CN103864669A - Novel crystal form of Mitiglinide calcium and preparation method thereof - Google Patents
Novel crystal form of Mitiglinide calcium and preparation method thereof Download PDFInfo
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract
The invention provides a novel crystal form of Mitiglinide calcium. The X-ray powder diffraction pattern has characteristic absorption peaks at 2 theta pf about 5.40 and 17.24; and the DSC diagram shows no obvious endothermic peak at 120 DEG C. Compared with dihydrate of Mitiglinide calcium, the novel crystal form has better bioavailability and excellent stability. The invention also discloses a method for preparing the novel crystal form. The method includes the following steps: mixing an organic solvent with Mitiglinide calcium, heating to a completely melt state, and then removing the solvent to obtain the novel crystal form. The invention also discloses purpose of the novel crystal form and a pharmaceutical preparation containing the novel crystal form.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to new crystal of a kind of S 21403 and preparation method thereof.
Background technology
Diabetes (diabetes) are by inherited genetic factors, immunologic function disorder, infected by microbes and toxin thereof, free radical toxin, the various virulence factors of mental element etc. act on body and cause hypoinsulinism, insulin resistant etc. and cause sugar, protein, fat, a series of metabolism disorder syndromes such as power and water Xie Zhi, clinically taking hyperglycemia as principal feature, can there is diuresis in model case, many drinks, many foods, the performance such as become thin, i.e. " three-many-one-little " symptom, diabetes (blood sugar) cause complication once control bad meeting, cause kidney, eye, the exhaustion pathology at the positions such as foot, and cannot cure.China is large-scale Diabetes Epidemiological Investigation demonstration several times, and diabetes mellitus in China morbidity significantly increases, and has risen 10 times in the past in 30 years.2007-2008, under diabetology branch of Chinese Medical Association tissue, in the whole nation, 14 provinces and cities have carried out the epidemiology survey of diabetes.By weighted analysis, estimate that 20 years old above grownup's diabetes prevalence of China is 9.7%, Chinese Adult diabetes sum reaches 9,240 ten thousand, wherein rural area 4,310 ten thousand, 4,930 ten thousand left and right, city.China may become the country that diabetes number of patients is maximum.In diabetic subject, the shared ratio of diabetes B is about 90-95%.
S 21403 (Mitiglinide Calcium), chemistry (-)-2 (S)-benzyl-4 oxo-4-(cis-perhydroisoindole-2-yl)-Calcium Butyrate monocalcium salt compound by name, how class hyperglycemia medicine of the novel row of being developed by Japanese Kissei Pharmaceutical Co., Ltd., is used for the treatment of diabetes B.Mitiglinide insulin secretion accelerating is rapid-action, and acting duration is short, avoids continuing thereby can reduce rapidly diabetic subject's postprandial blood sugar the hypoglycemia untoward reaction that hypoglycemic causes.
Bibliographical information, mitiglinide, compared with repaglinide, Na Gelie a kind of apple and traditional sulfonylureas, has following advantage: (1) mechanism of action novelty, onset is faster, and acting duration is shorter.This product is by closing the ATP dependency K passage on pancreatic beta cell film, causes stream in Ca, Ca concentration in cell is increased and makes the vesica threshing of extracellular insulin-containing, thereby stimulate the secretion of Regular Insulin.(2) curative effect is stronger.(3) administration is flexible.Often inferior to taking medicine before the meal.Abroad the tracking investigation after 2500 many cases patients uses is shown, patient is very satisfied to the handiness of mitiglinide administration, and more than 95% patient selects will continue to take this type of antidiabetic drug.(4) there is the laudatory title of " external pancreas ".Mitiglinide effect mainly concentrates on and reduces postprandial hyperglycemia.(5) early stage and slight diabetic subject's first-line treatment medicine.(6) safe, better tolerance.Life-time service mitiglinide can not produce the medicine source property hypoglycemia causing because of drug accumulation yet.The adverse reaction rate of mitiglinide is with blank consistent, because of untoward reaction therapy discontinued person only 0.3%.Therefore, the better tolerance of mitiglinide, patient's compliance is high.
Document Chem.Pharm.Bull, 45(9) 1518-1520(1997) detailed preparation process of S 21403 is disclosed, the document is not reported crystal formation.Existing document only has Chinese patent CN1634885B to report the crystal formation of S 21403, but it should be noted that this crystal formation is the crystal formation of dihydrate.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of mitiglinide calcium cpd of crystal habit, compared with the dihydrate crystal formation that this crystal habit is reported with Chinese patent CN1634885B, there is more excellent bioavailability, transformation period is also more better than mitiglinide calcium salt dihydrate, and there is splendid stability, and the advantages such as this crystal habit is beneficial to the operation in preparation process, quality controllable.
The crystal formation of S 21403 provided by the invention, its X-ray powder diffraction collection of illustrative plates has following characteristics: being about 5.40,17.24 places at 2 θ has charateristic avsorption band to exist; Its DSC figure occurs without obvious endotherm(ic)peak at 120 DEG C, has a little endotherm(ic)peak, has sharp-pointed endotherm(ic)peaks and be about the endothermic signal of 13.2796J/g at the peak temperatures of 229.73 DEG C within the scope of 169.09 DEG C of peak temperatures.2926.2,2853.7,1621.2,1555.9,1446.9,1334.9cm its infrared absorption spectrum has following charateristic avsorption band:
-1.
S 21403 new crystal of the present invention is without crystal water or recrystallisation solvent.
Ratio in S 21403 new crystal bulk drug of the present invention reaches more than 50% and can reach object of the present invention, preferably more than 70%, more preferably more than 95%.
The present invention also provides a kind of method of preparing S 21403 new crystal of the present invention, and the method comprises the following steps:
The first step, mixes organic solvent and S 21403, is heated to completely molten clear; Second step, removes solvent, is drying to obtain new crystal.
The organic solvent that the first step reaction is described, is selected from the aqueous solution of methyl alcohol, ethanol, ethanol, for one or more combination wherein, is preferably methyl alcohol.
The method that removes solvent that second step reaction is described, comprises one or more combination of the methods such as distillation, concentrating under reduced pressure, freeze-drying, volatilization, is preferably concentrating under reduced pressure.
The present invention also provides the S 21403 of described new crystal for the preparation of the purposes of the pharmaceutical preparation for the treatment of diabetes and secondary illness thereof.
The present invention also provides the pharmaceutical composition made from S 21403 new crystal of the present invention.
S 21403 new crystal provided by the invention and suitable pharmaceutical excipient that S 21403 new crystal composition of the present invention contains physiology significant quantity, described composition is the medically acceptable pharmaceutical preparation that S 21403 new crystal and pharmaceutical excipient are mixed with.
Pharmaceutical preparation of the present invention can be any oral preparations, and these formulations comprise: tablet, capsule, sustained release preparation, controlled release preparation, suspensoid etc.
The pharmaceutical preparation of new crystal of the present invention can be prepared solid oral composition by conventional methods such as mixing, filling, compressing tablet, granulations, by dispersion technology, the active substance of new crystal is dispersed in composition.
The pharmaceutical preparation of new crystal of the present invention can be oral liquid form, for example, adopt water-based or oily suspensions, solution, emulsion, syrup etc., or can be a kind of water before use or the composite drying products of other suitable carriers.This liquid preparation can contain conventional additive, such as suspension agent, for example sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible-fat, for example Prunus amygdalus oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerine; For example para hydroxybenzene methyl esters of sanitas or propylparaben or Sorbic Acid, can contain conventional perfume compound or tinting material, Drug coating and if need.
Preparation of the present invention can be prepared by pharmaceutics routine techniques.
S 21403 new crystal prepared by the present invention can make bioavailability significantly improve and also stability splendid, crystal formation storage, in preparation process without obviously turning brilliant phenomenon.
Brief description of the drawings
The infrared spectra of the S 21403 new crystal of Fig. 1: embodiment 1;
The thermogram spectrum of the S 21403 new crystal of Fig. 2: embodiment 1;
The X-ray powder diffraction of the S 21403 new crystal of Fig. 3: embodiment 1;
Fig. 4: the bioavailability curve of S 21403 new crystal and dihydrate crystal formation.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this.In all embodiment, ultimate analysis adopts Elementar Vario EL III type elemental analyser, and mass spectrum adopts AGILENT 1100 LC/MS mass spectrographs,
1bRUKER AV-500 type nuclear magnetic resonance analyser for H-NMR, fusing point aspect adopts NETZSCH DSC 204t-sensor/E type differential thermal analyzer owing to following to decompose, and crystal formation adopts the X ' TRA of Thermo company type X-ray diffractometer to measure; HPLC adopts the peace system of wearing.
The preparation of embodiment 1 S 21403 new crystal
In the reaction flask of 250ml, add methyl alcohol 100ml, stir the lower S 21403 10.0g(HPLC:99.94% that drops into), be heated to 60 DEG C and make to dissolve completely.At 50 DEG C, low vacuum, under 0.02Mpa, is concentrated into dryly, and 50 DEG C of vacuum-dryings of solid obtain S 21403 new crystal 9.98g(HPLC:99.92%).Yield: 99.8%.
The preparation of embodiment 2 S 21403 new crystal
In the reaction flask of 250ml, add dehydrated alcohol 210ml, stir the lower S 21403 5.00g(HPLC:99.94% that drops into).Be heated to backflow, add 11.0g water.Until completely molten clear after, at 60 DEG C, low vacuum, under 0.02Mpa, is concentrated into dryly, 50 DEG C of vacuum-dryings of solid obtain S 21403 new crystal 4.94g(HPLC:99.87%).Yield: 98.8%.
The preparation of embodiment 3 S 21403 new crystal
In the reaction flask of 250ml, add 95% ethanol 220ml, stir the lower S 21403 5.00g(HPLC:99.94% that drops into).Be heated to backflow, until completely molten clear after, at 55 DEG C, low vacuum, under 0.02Mpa, is concentrated into dryly, 45 DEG C of forced air dryings of solid obtain S 21403 new crystal 4.92g(HPLC:99.91%).Yield: 98.4%.
The mensuration of embodiment 4 S 21403 new crystal physical propertys
By FT-IR(KBr compressing tablet-transmission method) infrared spectra that detects embodiment 1-3 S 21403 new crystal shows, 2926.2,2853.7,1621.2,1555.9,1446.9,1334.9cm the S 21403 of new crystal has following absorption:
-1, the infrared spectra of the S 21403 new crystal of embodiment 1 as shown in Figure 1.
With dsc (DSC) detection S 21403 new crystal, its DSC of the S 21403 of new crystal is without endotherm(ic)peak appearance below 120 DEG C, and therefore, this crystal formation is containing crystal water, also non-solvent compound.Within the scope of 169.09 DEG C of peak temperatures, there is a little endotherm(ic)peak, have a sharp-pointed endotherm(ic)peak and the endothermic signal for 13.2796J/g at the peak temperatures of 229.73 DEG C, as the thermogram of the S 21403 new crystal of embodiment 1 is composed as shown in Figure 2.
By X-ray diffraction method, the S 21403 of crystal formation is detected, its testing conditions is: the sweep velocity with 8 scans between 2 θ value 2-40 degree, uses the x radiation x of Cu-Ka40kV40mA, and its slit is 2/4/0.5/0.2.The X-ray powder diffraction of the S 21403 of the new crystal representing with 2 θ values and spacing (d value) should be about 5.40,17.24 places or d value at 2 θ and be about 16.352,5.139 places and have characteristic peak, and the X-ray powder diffraction of the S 21403 new crystal of embodiment 1 as shown in Figure 3.
The bioavailability of embodiment 5 S 21403 different crystal forms
Below, by the bioavailability contrast of S 21403 new crystal of the present invention and dihydrate crystal formation, the excellent results of new crystal of the present invention is described.
The S 21403 new crystal of embodiment 1 is labeled as to crystal formation 04173, and the crystal formation preparing by CN1634885B embodiment 1 is labeled as crystal formation 0301.
Test method: adopt 24 SD rats, respectively quiet note (iv), gavage (po) gives two kinds of crystal formations (crystal formation 0301, crystal formation 04173) S 21403 CMC-Na suspension, take a blood sample in different time points, measure mitiglinide calcium concn in blood plasma with LC-MS method, calculate medicine for parameter and AUC(0-t with DAS).Bioavailability F=gavage AUC (0-t)/quiet note AUC (0-t) * 100%.The data of the bioavailability of two kinds of crystal formations are as shown in table 1 below, and its graphic representation as shown in Figure 4.
Table 1 bioavailability correlation data table
Above data show, the bioavailability (90.38%) of S 21403 new crystal (04173 crystal formation) is greater than the bioavailability (58.50%) of mitiglinide calcium salt dihydrate crystal formation (0301 crystal formation).
The stability of embodiment 6 S 21403 new crystal
Below novel mitiglinide crystalline study on the stability, so that the stability of S 21403 new crystal to be described.
Get the novel mitiglinide crystalline sample of embodiment 1, be placed in respectively under following condition (40 DEG C-RH75%, 25 DEG C-RH65%) and investigate its stable crystal form, crystal formation content, detects the variation of every quality index, and the data obtained is as shown in table 2:
Table 2 novel mitiglinide crystalline study on the stability result
From form, can find out that under above-mentioned condition, this new crystal is to have good stability, impurity is without obvious increase.
Will speed up experiment and the sample of the experiment that keeps sample for a long time carries out infrared, DSC and X-ray diffraction test, data results shows that crystal formation is stable, without obvious crystal conversion phenomenon.
Claims (9)
1. a crystal formation for S 21403, is characterized in that:
Its X-ray powder diffraction collection of illustrative plates has following characteristics: being about 5.40,17.24 places at 2 θ has charateristic avsorption band to exist;
Its DSC figure occurs without obvious endotherm(ic)peak at 120 DEG C.
2926.2,2853.7,1621.2,1555.9,1446.9,1334.9cm 2. crystal formation claimed in claim 1, is characterized in that its infrared absorption spectrum has following charateristic avsorption band:
-1.
3. crystal formation claimed in claim 1, is characterized in that its DSC exists a little endotherm(ic)peak, has sharp-pointed endotherm(ic)peaks and be about the endothermic signal of 13.2796J/g at the peak temperatures of 229.73 DEG C within the scope of 169.09 DEG C of peak temperatures.
4. the crystal formation in claim 1-3 any one, its purity is greater than 95%.
5. the preparation method of the crystal formation of the S 21403 described in claim 1 to 4, step comprises: organic solvent and S 21403 are mixed, be heated to completely molten clearly, then remove solvent, to obtain final product.
6. preparation method claimed in claim 5, is characterized in that described organic solvent is selected from one or more the combination in the aqueous solution of methyl alcohol, ethanol, ethanol, is preferably methyl alcohol.
7. preparation method claimed in claim 5, is characterized in that described one or more the combination that solvent comprises the methods such as distillation, concentrating under reduced pressure, lyophilize, volatilization that removes, and is preferably concentrating under reduced pressure.
8. a pharmaceutical preparation, said preparation contains S 21403 and the pharmaceutically acceptable vehicle in claim 1-4 any one.
9. the S 21403 in claim 1-4 any one is for the preparation of the purposes of the pharmaceutical preparation for the treatment of diabetes and secondary illness thereof.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1844096A (en) * | 2006-05-24 | 2006-10-11 | 严洁 | Preparation of mitiglinide calcium and its quality control method |
| CN101627971A (en) * | 2008-07-14 | 2010-01-20 | 严洁 | Nanocrystallized mitiginide calcium hydrate orally disintegrating tablet and preparation method thereof |
| CN102101838A (en) * | 2010-12-06 | 2011-06-22 | 张家港田由新材料科技有限公司 | Preparation method of mitiglinide calcium |
| CN102382033A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Preparation methods for optical activity mitiglinide ester and mitiglinide salt |
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- 2012-12-14 CN CN201210544505.5A patent/CN103864669A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1844096A (en) * | 2006-05-24 | 2006-10-11 | 严洁 | Preparation of mitiglinide calcium and its quality control method |
| CN101627971A (en) * | 2008-07-14 | 2010-01-20 | 严洁 | Nanocrystallized mitiginide calcium hydrate orally disintegrating tablet and preparation method thereof |
| CN102382033A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Preparation methods for optical activity mitiglinide ester and mitiglinide salt |
| CN102101838A (en) * | 2010-12-06 | 2011-06-22 | 张家港田由新材料科技有限公司 | Preparation method of mitiglinide calcium |
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