CN105017216A - Dexlansoprazole crystal form III and preparation method and application thereof - Google Patents
Dexlansoprazole crystal form III and preparation method and application thereof Download PDFInfo
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- CN105017216A CN105017216A CN201410152736.0A CN201410152736A CN105017216A CN 105017216 A CN105017216 A CN 105017216A CN 201410152736 A CN201410152736 A CN 201410152736A CN 105017216 A CN105017216 A CN 105017216A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to the field of a medical technology and relates to a dexlansoprazole crystal form III, its preparation method and an application of the dexlansoprazole crystal form III in preparation of medicines for treatment of various degrees of erosive esophagitis (EE), maintenance treatment of erosive esophagitis and relief of burning heat sensation, stomach burning heat sensation caused by non-erosive gastroesophageal reflux disease (GERD) and the like. The dexlansoprazole crystal form III is characterized by X-ray powder diffraction spectrum, differential thermal analysis spectrum and infrared spectrum. X-ray powder diffraction characteristic absorption peak (2 theta) values of the crystal form are 6.66, 9.18, 9.94, 10.96, 13.04, 14.74, 14.94, 15.42, 15.66, 17.62, 19.72, 21.00, 24.04, 26.10 and 28.68. The crystal form shows excellent physicochemical property, is economic in solvent recovery, has relatively stable water content and can be directly used in preparations of drugs such as capsules and granules so as to improve properties of preparations.
Description
Technical field
The invention belongs to medical art, relate to treatment gastrointestinal tract disease technical field of pharmaceuticals particularly, more particularly, the present invention relates to Dexlansoprazole crystal form III and preparation method thereof and the erosive esophagitis (EE) for the preparation of the various degree for the treatment of, the maintaining treatment of erosive esophagitis and alleviation burning sensation, the application of the medicine of the aspects such as the scorching hot sense that Non-erosive gastroesophageal reflux disease (GERD) causes.
Background technology
Gastroesophageal reflux disease (gastroesophageal reflux disease, GERD) means that gastric content reflux enters oesophagus, causes a kind of disease of malaise symptoms and (or) complication.GERD can be divided into Non-erosive reflux disease (non-erosivereflux disease, NERD), erosive esophagitis (erosive esophagitis, EE) and Barrett oesophagus (Barrett ' s esophagus, BE) three types, also can be described as GERD relative disease.NERD means to there is the relevant malaise symptoms of reflux, but has no BE and Esophageal Mucosa breakage under scope.EE is the section mucous membrane breakage far away of visible oesophagus under meaning scope.Los Angeles meeting in 1994 proposes clear and definite EE grade scale, is divided into A ~ D level according to the severity of esophageal lesion under scope.BE mean the tesselated epithelium of oesophagus section far away replace by cylindrical epithelium.In three kinds of disease form of GERD, NERD is the most common, and EE can merge esophagostenosis, ulcer and digestive tract hemorrhage, and BE likely develops into adenocarcinoma of esophagus.The symptom relevant to reflux is called reflux symptom group.Typical and common reflux symptom is heartburn and reflux, other rare or atypical related symptoms comprise following one or more, as epigastric pain, pectoralgia, belch, abdominal distension, epigastric discomfort, foreign body in pharynx sense, odynophagia, dysphagia etc., in addition the outer symptom of oesophagus is also had, as chronic cough, pharyngolaryngitis, asthma etc.
The harm of GERD is very large, and patient need stand the torment of disease misery for a long time, and GERD night-time attack can be slept by severe jamming, and patient works by day energy can be obviously not enough, and quality of life can obviously reduce.And the recurrence rate of GERD is very high.After research display drug withdrawal, the recurrence rate of 1 year is that the recurrence rate of 65% ~ 80%, 2 years almost reaches 100%.GERD is common disease, and global different areas morbidity is also not identical.The morbidity of West Europe and North America GERD symptom is 10% ~ 20%.The morbidity of China GERD is about 10%, and wherein the metropolitan number of patients in developed area will far more than the number of patients in common rural area, and the recall rate of reflux esophagitis raises just year by year.
Gastric acid secretion inhibiting is the basic skills for the treatment of GERD at present.The medicine of gastric acid inhibitory comprises bisfentidine (H2RA) and proton pump inhibitor (PPI) etc.The appearance of proton pump inhibitor (PPI) is a breakthrough for the treatment of GERD.PPI acts on gastric mucosa parietal cell specifically, reduces the activity of the H+/K+-ATP enzyme in parietal cell, thus can forcefully gastric acid inhibitory secretion relief of symptoms and esophagitis is healed.To healing erosive esophagitis, be better than H2 receptor antagonist.
R-lansoprazole of the present invention is PPI, is used for the treatment of the erosive esophagitis (EE) of various degree clinically, the maintaining treatment of erosive esophagitis and alleviation burning sensation, the scorching hot sense that Non-erosive gastroesophageal reflux disease (GERD) causes.
R-lansoprazole, English name Dexlansoprazole, chemical structural formula is:
R-lansoprazole has I, II two kind of crystal habit, the Dexlansoprazole crystal form III that the present inventor finds in an experiment is unexpectedly different from above crystal formation, it shows excellent physico-chemical property, solvent reclaims economical, and the relatively stable and preparation that can be directly used in medicine of water content is as improved the performance of preparation in capsule and granule.The present invention is based on above-mentioned discovery to be accomplished.
Summary of the invention
The object of the present invention is to provide a kind of Dexlansoprazole crystal form III, be used for the treatment of the erosive esophagitis (EE) of various degree, the maintaining treatment of erosive esophagitis and alleviation burning sensation, the scorching hot sense that Non-erosive gastroesophageal reflux disease (GERD) causes.
Another object of the present invention is the preparation method of the Dexlansoprazole crystal form III providing applicable suitability for industrialized production.
Another object of the present invention is to provide the pharmaceutical composition containing Dexlansoprazole crystal form III.
A further object of the invention discloses the application of Dexlansoprazole crystal form III in preparation treatment gastrointestinal tract disease medicine.
Dexlansoprazole crystal form III disclosed in this invention has good fusing point and quality, and its quality purity is at least 99.5%.Dexlansoprazole crystal form III has the performance synthesized on a large scale or be mixed with needed for therapeutic preparation, to light, wet, thermally-stabilised, is convenient to produce, store.
For realizing above-mentioned purpose of the present invention, adopt following technical scheme:
Dexlansoprazole crystal form III of the present invention is ethyl acetate and normal hexane solvation shape, and it uses Cu-Ka radiation, and X-ray powder diffraction spectrum (" XRD ") as shown in Figure 1.The X-ray powder diffraction spectrum represented to spend 2 θ has peak 6.66,9.18,9.94,10.96,13.04,14.74,14.94,15.42,15.66,17.62,19.72,21.00,24.04,26.10 and 28.68; 2 θ measuring error are ± 0.2.
Infrared absorption spectrum is 3082,2983,2890,2808,2696,1584,1478,1440,1305,1265,1225,1044,1007,858,659 and 417cm
-1there is characteristic spectrum belt, as shown in Figure 2.
Its DSC endothermic transition, at 137.11-139.78 DEG C, is shown in Fig. 3.
Dexlansoprazole crystal form III provided by the invention, testing method is as follows:
1.X-ray powder diffraction:
Instrument: Rigaku D/MAX-2500.1708X ray polycrystalline powder diffractometer
Target: Cu-K а radiation, 2 θ=2-40 DEG C
Step angle: 0.04 DEG C
Computing time: 0.5 second
Pipe pressure: 40KV
Guan Liu: 100mA
Sweep velocity: 8 DEG C/min
Filter disc: graphite monochromator
2. dsc (DSC):
Instrument: Rigaku standard type TG-DTA analyser
Temperature range: room temperature ~ 300 DEG C
Heat-up rate: 1 DEG C/min
3. infrared spectra (IR):
Instrument: PE-983G infrared spectrometer
Sample preparation: KBr compressing tablet
4. fusing point:
Instrument: YTR-3 type melting point apparatus (Precision Instrument Factory, Tianjin Univ.)
The present invention prepares the method for Dexlansoprazole crystal form III, comprises and adds in crystallization solvent by R-lansoprazole raw material, heating, backflow, filtration, filtrate room temperature places refrigerator 18-24 hour, filters, filter cake washing, 50-60 DEG C of drying under reduced pressure, obtained crystalline R-lansoprazole.Wherein said crystallization solvent is ethyl acetate and normal hexane, and described ethyl acetate and the ratio of normal hexane are 1:5.
Crystal habit R-lansoprazole physico-chemical property and pharmacodynamic study thereof
One, the stability of Dexlansoprazole crystal form III
Get Dexlansoprazole crystal form III in weighing bottle, respectively at 60 DEG C, 4500 ± 500LX illumination, and place under 75% relative humidity, in sampling in 5 days, 10 days, HPLC method measured related substance, and result is as table 1.
Table 1 Dexlansoprazole crystal form III factors affecting stability measurement result
Conclusion: Dexlansoprazole crystal form III 60 DEG C, place 10 days under 4500 ± 500LX illumination and 92.5% relative humidity, related substance is showed no obvious increase.
Two, the pharmacokinetics after Oral Administration in Rats R-lansoprazole 2 kinds of crystal formation raw materials
Test materials and method
1. tested raw material:
The Dexlansoprazole crystal form III of Tianjin Inst. of Materia Medica synthesis and former powder crystal formation.
2 grouping administrations
Select Wistar rat 20, be divided into 2 groups at random by body weight, often organize 10, male and female dual-purpose, fasting is after 16 hours, and each group former powder of oral administration gavage R-lansoprazole and Dexlansoprazole crystal form III respectively, dosage is respectively 30mg/kg.Get blood, separation of serum respectively at 0.17,0.5,1,2,3,4,6,8,12,18 and 24 hour eye socket after administration ,-20 DEG C of preservations are to be measured.
3 chromatographic conditions
Stationary phase: Diamonsil
tMc
18post, 10 μm, 250 × 4.6mm(I.D.), column temperature 30
Moving phase: methyl alcohol: water=70:30, flow velocity: 1ml/min.
Determined wavelength: 215nm, sensitivity: 0.005AUFS.
Sample size: 20 μ l.
4 blood sample treatments
Get rat blood serum 200 μ l, add interior mark (R-lansoprazole intermediate 200 μ g/ml) 10 μ l, after mixing, add DMF(N, dinethylformamide) 200 μ l, vibration 10min, place 30 minutes, with the centrifugation 10min of 10000 turns/min, get supernatant liquor 20 μ l sample introduction.
5 determination of plasma concentration
After bioassay standard curve, draw linear regression equation (y=ax+b).After the administration of mensuration rat, the ratio of blood sample gained peak area, calculates Plasma Concentration according to linear regression equation, and calculates medicine for parameter through 3P97 medicine for computation program.
6 instruments
HPLC test macro: Shimadzu SPD-10A Uv detector, Hi-Tech P4000 high-pressure pump, LabAllianceAS1000 automatic sampler, ANASTAR chromatographic working station.
HT-230A column oven: Tianjin Hengao Technology Development Co., Ltd. produces.
TGL-16G table model high speed centrifuge: Anting Scientific Instrument Factory, Shanghai manufactures.
The miniature vortex mixed instrument of WX-80A: Shanghai Hu Xi analytical instrument factory produces.
7. result of study
In table 2.
Pharmacokinetic study results after table 2 Oral Administration in Rats R-lansoprazole 2 kinds of crystal formation raw materials
Note: in table, data are mean number ± standard deviation (n=6).
Conclusion: the pharmacokinetic after Oral Administration in Rats R-lansoprazole kind crystal formation raw material shows, the Dexlansoprazole crystal form III of Oral Administration in Rats gavage 30mg/kg and former powder, from medicine for parameter, there is no difference between the different parameters of Dexlansoprazole crystal form, absorption in animal body, eliminate basically identical.
Dexlansoprazole crystal form III of the present invention is at the erosive esophagitis (EE) of the various degree for the treatment of, the maintaining treatment of erosive esophagitis and alleviation burning sensation, the aspects such as the scorching hot sense that Non-erosive gastroesophageal reflux disease (GERD) causes show higher biological activity.
Pharmaceutical composition provided by the invention contains Dexlansoprazole crystal form III and pharmaceutically acceptable carrier.
Dexlansoprazole crystal form III of the present invention is suitable for oral Preparation, as tablet comprises fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coated tablet etc.; Capsule comprises hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.; Granule comprises mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.; Oral solution; Oral suspensions; Syrup etc.R-lansoprazole micro mist of the present invention, is also suitable for the preparation of external preparation as gelifying agent, ointment, ointment, paste, patch etc.When preparing oral solid formulation, R-lansoprazole and suitable pharmaceutical excipient can be made particle pack or load gelatine capsule or tabletted.
Pharmacologically acceptable carrier comprises one or more pharmaceutical excipients, such as tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant and lubricant.Composition can be generally 30-60mg containing 50-500mg() the R-lansoprazole of crystal habit.The peroral administration optimised form of this composition is capsule, capsule generally every be generally 30-60mg containing 50-500mg() the R-lansoprazole of crystal habit.The best is every R-lansoprazole containing 30mg, 60mg crystal habit.
Accompanying drawing explanation
Fig. 1 is the XRD figure of Dexlansoprazole crystal form III;
Fig. 2 is the infrared spectrogram of Dexlansoprazole crystal form III;
Fig. 3 is the differential thermogram of Dexlansoprazole crystal form III.
Embodiment
The following examples illustrate further of the present invention, instead of limit.
Except as otherwise noted, in this article, temperature refers to centigradetemperature (DEG C), and room temperature refers to about 18-23 DEG C.Characterize by several method (normally using XRD, DSC and IR) characteristic to them.
embodiment 1
The preparation of Dexlansoprazole crystal form III: get R-lansoprazole 10 grams and insert in 250 milliliters of round-bottomed flasks, add 60 milliliters of analytical pure ethyl acetate and 300 ml n-hexanes and gac, heating, backflow, filtration, filtrate room temperature places 1 hour, filter, filter cake washing, 50-60 DEG C of drying under reduced pressure, obtain 9.8 grams of Dexlansoprazole crystal forms, fusing point 137-140 DEG C.
The XRD figure of Dexlansoprazole crystal form III is having peak 6.66,9.18,9.94,10.96,13.04,14.74,14.94,15.42,15.66,17.62,19.72,21.00,24.04,26.10 and 28.68.
Infrared absorption spectrum is 3082,2983,2890,2808,2696,1584,1478,1440,1305,1265,1225,1044,1007,858,659 and 417cm
-1have characteristic spectrum belt, its DSC endothermic transition is at 137.11-139.78 DEG C.
Refer to Fig. 1, Fig. 2, Fig. 3.
embodiment 2
Prepared by Dexlansoprazole crystal form III30mg capsule
Preparation has the capsule of following composition:
Preparation process:
Feed intake by formula preparation 1000 amounts in batch for having in the wet granulator of high shear force of kilogram levels; Dexlansoprazole crystal form III is placed in wet granulator and adds sucrose one starch spheroidal particle, magnesiumcarbonate, pure sucrose, W-Gum, low-substituted hydroxypropyl cellulose and hydroxy propyl cellulose successively, stirs and mixes for 30 minutes.With water softwood, granulate in oscillating granulator 24 mesh sieve, and by obtained wet granular in 60 DEG C of baking ovens dry 4 hours, sieve whole grain with 30 orders concussions.Encapsulated.
embodiment 3
Prepared by Dexlansoprazole crystal form III60mg capsule
Preparation has the capsule of following composition:
Preparation process
Feed intake by formula preparation 1000 amounts in batch for having in the wet granulator of high shear force of kilogram levels; Dexlansoprazole crystal form III is placed in wet granulator and adds sucrose one starch spheroidal particle, magnesiumcarbonate, pure sucrose, W-Gum, low-substituted hydroxypropyl cellulose and hydroxy propyl cellulose successively, stirs and mixes for 30 minutes.With water softwood, granulate in oscillating granulator 24 mesh sieve, and by obtained wet granular in 60 DEG C of baking ovens dry 4 hours, sieve whole grain with 30 orders concussions.Encapsulated.
embodiment 4
Dissolution determination:
Operate according to " Chinese Pharmacopoeia " 2010 editions two requirements in accordance with the law, with phosphate buffered saline buffer (0.05mol/LpH8) 1000ml for solvent, adjustment rotating speed was per minute 100 turns, in sampling in 5,10,20,30,45,60 minutes, determined by ultraviolet spectrophotometry, the dissolution results of sample is as follows:
Table 3 R-lansoprazole preparation dissolution determination result (%)
| Sample | 5 minutes | 10 minutes | 20 minutes | 30 minutes | 45 minutes | 60 minutes |
| Crystal form II I | 73.17 | 92.80 | 98.07 | 101.1 | 102.0 | 102.4 |
| Former powder | 76.22 | 95.12 | 99.69 | 101.2 | 102.1 | 102.8 |
Claims (7)
1. a Dexlansoprazole crystal form III, it is characterized in that, described crystal formation uses Cu-Ka radiation, and this crystal form X-ray powder diffraction charateristic avsorption band (2 θ) value is: 6.66,9.18,9.94,10.96,13.04,14.74,14.94,15.42,15.66,17.62,19.72,21.00,24.04,26.10 and 28.68; 2 θ measuring error are ± 0.2.
2. Dexlansoprazole crystal form III as claimed in claim 1, is characterized in that, infrared absorption spectrum is 3082,2983,2890,2808,2696,1584,1478,1440,1305,1265,1225,1044,1007,858,659 and 417cm
-1there is characteristic spectrum belt.
3. Dexlansoprazole crystal form III as claimed in claim 1 or 2, it is characterized in that, its DSC endothermic transition is at 137.11-139.78 DEG C.
4. the preparation method of a Dexlansoprazole crystal form III as claimed in claim 1 or 2, it is characterized in that: R-lansoprazole raw material is joined in crystallization solvent, heating, backflow, filtration, filtrate room temperature is placed or freezing 18-24 hour, filter, filter cake washing, 50-60 DEG C of drying under reduced pressure, obtained crystal habit R-lansoprazole.
5. preparation method as claimed in claim 4, it is characterized in that, described crystallization solvent is ethyl acetate and normal hexane; Described ethyl acetate and the ratio of normal hexane are 1:5.
6. a pharmaceutical composition, is characterized in that, said composition is containing the Dexlansoprazole crystal form III described in claim 1 or 2 and one or more pharmaceutical excipients.
7. Dexlansoprazole crystal form III as claimed in claim 1 or 2 is as the erosive esophagitis (EE) of activeconstituents in the various degree of preparation treatment, the maintaining treatment of erosive esophagitis and alleviation burning sensation, the application of the scorching hot sense medicine aspect that Non-erosive gastroesophageal reflux disease (GERD) causes.
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| CN109111430A (en) * | 2017-06-26 | 2019-01-01 | 江苏豪森药业集团有限公司 | A kind of Dexlansoprazole crystal form A and preparation method thereof |
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