CN106749186B - A kind of novel crystal forms and preparation method thereof of R-lansoprazole sodium - Google Patents
A kind of novel crystal forms and preparation method thereof of R-lansoprazole sodium Download PDFInfo
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Abstract
The invention discloses novel crystal forms A of a kind of R-lansoprazole sodium Dimethylacetamide solvate and preparation method thereof, and x-ray diffractogram of powder spectrum is in 2 θ value of the angle of diffraction 5.9,7.6,12.2,12.7,16.6,18.4,20.5, there is characteristic diffraction peak at 25.8,26.8,31.4 degree.The preparation method of novel crystal forms A is that R-lansoprazole sodium is added to the in the mixed solvent of dimethyl acetamide and water, and suitable viscosity modifier and antioxidant is added, is added obtained by the slow crystallization of poor solvent after dissolution clarification.The advantages that novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate of the present invention has crystal size moderate, good fluidity, is not easy to assemble and degrade, and stability is good, is very suitable for hot-melt extrusion process.Meanwhile the step of preparing novel crystal forms A, is easy, at low cost, high income, solvent safety is nontoxic, is very beneficial to industrialized production.
Description
Technical field
The invention belongs to field of medicine preparing technology, it is related to a kind of R-lansoprazole sodium Dimethylacetamide solvate
Novel crystal forms A and preparation method thereof.
Background technique
R-lansoprazole (Dexlansoprazole, R- (+)-Lansoprazole), chemical name are (R)-(+) -2-
([3- methyl -4- (2,2,2- trifluoro ethoxy) pyridine -2- base] methylsulfinyl) -1H- benzimidazole, structural formula is such as
Shown in lower,
。
R-lansoprazole is the esophagitis treatment new drug of Japanese Takeda Pharmaceutical Company Limited research and development, January in 2009 the 30 Nikkei U.S.
FDA approval listing.The medicine is single enantiomer of proton pump inhibitor Lansoprazole, for treatment and Non-erosive gastroesophageal reflux
Sick relevant heartburn and different degrees of erosive esophagitis than Lansoprazole there is higher bioavilability and less pair to make
With.
The physicochemical property of R-lansoprazole itself is extremely unstable.It is similar with R-lansoprazole, esomeprazole free state
Chiral centre encounters inorganic strong alkali and is easy racemization, is exposed in acid air then color blackening quickly, esomeprazole must be made
For at just suitable preparation needs after esomeprazole magnesium or Esomeprazole sodium.But unlike esomeprazole, right orchid
Rope draws azoles to be not easily formed above-mentioned salt form, or is not easy to be purified at crystal after salt, and there are related
Defect in terms of the physicochemical properties such as substance is higher, and stability is very poor.
In order to overcome the defect of R-lansoprazole stability difference, existing researcher is dedicated to developing a kind of stabilization more mostly
Good R-lansoprazole novel crystal forms.
The military field pharmacy of the Japan that original is ground discloses a series of crystal form results of study.Such as WO2000/78745 (patent families
CN1150186C a kind of a kind of anhydrous crystal forms Form I and hydrate crystal forms Form II containing 1.5 molecular crystalline water) is disclosed.
WO2001/87874 discloses a kind of hydrate crystal forms that crystalline water molecules number is not known between 0~1.0.Have again later
WO2002/44167 discloses the crystal form for having identical interplanar distance (d) characteristic peak with Form I.Then Wu Tian company exists
WO2009/88857 systematically disclose Form I, II, III, IV, V, VI crystal form and Form I Methanol Solvate,
Alcohol solvent compound, 1.5 hydrates (continuing to dry 1.0 hydrates of getting back), and disclose above-mentioned all crystalline substances
The preparation process of mutual inversion of phases between type.
Patent CN1150186C discloses amorphous dexlansoprazole, crystallization R-lansoprazole (fusing point, 147~148 DEG C)
With the R-lansoprazole form and preparation method thereof for containing 1.5 water.
TEVA company discloses Dexlansoprazole from the one of Form X to Form XIV in WO2010039885
Serial crystal form.
HANMI company, South Korea discloses a kind of Form A crystal form in WO2010/056059.Although system is claimed by above-mentioned company
It is standby to have obtained stable crystal form, but reality does not all overcome the disadvantage of R-lansoprazole stability difference thoroughly.
Also there is fragmentary report in existing literature, it, may be to a certain degree if R-lansoprazole to be made into the form of sodium salt
Upper raising stability.Chinese patent CN1329003A discloses the preparation method of optical purity lansoprazole, and specifically discloses cream
The Dexlansoprazole sodium salt of white amorphous powder shape.
US20030181487 is described and sodium hydrate aqueous solution is added in the ethanol solution of Dexlansoprazole, is passed through
After the operations such as the repeated multiple times reduced pressure of a series of complex and addition poor solvent, Dexlansoprazole sodium salt is obtained
Crude product, then the crystallization that flows back in toluene and alcohol mixed solvent obtains highly finished product, but the process is extremely complex, work
It is poor that industry amplifies feasibility.
PCT Patent WO2012095859 discloses a series of Dexlansoprazole sodium salt of solid forms, including crystal form 1,
Crystal form 2 and amorphous substance, preparation process is relatively easy, reproducible.
Have above-mentioned background it is found that need on the basis of existing technology, invent a kind of stability is good, granularity is moderate, flowing
Property good, the pharmaceutical R-lansoprazole sodium of safety novel crystal forms, while need to guarantee that the method and step for preparing the novel crystal forms is easy, weight
Renaturation is good, high income, is conducive to industrialized production.
Torching mark (HME) is also known as melt extrusion technology, refers to using mono-/bis-screw extruder, passes through material
Solid Conveying and Melting, melting, three stage of melt conveying are gone through, under the effect of the strong shear of kneading device and screw element, it is mixed to obtain height
Close the shaped article of dispersion.Hot-melt extruded process can realize mixing, granulation and a variety of unit behaviour of moulded products on one device
Make, have process few, low energy consumption, at low cost, and yield is high, serialization, can closed production the features such as.The technology is improving indissoluble
Property drug dissolution, have in terms of preparing sustained release preparation and local administration preparation and break through sexual clorminance, it has also become preparation technique medicine
A new hot spot in object transmission system.Especially valuable is that preparation process is easily industrialized amplification production.The prior art
In have not been reported R-lansoprazole sodium for hot-melt extrusion process report, more do not filter out suitable for hot-melt extrusion process
R-lansoprazole sodium novel crystal forms.
Summary of the invention
It is poor for R-lansoprazole stability in the prior art, it is sensitive to temperature humidity, applied to being operated in preparation process
Difficulty is big, high production cost, and the not high defect of formulation products stability is not suitable for hot-melt extrusion process more especially
Drug degradation is obvious in defect, such as reflow process, and the present invention provides a kind of R-lansoprazole sodium dimethylacetamide solvents
The physicochemical property of novel crystal forms A of compound and preparation method thereof, novel crystal forms A are more preferable, and fusing point is suitable for that stability is strong, very convenient
Various kinds of drug dosage form is made, also facilitates applicable hot-melt extrusion process processing.
It is another object of the present invention to provide the novel crystal forms A of the R-lansoprazole sodium to treat gastric ulcer, ten in preparation
Application in two Duodenalulcers and reflux esophagitis and eliminating pylorus drug.
In order to achieve the above object, the present invention is achieved by the following technical programs.
The present invention provides a kind of novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate, and this of every mole is new
Include 1 mole of dimethylacetamide solvent molecule in crystal form A, structural formula is as follows:
。
The novel crystal forms A of R-lansoprazole sodium of the present invention, x-ray diffractogram of powder spectrum are 5.9,7.6 in 2 θ of the angle of diffraction,
Have characteristic diffraction peak at 12.2,12.7,16.6,18.4,20.5,25.8,26.8,31.4 degree, wherein 2 θ value error ranges be ±
0.2, and the map is as shown in Figure of description 1.
Novel crystal forms A, the DSC map of R-lansoprazole sodium of the present invention has endothermic characteristics peak at 132.4 ± 1 DEG C,
204.6 ± 1 DEG C have exothermic characteristic peak；And the map is as shown in Figure of description 2.
The novel crystal forms A of R-lansoprazole sodium of the present invention, Fourier transform infrared spectroscopy are 3383 ± 2 in wave number,
3134 ± 2,3072 ± 2,2975 ± 2,1646 ± 2,1583 ± 2,1475 ± 2,1441 ± 2,1316 ± 2,1265
± 2,1198 ± 2,1168 ± 2,1111 ± 2,1036 ± 2,972 ± 2,915 ± 2,857 ± 2,745 ± 2,662 ± 2
cm-1There is characteristic absorption peak at place, and the map is as shown in Figure of description 3；And the thermogravimetric of the novel crystal forms A of above-mentioned R-lansoprazole sodium
TG map is analyzed as shown in Figure of description 4.
The new of R-lansoprazole sodium Dimethylacetamide solvate of the present invention is prepared the present invention also provides a kind of
The method of crystal form A, comprises the following steps:
(1) R-lansoprazole sodium is added to the in the mixed solvent of dimethyl acetamide and water, dimethyl acetamide: water
Volume ratio is 1:0.5~1, and above-mentioned mixed solvent volume is 4~6 times of R-lansoprazole sodium novel crystal form A weight, and unit is mL/
g；
(2) suitable viscosity modifier and antioxidant, the stirring and dissolving at 25~40 DEG C is added；
(3) under conditions of applying ultrasonic wave effect, poor solvent is added dropwise into solution, poor solvent volume is dimethyl
2~4 times of the mixed solvent volume of acetamide and water；Wherein, poor solvent is that ether solvent either ketones solvent, ethers are molten
Agent is selected from methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, methyltetrahydrofuran, ether, isopropyl ether, one of methyl phenyl ethers anisole；Ketone
Class solvent is selected from acetone, methyl iso-butyl ketone (MIBK), butanone, methyl butyl ketone, methyl isopropyl Ketone, and one in methyl tertbutyl ketone
Kind；
(4) it is cooled to 0~5 DEG C, continues 1~3h of stirring, suction filtration is formed by suspension；
(5) dry under conditions of 35~45 DEG C of temperature and 0~0.1Mpa of vacuum degree, obtain R-lansoprazole sodium dimethyl
The novel crystal forms A of acetamide solvate；
Wherein, described " viscosity modifier " is selected from Macrogol 6000, Macrogol 4000, PVP K30, copolyvidone
One or more of S630；The weight of viscosity modifier be added R-lansoprazole sodium novel crystal form A weight 0.05%~
0.2%；" antioxidant " is selected from butylated hydroxy anisole, propylgallate, one of cysteine hydrochloride or several
Kind, the weight of antioxidant is the 0.1%~0.5% of the R-lansoprazole sodium novel crystal form A weight being added.
Preferably, viscosity modifier is copolyvidone S630, and dosage is the R-lansoprazole sodium novel crystal form A weight being added
0.2%；Antioxidant is propylgallate, and dosage is the 0.2% of the R-lansoprazole sodium novel crystal form A weight being added.
Preferably, poor solvent is methyl tertiary butyl ether(MTBE), and volume is the mixed solvent volume of dimethyl acetamide and water
3 times；Or poor solvent is methyl iso-butyl ketone (MIBK), volume is 4 times of the mixed solvent volume of dimethyl acetamide and water.
Preferably, in step 3, the drop rate of poor solvent be it is per minute be added dropwise poor solvent total volume 0.3%~
3%；Ultrasonic wave is referred to during poor solvent crystallization is added dropwise, and ultrasonic wave acting frequency is 20 KHz~50KHz, function
Rate is 50 W~100W；The rate of temperature fall of " cooling " described in step 4 is 0.3 DEG C~1 DEG C/min.
The present invention also provides above-mentioned R-lansoprazole sodium novel crystal form A in the solid dispersions for preparing R-lansoprazole sodium
Purposes, the solid dispersions are the carrier materials and other are pharmaceutically acceptable auxiliary by R-lansoprazole sodium novel crystal form A
What material was prepared using torching mark.
It is further preferred that the carrier material is selected from PVP class, polyacrylic resins, cellulose family, surfactant
Class, insoluble framework material, erodible framework material, one or more of hydrophilic back bone material；And resulting solid point
Granular media further wraps gastric solubility coating or enteric coatings, can get the particle discharged under different pH environment, as system
Agent intermediate uses.
The main granularity of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate of the present invention is 90 μm of left sides
The right side, so that crystal size is moderate, good fluidity is not easy to assemble and degrade, facilitates the operation in production process.
The present invention achieves following beneficial technical effect.
(1) in the experimentation for investigating R-lansoprazole sodium different crystal forms, the present inventor is surprisingly had found, right Lan Suola
Azoles sodium can form solvate with dimethyl acetamide, it may be possible to carbonyl in oxygen atom and solvent molecule on sulfinyl or
Dimethylamino forms hydrogen bond.Dimethyl acetamide is a kind of polar non-solute, and thermal stability is good, steady even if boiling point
It is fixed not decompose.The inventors discovered that in the mixed solvent comprising dimethyl acetamide and water special ratios with appropriate viscosity
In, ethers or ketone poor solvent are added dropwise under ultrasound condition, the Dexlansoprazole sodium in system can be forced and dissociate
Come, then be precipitated in conjunction with ratio of the dimethyl acetamide according to 1:1 rich in hydrogen bond motif and at a slow speed, is detached from original solution
It keeps stablizing after system, so as to form the novel crystal forms A of physicochemical property aspect very advantageous.
(2) present invention under suitable concentration, temperature and time, passes through raw material using dimethyl acetamide as solvent composition
R-lansoprazole sodium prepares the novel crystal forms A of the Dimethylacetamide solvate of the sodium salt.Poor solvent is added in the process,
On the one hand yield can be improved, on the other hand suspension density can be reduced by diluting effect, by the way that suitable viscosity tune is added
Agent and antioxidant are saved, prevents crystal from coalescing and being conducive to be precipitated, while avoiding the oxidation of the sulfoxide structure in Crystallization Process, reached
The good effect of journey high income, crystal habit.Solvent dimethyl acetamide, safe and non-toxic used in the present invention, molten residual limitation requirement
It is not high, it is used as the solvent of injection and non-injection pharmaceutical preparation extensively, and in the solvent of intramuscular injection and intravenous injection.This
The preparation method that the Dimethylacetamide solvate for the R-lansoprazole sodium that invention provides obtains novel crystal forms A is simple, gained filter
Cake is without washing, time-consuming short, high income.
(3) the more beneficial effect of the present invention is also embodied in crystal habit and stability.Novel crystal forms A's provided by the invention
Plane of crystal is bright and clean, PXRD and DSC characteristic peak is sharp, shows crystal form purity height；Granularity is not easy to coalesce at 90 μm or so.
(4) Dimethylacetamide solvate of R-lansoprazole sodium provided by the invention obtains the desolventizing of novel crystal forms A
About 132.4 ± 1 DEG C of temperature, about 204.6 ± 1 DEG C of decomposition temperature, heat resistance is good.
(5) novel crystal forms A provided by the invention compares the control crystal form of R-lansoprazole sodium, more not easy to moisture absorption, mobility
Good, stable in physicochemical property is also especially suitable for hot-melt extrusion process, has opened up wide prospect sky for the use of solid dispersions
Between.
Detailed description of the invention
Fig. 1 is the powder x-ray diffraction PXRD figure of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate
Spectrum.
Fig. 2 is the DSC map of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate.
Fig. 3 is the infared spectrum of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate.
Fig. 4 is the TG map of the novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate.
Specific embodiment
It below will be by the specific embodiment of embodiment form, further specifically to above content of the invention
It is bright, but the range that this should not be interpreted as to aforementioned body of the present invention is limited only to following embodiment.It is all above-mentioned based on the present invention
The technology that content is realized all belongs to the scope of the present invention.
The preparation of 1 R-lansoprazole sodium novel crystal form A of embodiment
R-lansoprazole sodium 50g is added to the in the mixed solvent of dimethyl acetamide 200mL and purified water 100mL, is added
0.1g copolyvidone S630 and 0.1g propylgallate, the stirring and dissolving at 35 DEG C~40 DEG C are applying ultrasonic wave effect
Under conditions of, ultrasonic wave acting frequency is 20 KHz~50KHz, and power is 50 W~100W, is slowly added dropwise in Xiang Shangshu solution
Methyl tertiary butyl ether(MTBE) 900mL is cooled to 0~5 DEG C under conditions of maintaining rate of temperature fall to be 0.3~1 DEG C/min, continue stirring 1~
3h will be formed by suspension suction filtration and press dry, dry under conditions of 35~45 DEG C of temperature and 0~0.1Mpa of vacuum degree, obtain
The novel crystal forms A about 57g of R-lansoprazole sodium Dimethylacetamide solvate, yield 93%.
The preparation of 2 R-lansoprazole sodium novel crystal form A of embodiment
R-lansoprazole sodium 50g is added to the in the mixed solvent of dimethyl acetamide 200mL and purified water 200mL, is added
0.1gPEG4000 and 0.1g cysteine hydrochloride, the stirring and dissolving at 35~40 DEG C, in the item for applying ultrasonic wave effect
Under part, ultrasonic wave acting frequency is 20 KHz~50KHz, and power is 50 W~100W, and methyl is slowly added dropwise in Xiang Shangshu solution
Isobutyl ether 1600mL is cooled to 0~5 DEG C, continues 1~3h of stirring under conditions of maintaining rate of temperature fall to be 0.3~1 DEG C/min,
Suspension suction filtration will be formed by press dry, it is dry under conditions of 35~45 DEG C of temperature and 0~0.1Mpa of vacuum degree, obtain right orchid
Rope draws the novel crystal forms A about 54g of azoles sodium Dimethylacetamide solvate, yield 88%.
The preparation of 3 R-lansoprazole sodium novel crystal form A of embodiment
R-lansoprazole sodium 50g is added to the in the mixed solvent of dimethyl acetamide 200mL and purified water 100mL, is added
0.1g PVP K30 and 0.1g butylated hydroxy anisole, the stirring and dissolving at 35~40 DEG C are applying ultrasonic wave effect
Under the conditions of, ultrasonic wave acting frequency is 20~50KHz, and power is 50~100W, and isopropyl ether is slowly added dropwise in Xiang Shangshu solution
900mL is cooled to 0~5 DEG C, continues 1~3h of stirring, will be formed under conditions of maintaining rate of temperature fall to be 0.3~1 DEG C/min
Suspension suction filtration press dry, it is dry under conditions of 35~45 DEG C of temperature and 0~0.1Mpa of vacuum degree, obtain R-lansoprazole sodium
The novel crystal forms A about 55g of Dimethylacetamide solvate, yield 89%.
The preparation of 4 R-lansoprazole sodium novel crystal form A of embodiment
R-lansoprazole sodium 50g is added to the in the mixed solvent of dimethyl acetamide 200mL and purified water 100mL, is added
0.1g copolyvidone S630 and 0.1g propylgallate, the stirring and dissolving at 35~40 DEG C are applying ultrasonic wave effect
Under the conditions of, ultrasonic wave acting frequency is 20~50KHz, and power is 50~100W, and methyl- tert fourth is slowly added dropwise in Xiang Shangshu solution
Base ketone 900mL is cooled to 0~5 DEG C, continues 1~3h of stirring, by institute under conditions of maintaining rate of temperature fall to be 0.3~1 DEG C/min
The suspension suction filtration of formation press dry, dry under conditions of 35~45 DEG C of temperature and 0~0.1Mpa of vacuum degree, obtains right Lan Suola
The novel crystal forms A about 57g of azoles sodium Dimethylacetamide solvate, yield 93%.
The preparation of the comparison crystal form 1 of embodiment 5
It is prepared referring to specification Example5 of page 15 in PCT Patent WO2012095859A1.R-lansoprazole 25g
It is dissolved in dehydrated alcohol 250mL, 32.5g sodium iso-octoate is added, is stirred to react 30min, solvent is removed under reduced pressure, add in residue
Enter 250mL normal heptane, 3h is stirred at room temperature, filters, it is dry, obtain the comparison about 18.5g of crystal form 1.
The preparation of the comparison crystal form 2 of embodiment 6
It is prepared referring to specification Example8 of page 16 in PCT Patent WO2012095859A1.
Right Lan Sula azoles 10g is dissolved in the in the mixed solvent of dehydrated alcohol 100mL and water 5mL, is cooled to -5 DEG C, and 2.2g is added
Sodium hydroxide, -5 DEG C of stirring 30min, 80mL normal heptane is added into reaction solution, is continued to stir 30min, is collected solid, does
It is dry, obtain the comparison about 6g of crystal form 2.
The characterization of the novel crystal forms A of 7 R-lansoprazole sodium Dimethylacetamide solvate of embodiment
By X-ray method (x-ray powder diffraction in Chinese Pharmacopoeia annex) by R-lansoprazole sodium obtained above
The novel crystal forms A of Dimethylacetamide solvate is placed on powder diffractometer (Thermo X ' TRA type X-ray diffractometer), is used
Cu-K α 40kV~40mA x-ray radiation, the 2 θ angles with the scanning speed of 8 degree mins at 3~50 degree are scanned.Pass through
Differential thermal analysis (DSC) method, on 204 type differential thermal analyzer of NETZSCH DSC, with 10 DEG C/min heating rate, 30~300
Scanning in DEG C temperature range.The PXRD map is shown in attached drawing 1.The DSC map is shown in attached drawing 2.
The estimation of stability of the novel crystal forms A of 8 R-lansoprazole sodium Dimethylacetamide solvate of embodiment
By comparison crystal form obtained 1 and comparison crystal form 2, carry out with R-lansoprazole sodium novel crystal form A of the invention influence because
Element test, accelerated stability test, test method refer to referring to bulk pharmaceutical chemicals in Chinese Pharmacopoeia annex and drug preparation stability test
Lead principle.
(1), influence factor is tested:
1) comparison crystal form 1 and comparison crystal form 2, and R-lansoprazole sodium novel crystal form A of the invention, in 60 hot test: are taken
It places 10 days at a temperature of DEG C, was sampled in the 5th day and the 10th day, measure indices and 0 day, test result is as follows.
2) high humidity test: taking former comparison crystal form 1 and comparison crystal form 2, and R-lansoprazole sodium novel crystal form A of the invention, in
It places 10 days under RH75%, was sampled in the 5th day and the 10th day, measurement indices were compared with 0 day sample, and test result is such as
Under.
3) strong illumination is tested: take comparison crystal form 1 and comparison crystal form 2, and R-lansoprazole sodium novel crystal form A of the invention,
It is placed 10 days under conditions of illumination is (4500 ± 500) lx, was sampled in the 5th day and the 10th day, measure indices and 0 day sample
Product are compared, and test result is as follows.
(2) accelerated stability test:
Will comparison crystal form 1 and comparison crystal form 2, with R-lansoprazole sodium novel crystal form A of the invention in climatic chamber into
Row 6 months accelerated stability tests.Experimental condition is: 40 DEG C/75% relative humidity (RH), takes respectively at 0,1,2,3,6 month
Sample carries out purity and foreign impurity matters test (high performance liquid chromatography), as a result as follows.
From the foregoing, it will be observed that the stability of R-lansoprazole sodium novel crystal form A is better than comparison crystal form 1 and crystal form 2 in the prior art.
Especially under high temperature, high humidity and illumination condition, the stability of R-lansoprazole sodium novel crystal form A has obvious raising.
9 wettability test of embodiment
Crystal form 1 and comparison crystal form 2 will be compared, is placed in dynamic vapor sorption with R-lansoprazole sodium novel crystal form A of the invention
In instrument, 40 DEG C of temperature is hereinafter, record weight when mass change in 3 hours is less than 0.01g.
The applicability that 10 different crystal forms of embodiment are applied to hot-melt extrusion process is investigated
The related substance of comparison crystal form 1(that the present inventor such as weighs at the weight is that 0.11%), (related substance is comparison crystal form 2
0.12%), novel crystal forms A (related substance is 0.10%), chooses water soluble carrier material PEG6000 and enteric solubility carrier material acetic acid
Succinic acid hydroxypropyl methyl cellulose HPMCAS is representative, using Compritol 888 ATO as plasticizer, according to following parts by weight
Prescription carries out hot-melt extruded and prepares solid dispersion particles: 1 part of bulk pharmaceutical chemicals, 10 parts of carrier material, 2 parts of Compritol 888 ATO.Knot
Fruit is as follows.
11 R-lansoprazole sodium novel crystal form A tablet of embodiment and preparation process
R-lansoprazole sodium novel crystal form A 30g, in terms of R-lansoprazole
Pregelatinized starch 75g
Low substituted hydroxypropyl cellulose 20g
Microcrystalline cellulose 45g
Appropriate PVP K30
Magnesium stearate 2g
1000 are prepared altogether
Preparation process: R-lansoprazole sodium novel crystal form A, microcrystalline cellulose, pregelatinized starch and the low substitution of recipe quantity are taken
Hydroxypropylcellulose is uniformly mixed respectively through 100 mesh sieves；Make wetting agent, 20 mesh with 3% PVP K30 aqueous solution
Sieve granulation, dry, 20 mesh sieves；It is mixed into the magnesium stearate of recipe quantity, tabletting to obtain the final product.
The dissolution rate of 12 R-lansoprazole sodium novel crystal form A tablet of embodiment is evaluated
Dissolving-out method: the dissolution method of Chinese Pharmacopoeia annex
Paddle method revolving speed: 50 turns
Medium temperature: 37 ± 0.5 DEG C
Measuring method: UV-VIS spectrophotometry
Calculation method: external standard method
Contrast solution preparation method: taking the dry reference substance to constant weight appropriate, accurately weighed, is diluted to often with dissolution medium
The solution of about 5 μ g in 1ml.
The comparison crystal form 1 of weight such as take respectively, comparison crystal form 2 and novel crystal forms A of the present invention are as bulk pharmaceutical chemicals, according to embodiment
12 prescriptions and method, each obtained respective tablets.Every batch of 6, using water as dissolution medium, according to above-mentioned dissolution and measuring method into
Row test.Take solution appropriate and fluid infusion respectively at 5min, 10min, 15min, 30min, 45min, 60min, filtration, precision measures
Appropriate filtrate, solubilization go out the solution that medium water is diluted to about 10 μ g in every 1ml, dissolution rate are calculated according to absorbance, as a result such as
Shown in following table.
From the foregoing, it will be observed that the dissolution rate of novel crystal forms A tablet of the present invention is greater than the dissolution speed of the tablet of comparison crystal form 1 and 2
Rate, the present invention have outstanding dissolving out capability using tablet made of R-lansoprazole sodium novel crystal form A.
Embodiment 13 is directed to the Experiment on therapy of helicobacter pylori
The bacterial strain that the present inventor selects is helicobacter pylori NCTC11637 in international standard bacterial strain.Test specimen is pair
Than crystal form 1 and comparison crystal form 2, with R-lansoprazole sodium novel crystal form A of the invention.Experimental material is tryptose soya agar,
Horse whole blood, spiral are coated with instrument and mixed gas incubator.
Plate incorporation test: 1) prepared by plate: preparation concentration containing R-lansoprazole is 0.200 μ of μ g/ml~200 g/ml's
Serial blood plate (containing 10% horse whole blood)；2) apply bacterium: it is about 107 that PBS, which dilutes Hp (helicobacter pylori) to bacterial concentration,
Cfu/ml applies bacterium using spiral coating instrument, and each concentration of every kind of bacterium of every medicine applies two pieces of plates (every 50 μ l bacterium solution of plate), is placed in
In mixed gas (nitrogen 85%, carbon dioxide 10%, oxygen 25%) 37 DEG C culture 72 hours after observe result；3) it is tested more than
Process is in triplicate.Above-mentioned sample is as shown in the table to the fungistatic effect (ug/mL) of NCTC11637.
Conclusion: it as seen from the above table, compares and comparison crystal form 1 and 2, R-lansoprazole sodium dimethylacetamide provided by the invention
The novel crystal forms A of amine solvent compound has stronger fungistatic effect to helicobacter pylori.
The novel crystal forms A for the R-lansoprazole sodium Dimethylacetamide solvate that the present invention is disclosed and proposed and preparation side
Method, those skilled in the art can be by using for reference present disclosure, and the links such as appropriate feed change, technological parameter are realized.Of the invention
Method has been described by preferred embodiment with product, related technical personnel obviously can not depart from the content of present invention,
Method described herein and product are modified in spirit and scope or appropriate changes and combinations realize the technology of the present invention.
Claims (8)
1. a kind of novel crystal forms A of R-lansoprazole sodium Dimethylacetamide solvate, which is characterized in that the every mole new crystalline substance
It include 1 mole of dimethylacetamide solvent molecule in type A, structural formula is as follows,
；
Its x-ray diffractogram of powder spectrum is 5.9,7.6,12.2,12.7,16.6,18.4,20.5,25.8 in 2 θ of the angle of diffraction,
There is characteristic diffraction peak at 26.8,31.4 degree, wherein 2 θ value error ranges are ± 0.2, and the map is as shown in Figure of description 1；
Its DSC map has endothermic characteristics peak at 132.4 ± 1 DEG C, has exothermic characteristic peak at 204.6 ± 1 DEG C, the map such as specification
Shown in attached drawing 2.
2. the novel crystal forms A of R-lansoprazole sodium according to claim 1, which is characterized in that its Fourier transform infrared light
Spectrum is 3383 ± 2,3134 ± 2,3072 ± 2,2975 ± 2,1646 ± 2,1583 ± 2,1475 ± 2,1441 in wave number
± 2,1316 ± 2,1265 ± 2,1198 ± 2,1168 ± 2,1111 ± 2,1036 ± 2,972 ± 2,915 ± 2,857
± 2,745 ± 2,662 ± 2 cm-1There is characteristic absorption peak at place, and the infared spectrum is as shown in Figure of description 3；And novel crystal forms A
Thermogravimetric analysis TG map as shown in Figure of description 4.
3. a kind of prepare the novel crystal forms A such as R-lansoprazole sodium Dimethylacetamide solvate any in claim 1~2
Method, which is characterized in that comprise the following steps:
(1) R-lansoprazole sodium is added to the in the mixed solvent of dimethyl acetamide and water, dimethyl acetamide: the volume of water
Than for 1:0.5~1, above-mentioned mixed solvent volume is 4~6 times of R-lansoprazole sodium weight, and unit is mL/g；
(2) suitable viscosity modifier and antioxidant, the stirring and dissolving at 25~40 DEG C is added；
(3) under conditions of applying ultrasonic wave effect, poor solvent is added dropwise into solution, poor solvent volume is dimethylacetamide
2~4 times of the mixed solvent volume of amine and water；Wherein, poor solvent is ether solvent either ketones solvent, ether solvent choosing
From methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, methyltetrahydrofuran, ether, isopropyl ether, one of methyl phenyl ethers anisole；Ketone is molten
Agent is selected from acetone, methyl iso-butyl ketone (MIBK), butanone, methyl butyl ketone, methyl isopropyl Ketone, one of methyl tertbutyl ketone；
(4) it is cooled to 0~5 DEG C, continues 1~3h of stirring, suction filtration is formed by suspension；
(5) dry under conditions of 35~45 DEG C of temperature and 0~0.1Mpa of vacuum degree, obtain R-lansoprazole sodium dimethylacetamide
The novel crystal forms A of amine solvent compound；
Wherein, described " viscosity modifier " is selected from Macrogol 6000, Macrogol 4000, PVP K30, copolyvidone S630
One or more of, the dosage of viscosity modifier is the 0.05%~0.2% of the R-lansoprazole sodium novel crystal form A weight being added；
" antioxidant " is selected from butylated hydroxy anisole, propylgallate, and one or more of cysteine hydrochloride resists
Oxidizer is the 0.1%~0.5% of the R-lansoprazole sodium novel crystal form A weight being added.
4. preparation method according to claim 3, which is characterized in that viscosity modifier is copolyvidone S630, dosage
It is the 0.2% of the R-lansoprazole sodium novel crystal form A weight being added；Antioxidant is propylgallate, and dosage is the right orchid being added
Rope draws the 0.2% of azoles sodium novel crystal form A weight.
5. the preparation method according to claim 4, which is characterized in that poor solvent is methyl tertiary butyl ether(MTBE), and volume is
3 times of dimethyl acetamide and the mixed solvent volume of water；Or poor solvent is methyl iso-butyl ketone (MIBK), volume is dimethyl
4 times of the mixed solvent volume of acetamide and water.
6. preparation method according to claim 5, which is characterized in that in step 3, the drop rate of poor solvent is every point
The 0.3%~3% of poor solvent total volume is added dropwise in clock；Ultrasonic wave, and ultrasound are referred to during poor solvent crystallization is added dropwise
Wave acting frequency is 20KHz~50KHz, and power is 50W~100W；The rate of temperature fall of " cooling " described in step 4 is 0.3 DEG C~
1℃/min。
7. any R-lansoprazole sodium novel crystal form A is in the solid dispersions for preparing R-lansoprazole sodium in such as claim 1~2
In purposes, which is characterized in that the solid dispersions are by R-lansoprazole sodium novel crystal form A, carrier material and other pharmacy
What upper acceptable auxiliary material was prepared using torching mark.
8. purposes according to claim 7, which is characterized in that the carrier material is selected from PVP class, polyacrylic resin
Class, cellulose family is surfactant-based, insoluble framework material, erodible framework material, one of hydrophilic back bone material
Or it is several；And resulting solid dispersions further wrap gastric solubility coating or enteric coatings, can get in different pH rings
The particle discharged under border is used as preparation intermediate.
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| CN101977909A (en) * | 2008-03-18 | 2011-02-16 | 雷迪博士实验室有限公司 | Dexlansoprazole process and polymorphs |
| WO2012095859A1 (en) * | 2011-01-12 | 2012-07-19 | Hetero Research Foundation | Polymorphs of dexlansoprazole salts |
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| CN101137371A (en) * | 2005-01-14 | 2008-03-05 | 克卡制药新梅斯托股份公司 | Process for preparing lansoprazole |
| CN101977909A (en) * | 2008-03-18 | 2011-02-16 | 雷迪博士实验室有限公司 | Dexlansoprazole process and polymorphs |
| WO2012095859A1 (en) * | 2011-01-12 | 2012-07-19 | Hetero Research Foundation | Polymorphs of dexlansoprazole salts |
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Application publication date: 20170531 Assignee: Chongqing Dikang Changjiang Pharmaceutical Co.,Ltd. Assignor: NANJING HAIRONG PHARMACEUTICAL Co.,Ltd.|Chengdu Di Kang medicine companies LLC Contract record no.: X2021510000035 Denomination of invention: A new crystal form of right lansoprazole sodium and its preparation method Granted publication date: 20190305 License type: Common License Record date: 20210916 |