the present invention, wherein the step in preparation of compounds shown in the formula (RC)
(1) it carries out in the presence of a strong base, the highly basic is selected from sodium hexamethyldisilazide, lithium hexamethyldisilazide, pregnancy
Two silicon substrate potassamide of base, sodium tert-butoxide, sodium methoxide, sodium hydride, sodium ethoxide, the preferred sodium hexamethyldisilazide of highly basic.
A specific embodiment according to the present invention, wherein the step in preparation of compounds shown in the formula (RC)
(1) molar ratio of Chinese style (DPPO) compound and formula (D7) compound is 1:1.0~1.5, preferably 1:1.0~1.1, most preferably 1:
1.05。
A specific embodiment according to the present invention, wherein the step in preparation of compounds shown in the formula (RC)
(1) and step (2) in the presence of a solvent, the solvent be selected from tetrahydrofuran, 2- methyltetrahydrofuran, glycol dinitrate
Ether, Isosorbide-5-Nitrae-dioxane or ether, or combinations thereof, the preferred tetrahydrofuran of solvent.
A specific embodiment according to the present invention, wherein the step in preparation of compounds shown in the formula (RC)
(2) it carries out in the presence of a strong base, the highly basic is selected from n-BuLi, lithium diisopropylamine (LDA), two silicon substrate ammonia of hexamethyl
Base sodium (NaHMDS), lithium hexamethyldisilazide (LiHMDS), preferably n-BuLi.
A specific embodiment according to the present invention, wherein the step in preparation of compounds shown in the formula (RC)
(2) it carries out at -50 DEG C~-80 DEG C, is preferably carried out at -60 DEG C~-75 DEG C.
A specific embodiment according to the present invention, the wherein step (2) in preparation of compounds shown in formula (RC)
The molar ratio of the highly basic and formula (R1) compound is 1:1.0~1.2；It is preferred that 1.0:1.1.
A specific embodiment according to the present invention, the wherein step (2) in preparation of compounds shown in formula (RC)
The molar ratio of formula (R1) compound and formula (D7) compound is 1:1.0~1.5；It is preferred that 1:1.0~1.1.
A specific embodiment according to the present invention, the present invention provides impurity formulas in a kind of control rosuvastain calcium
(RC-Ca) method of compounds content is changed by controlling the content of R1 compound Chinese style (RC) compound to control formula (RC-Ca)
Close the content of object.
A specific embodiment according to the present invention, the present invention provides impurity formulas in a kind of control rosuvastain calcium
(RC-Ca) method of compounds content is changed by controlling the content of R1 compound Chinese style (RC) compound to control formula (RC-Ca)
The content for closing object, it is miscellaneous in rosuvastain calcium when the content by controlling R1 compound Chinese style (RC) compound is lower than 0.25%
The content of matter RC-Ca is lower than 0.10%.
The present invention obtains following beneficial effect:
1) present invention firstly discloses the structures of rosuvastain calcium unknown impuritie formula (RC-Ca) compound, cut down to auspicious relax
The quality research of statin calcium is of great significance；
2) present invention firstly discloses the preparation methods of rosuvastain calcium unknown impuritie formula (RC-Ca) compound, are auspicious
It relaxes and cuts down statin calcareous quantity research impurity reference substance is provided, while providing a kind of effective method to the control of the impurity to ensure auspicious
It relaxes and cuts down impurity < 0.10% in statin calcium finished product.
The present invention provides formula (RC-Ca) compounds process for production thereof, easy to operate efficiently reaction condition is more moderate, safety
Property it is strong, it is easily controllable, be suitable for impurity preparation be used as reference substance.To monitor product quality.
Detailed description of the invention
Fig. 1 RC liquid phase detects spectrogram
Fig. 2 RC nucleus magnetic hydrogen spectrum
Fig. 3 RC nuclear-magnetism carbon spectrum
Fig. 4 formula (RC-Ca) compound liquid phase detects spectrogram
Fig. 5 formula (RC-Ca) compound nucleus magnetic hydrogen spectrum
Fig. 6 formula (RC-Ca) compound nuclear-magnetism carbon spectrum
Fig. 7 R1 liquid phase detects spectrogram
Fig. 8 rosuvastain calcium detects spectrogram
Specific embodiment
Following typical reaction is used to illustrate the present invention.The technical staff in the art simple replacement done to invention
Or improvement etc. belongs within the technical solution that the present invention is protected.
Reagent used in the present invention is available on the market or can described method system through the invention
It is standby and obtain.In the present invention, NaHMDS indicates that hexamethyldisilane base amido sodium, n-BuLi indicate that n-BuLi, THF indicate tetrahydro
Furans, h indicate hour, and ml indicates that milliliter, M indicate mol/L.
HPLC and isomery detection method hereinafter is as follows
Instrument: Agilent 1206
Analytical column: SB-C18,4.6mm × 250mm, 5 μm of Zorbax (or equivalent pillar)
Mobile phase A: buffer-acetonitrile=95:5.
Mobile phase B: water-second eyeball=5:95
Diluent: acetonitrile
Buffer: precision weighs potassium dihydrogen phosphate 1.36g and dissolves in 1000mL water, stirs evenly, extremely with phosphoric acid tune PH
3.0 ± 0.05, filter simultaneously ultrasonic degassing.
Gradient:
| Time (min) | Mobile phase A % | Mobile phase B % |
| 0.01 | 10 | 90 |
| 15.0 | 0 | 100 |
| 25.0 | 0 | 100 |
| 30.0 | 10 | 90 |
| 35.0 | 10 | 90 |
Flow velocity: 1.0ml/min
Column temperature: 30 DEG C
Detector: UV detector, wavelength 240nm
Sample volume: 10 μ l
Runing time: 35 minutes
The preparation of embodiment 1:RC compound
40.0g compound (DPPO) and 500ml THF are added in 1000ml four-hole boiling flask, stirs dissolved clarification, nitrogen displacement 3
It is secondary, under nitrogen protection, interior temperature is dropped to -75.0 DEG C, 1.0M NaHMDS/THF solution 79.0ml is slowly added dropwise, controls Nei Wen -80.0
DEG C~-75.0 DEG C, it is added dropwise rear insulation reaction 2.0h, after insulation reaction, controls Nei Wen -80.0 DEG C~-75.0 DEG C, drop
Add compound (D7) THF solution (D7:23.1g, THF:20ml), after being added dropwise, insulation reaction 1.0h；It is controlled in sampling, until
Residual≤1.0% of compound (DPPO), reaction terminate in reaction solution.It is warmed to room temperature, 100ml saturated ammonium chloride solution is added and quenches
It goes out reaction, after being quenched, material is evaporated under reduced pressure, 50.0 DEG C of outer temperature, vacuum degree≤- 0.09MPa, and after being evaporated, 400.0g is added
Toluene dissolution, is washed, and concentration obtains compound (R1) 30.0g with 400.0g methanol crystallization.
30.0g compound (R1) and 500ml THF are added into 1000ml four-hole boiling flask, stirs dissolved clarification, nitrogen displacement 3
It is secondary, under nitrogen protection, interior temperature is dropped to -75.0 DEG C, Nei Wen -60.0 DEG C~-75.0 DEG C is controlled, is slowly added dropwise 1.66M n-BuLi's
Hexane solution 63ml, is added dropwise rear insulation reaction 2.0h, after insulation reaction, rises to 0 DEG C of interior temperature, controls Nei Wen -5 DEG C
~0 DEG C, the THF solution (D7:26.9g, THF:27ml) of compound (D7) is added dropwise, rear insulation reaction 1.0h is added dropwise；Reaction
After, it is warmed to room temperature, 70ml saturated ammonium chloride solution quenching reaction is added, after being quenched, with 600ml Cl2CH2Extraction, washing,
It is evaporated, R-1 crude product carried out column (Cl2CH2:CH3OH=20:1), isolated impurity RC 22.4g (yield 52%).Liquid phase
(HPLC) detection spectrogram is shown in that Fig. 1, RC appearance time are RT=15.7min；Structural confirmation hydrogen spectrum is shown in that Fig. 2, carbon spectrum are shown in Fig. 3；
MS(ESI)m/z:837(M+H)+；835(M-H)-.
1H NMR(500MHz,DMSO)δ7.68(s,2H),7.30(s,2H),6.57(s,1H),5.42(s,1H),4.50
(s,1H),4.16(s,2H),3.96(s,1H),3.86(s,2H),3.72(s,1H),3.45(s,2H),3.34(s,5H),2.53
(s, 8H), 2.36 (s, 2H), 2.21 (s, 2H), 1.66 (s, 1H), 1.47 (s, 1H), 1.42 (d, J=6.5Hz, 3H), 1.40
(s,7H),1.38(s,7H),1.31(s,2H),1.26(s,3H),1.20(s,5H),1.13(s,2H),1.05(s,2H)。
Embodiment 2: the preparation of formula RC-Ca compound
In nitrogen protection, RC compound 13.50g, acetonitrile 74.6g are put into reaction flask；Stirring heating controls interior temperature
35.0~40.0 DEG C, 0.02M hydrochloric acid 40g is added dropwise, finishes heat preservation 3.0~3.5 hours；Heat preservation terminates cooling, controls interior temperature 20.0
~25.0 DEG C, 1M sodium hydroxide 60.0g is added dropwise, keeps the temperature 1.0~1.5 hours；Heat preservation is finished, and adjusts PH to 7.0 with 1M hydrochloric acid solution
~7.5, adjusting terminates, and controls 40 DEG C of the < reduced pressures of outer temperature, and the ethyl acetate that 50ml is added in water phase extracts, and abandons organic phase, water
It is mutually cooled to room temperature, the calcium chloride water of 50ml10% is added, is stirred, filtering in 30 minutes is washed, 45 DEG C with the ice of 150ml
Vacuum drying obtains formula RC-Ca compound, 7.6g；Liquid phase (HPLC) detection spectrogram is shown in that Fig. 4, R1 appearance time are RT=
1.4min；Structural confirmation hydrogen spectrum is shown in that Fig. 5, carbon spectrum are shown in Fig. 6.
MS(ESI)m/z:682(M+H)+；680(M-H)-.
1H NMR(500MHz,DMSO)δ7.57(s,2H),7.22(s,2H),6.30(s,1H),5.30(s,1H),4.14
(s,1H),3.62(s,1H),3.37(s,4H),2.81(s,3H),2.67(s,2H),2.37(s,2H),2.29(s,1H),1.98
(s, 1H), 1.76 (s, 1H), 1.58 (s, 3H), 1.23 (s, 2H), 1.15 (s, 6H), 1.11 (d, J=1.7Hz, 1H), 1.09
(s, 1H), 1.08 (s, 1H), 1.00 (t, J=7.0Hz, 1H).
The preparation of embodiment 3:R1 compound
40.0g compound (DPPO) and 500ml THF are added in 1000ml four-hole boiling flask, stirs dissolved clarification, nitrogen displacement 3
It is secondary, under nitrogen protection, interior temperature is dropped to -75.0 DEG C, 1.0M NaHMDS/THF solution 79.0ml is slowly added dropwise, controls Nei Wen -80.0
DEG C~-75.0 DEG C, it is added dropwise rear insulation reaction 2.0h, after insulation reaction, controls Nei Wen -80.0 DEG C~-75.0 DEG C, drop
Add compound (D7) THF solution (D7:23.1g, THF:20ml), after being added dropwise, insulation reaction 1.0h；It is controlled in sampling, until
Residual≤1.0% of compound (DPPO), reaction terminate in reaction solution.It is warmed to room temperature, 100ml saturated ammonium chloride solution is added and quenches
It goes out reaction, after being quenched, material is evaporated under reduced pressure, 50.0 DEG C of outer temperature, vacuum degree≤- 0.09MPa, and after being evaporated, 400.0g is added
Toluene dissolution, is washed, and concentration obtains compound (R1) 30.0g with 400.0g methanol crystallization.Liquid phase HPLC detects spectrogram such as Fig. 7 institute
Show.As shown in fig. 7, the peak that the peak of RT=13.89min is R1, TR=15.68min is RC；Therefore illustrate to deposit really in R1 reaction
In RC impurity；
Embodiment 4: the preparation of rosuvastain calcium
In nitrogen protection, R1 10.0g, acetonitrile 70ml are put into reaction flask；Stirring heating；Warm 35.0 in control~
42.0 DEG C, 0.02M hydrochloric acid 19ml is added dropwise, finishes, keeps the temperature 3.0~4.0 hours；Heat preservation terminates cooling；Warm 20.0 in control~
25.0 DEG C of dropwise addition 1.0M sodium hydroxide solution 19ml keep the temperature 1.0~1.5 hours；Heat preservation is finished, and sodium chloride 4.8g is added, continues to drop
Temperature controls 0.0~-5.0 DEG C of interior temperature and adjusts PH to 3.0~4.0 with 1M hydrochloric acid and sodium chloride solution, and adjusting terminates；Stratification,
Abandon lower layer's water phase；The ice acetonitrile for controlling 0.0~-5.0 DEG C of addition 130ml of temperature in organic phase, is stirred 0.5~1.0 hour, heat preservation is finished
Filtering controls the methylamine water solution of 0.0~-5.0 DEG C of addition 2.2ml40% of temperature in organic phase；It is added dropwise and finishes, 0.0~5.0 DEG C of stirring
It filters within 1.0 hours, filter cake is washed with a small amount of acetonitrile；Wet product is placed in 35 DEG C of baking oven 8.0 hours dry；Rewinding obtains 8.0g first
Amine salt；Methylamine salting liquid is dissolved in 40ml purified water, 8% sodium hydroxide solution of 20 DEG C of < dropwise addition 7.2ml of interior temperature is controlled
Stirring 1.0 hours；Stirring terminates, and controls outer 40 DEG C of < of temperature, is evaporated under reduced pressure until the amount for steaming water is 32ml；Distillation terminates to mend
Add 32ml purified water；Outer 40 DEG C of < of temperature is controlled, is evaporated under reduced pressure until the amount for steaming water is 32ml；It is pure that 32ml is added in distillation end
Change water；Outer 40 DEG C of < of temperature is controlled, is evaporated under reduced pressure until the amount for steaming water is 32ml；It is pure that third time adds 40ml after distilling
Change water, cooling, controls interior temperature at 20 DEG C or so, CALCIUM CHLORIDE DIHYDRATE (1.45) solution of 8.4ml is added dropwise, stirs, 30 minutes mistakes
Filter is washed with the ice of 60ml, and 45 DEG C of vacuum dryings obtain rosuvastain calcium 8.8g.
It is as shown in Figure 8 that liquid phase (HPLC) detects spectrogram.The RT=4.585min of rosuvastain calcium appearance time shown in Fig. 8,
Wherein TR=1.419min is formula RC-Ca compound, therefore illustrates to be implicitly present in formula RC-Ca compound in rosuvastain calcium.
Embodiment 5: the R1 sample preparation containing different RC contents
The R1 sample of different purity is prepared by the method for adding impurity；Specific experiment operation:
The acetonitrile for weighing suitable R1 and RC, being dissolved in tetra- times of R1 amounts；Sampling HPLC is detected after stirring rising temperature for dissolving
| Serial number | RC content | RC quantity | R1 quantity | Acetonitrile |
| A | 0.10% | 0.010g | 9.990g | 40g |
| B | 0.13% | 0.013g | 9.987g | 40g |
| C | 0.16% | 0.016g | 9.984g | 40g |
| D | 0.19% | 0.019g | 9.981g | 40g |
| E | 0.22% | 0.022g | 9.978g | 40 |
| F | 0.25% | 0.025g | 9.975g | 40 |
| G | 0.28% | 0.028g | 9.972g | 40 |
Embodiment 6: using the R1 sample preparation rosuvastain calcium for containing different RC contents
Seven groups of samples of A, B, C, D, E, F, G, different Rosuvastains is prepared according to the method for embodiment 4 in Example 4
Spit of fland calcium sample is detected, and is as a result summarized as follows:
| Serial number | RC content | RC quantity | R1 quantity | Acetonitrile | RC-Ca in rosuvastain calcium |
| A | 0.10% | 0.010g | 9.990g | 40g | 0.04% |
| B | 0.13% | 0.013g | 9.987g | 40g | 0.05% |
| C | 0.16% | 0.016g | 9.984g | 40g | 0.06% |
| D | 0.19% | 0.019g | 9.981g | 40g | 0.07% |
| E | 0.22% | 0.022g | 9.978g | 40 | 0.08% |
| F | 0.25% | 0.025g | 9.975g | 40 | 0.10% |
| G | 0.28% | 0.028g | 9.972g | 40 | 0.11% |
Single contaminant is less than 0.10% in European Pharmacopoeia and USP requirement rosuvastain calcium finished product, and finished product is stringent
Single contaminant is controlled, just can guarantee the qualification of rosuvastain calcium quality.
Show to be implicitly present in RC in R1 by above data, and remaining RC impurity is prepared in rosuvastain calcium in R1
Process can be converted into impurity formula RC-Ca compound accordingly；In order to guarantee rosuvastain calcium lmpurities formula RC-Ca chemical combination
Object≤0.10%, RC content needs to control below 0.25% in R1.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. rosuvastain calcium impurity compound shown in formula (RC-Ca)
Formula 2. (RC) compound
The preparation method of formula described in claim 2 3. (RC) compound, comprising the following steps:
(1) it reacts to obtain formula (R1) compound by formula (DPPO) compound and formula (D7) compound
(2) it reacts to obtain formula (RC) compound by formula (R1) compound and formula (D7) compound
Formula (DPPO) compound, formula (D7) compound, the structure difference of formula (R1) compound and formula (RC) compound are as follows
It is shown:
The preparation method of formula described in claim 1 4. (RC-Ca) compound, comprising the following steps:
(1) formula (RC) compound reacts to obtain formula (RC-1) compound with acid；
(2) formula (RC-1) compound reacts to obtain formula (RC-2) compound with alkali；
(3) formula (RC-2) compound reacts to obtain formula (RC-Ca) compound with calcium salt；
Formula (RC) compound, formula (RC-1) compound, the structure difference of formula (RC-2) compound are as follows:
5. described according to the method described in claim 3, wherein the step (1) and step (2) carry out in the presence of a strong base
Highly basic is selected from sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium tert-butoxide, first
Sodium alkoxide, sodium hydride, sodium ethoxide, the preferred sodium hexamethyldisilazide of highly basic or n-BuLi.
6. according to the method described in claim 3, wherein step (1) Chinese style (DPPO) compound and formula (D7) compound
Molar ratio is 1:1.0~1.5, preferential 1:1.0~1.1, most preferably 1:1.05.
7. according to the method described in claim 3, wherein in the presence of a solvent, the solvent is selected from the step (2)
Tetrahydrofuran, 2- methyltetrahydrofuran, glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane or ether or combinations thereof, the solvent are preferred
Tetrahydrofuran.
8. according to the method described in claim 3, it is characterized in that mole of highly basic described in step (2) and formula (R1) compound
Than for 1:1.0~1.2；It is preferred that 1.0:1.1.
9. a kind of method for controlling rosuvastain calcium impurity content passes through control formula (R1) compound Chinese style (RC) compound
Content controls the content of impurity formula (RC-Ca) compound.
10. method as claimed in claim 9 is lower than 0.25% by the content of control (R1) compound Chinese style (RC) compound,
To control the content of impurity formula (RC-Ca) compound in rosuvastain calcium.
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| CN201910267433.6A CN109824606B (en) | 2019-04-03 | 2019-04-03 | Rosuvastatin calcium impurity and rosuvastatin calcium quality control method |
| CN202010904924.XA CN111943891B (en) | 2019-04-03 | 2019-04-03 | Rosuvastatin calcium impurity and rosuvastatin calcium quality control method |
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| CN201910267433.6A CN109824606B (en) | 2019-04-03 | 2019-04-03 | Rosuvastatin calcium impurity and rosuvastatin calcium quality control method |
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