CN104370886B - Iprazole crystal formation and its preparation method and application - Google Patents
Iprazole crystal formation and its preparation method and application Download PDFInfo
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Abstract
The invention discloses new M crystal formation of Iprazole and its preparation method and application. The new M crystal formation of Iprazole of the present invention, is easy to preparation. Iprazole crystal formation purity prepared by the inventive method is high, and impurity content is low. The required quantity of solvent of this preparation method is few, and low production cost is simple to operate, and reaction condition gentleness is easily controlled. Favorable reproducibility, acquisition target product crystal formation that can be stable.
Description
Technical field
The present invention relates to Iprazole novel crystal forms and preparation method thereof.
Background technology
Iprazole (Ilaprazole) chemistry is by name: 2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl] sulphonylBase]-5-(1 hydrogen-pyrroles-1-yl)-1 hydrogen-benzimidazole, its chemical structural formula is:
Iprazole, has another name called IY-81149, is new by a kind of irreversible of foreign drugmaker of Korea S one developmentType proton pump inhibitor, it is stronger than Omeprazole that it suppresses helicobacter pylori (HP) effect, and effective dose is only difficult to understand1/4 of azoles draws in U.S.A, be difficult for developing immunity to drugs, and toxic and side effect is not obvious; Iprazole and original like product phaseRatio, is causing delayed gastric emptying, parietal cell swelling and obviously having overcome in varying degrees original like productDrug withdrawal after the defect of the aspect such as gastric acid secretion bounce-back, can strengthen dyskinesis sample functional dyspepsia FD simultaneouslyAnd the curative effect of other acid-related diseases (GERD), and onset is faster, presses down sour better effects if, t1/2It is longer,Can continue to press down acid and control nocturnal acid secretion; Its metabolism is little to the dependence of CYP2C19, is subject to enzyme gene pleiomorphismAffect little. Long half time, whole day maintains that higher to press down sour water flat, stomach pH > time of 4 obviously extends, effectively subtractsThe phenomenon of few Control of Nocturnal Gastric Acid Breakthrough; Curative effect is not subject to liver cell inner cell pigment isodynamic enzyme CYP2C19 metabolic polymorphism shadowThe medicine ringing, individual difference is little; It is that treatment comprises Stomach duodenum ulcer, reflux esophagitis andZollinger-Ellisonsyndrome syndrome is at potent drug interior and gastric acid secretion treating correlative diseases.
After Iprazole oral administration, optionally enter parietal cell, be converted into sulfenamide active metabolite, withH+、K+Sulfydryl effect on-ATP enzyme, the covalent bond of formation disulfide bond, irreversible inhibition H+、K+-ATPEnzyme, the effect that produces gastric acid secretion inhibiting.
The novel potent proton pump of Iprazole Shi Li pearl group first listing of the whole world in 2007 suppresses enteric coatel tablets, suitableFor duodenal ulcer and reflux esophagitis. It presses down acid activity is the more than 4 times of Omeprazole, and Aomei drawsThe day dosing of azoles enteric coated preparations is 40mg, and Iprazole only needs 5～10mg; Long half time, does the used time in bodyBetween long, without CYP2C19 metabolism, also seldom by CYP3A4 enzymes metabolism, to different genotype patient withoutIndividual difference; Less adverse effect. For adapting to the patient of hemorrhage of digestive tract, performance Iprazole Acidinhibitor is strongFeature, pH in stomach is reached rapidly more than 6, hemostasis factor quick acting.
Patent CN101687848B discloses A, B, E, F, the I crystal formation of Iprazole compound, but onState that crystal formation still exists that drug effect is lower, the problem of less stable etc. Wherein racemic ilaprazole crystal form A is instituteThere is in crystal formation in aqueous solvent solubility minimum, but the most stable a kind of crystal formation of thermokinetics; Other four kinds of crystal formationsTo derive and obtain by diverse ways by crystal form A. Crystal formation F, compared with crystal form A, is more soluble in water-based solvent,And the biology of crystal form B and crystal formation F is acceptable poor, and it can be used to prepare depot drug product composition. Wherein describeThe preparation method of crystal form A: 3%NH4OH/ acetonitrile (MeCN) (6.00kg, 15.0 parts) packs burning intoIn bottle, adjust the temperature to 5 DEG C (2-8 DEG C), add Iprazole (0.400kg), stir 1 hour, elimination filterLiquid, filter cake 3%NH4OH/ acetonitrile (MeCN) (2 × 0.400kg, 2 × 1.00 parts) rinsing. Filter cake dressEnter flask, add 0.5%NH4OH/EtOH (0.200kg, 0.500 part) and at 20-25 DEG C reduced pressure concentration,Until there is no distillate. In flask, add 0.5%NH again4OH/EtOH (1.00kg, 2.50 parts), and twoChloromethanes (2.40kg, 6.00 parts). The solution obtaining is evaporated to ca.1.2L (3.00 amount) at 20-25 DEG C.Add again 0.5%NH4OH/EtOH (0.200kg, 0.500 part), is adjusted to 5 DEG C (2-8 DEG C), stirs 45 pointsClock. After elimination filtrate, use 0.5%NH4OH/EtOH (0.200kg, 0.500 part), EtOH (0.200kg, 0.500Part) and MTBE (2 × 0.200kg, 2 × 0.500 parts) rinsing. Filtration cakes torrefaction 2 hours, then in maximum temperature beUnder 53 DEG C of conditions, vacuum drying 92 hours, obtains racemic ilaprazole crystal form A.
Patent CN103172618A discloses Iprazole crystal form X, has wherein described the preparation method of crystal form X:Iprazole is dissolved in the mixed solvent of halogenated alkane and absolute methanol, more above-mentioned solvent is slowly added to secondIn ether solvents, stir until crystallize out, crystal Precipitation Temperature is 25 DEG C, and wherein said halogenated alkane is dichloroOne in methane, chloroform, the volume ratio of halogenated alkane and ether is 1:25～10, halogenated alkane and nothingThe volume ratio of water methanol is 1:1.
Summary of the invention
The object of the present invention is to provide a kind of novel, stable Iprazole new crystal form M and preparation method thereof.
Another object of the present invention is to provide this novel Iprazole crystal form M at treatment gastric ulcer, 12 fingersApplication in enterelcosis and reflux esophagitis and eradicate helicobacter pylori.
Iprazole M crystal formation, its chemical name is: 2-[[(4-methoxyl group-3-methyl)-2-pyridine radicals]-methyl] sulphonylBase]-5-(1 hydrogen-pyrroles-1-yl)-1 hydrogen-benzimidazole, its chemical structural formula is:
The X-ray powder diffraction of Iprazole M crystal formation of the present invention exists at angle of diffraction 2 θ: 7.030-7.060, 9.100-9.130、11.750-11.770、12.620-12.640、14.750-14.770、15.800-15.820、18.110-18.125、19.450-19.470、20.175-20.195、21.110-21.130、22.070-22.090、22.720-22.740、23.600-23.620、24.020-24.040、24.410-24.420、25.430-25.450、27.020-27.040, have characteristic peak within the scope of 27.800-27.815,28.850-28.870,31.340-31.360.
Further, Iprazole M crystal formation of the present invention1H-NMR(CDCl3) data are: 8.29-8.34 (d,1H)，7.65-7.70(d，1H)，7.45-7.55(s，1H)，7.35-7.40(m，1H)，7.10-7.15(s，2H)，6.65-6.70(d，1H)，6.35-6.45(s，2H)，4.80-4.90(dd，2H)，3.72-3.85(s，3H)，2.10-2.20(s，3H)。
Further, IR (KBr, the cm of Iprazole M crystal formation of the present invention-1) data are: 3415-3425,3185-3195，3095-3105，3055-3065，2960-2970，2930-2940，2885-2895，2830-2840，2555-2565，1730-1740，1625-1635，1575-1585，1515-1525，1470-1480，1430-1440，1405-1415，1380-1390，1350-1360，1330-1340，1290-1300，1265-1275，1250-1260，1210-1220，1160-1170，1110-1120，1085-1095，1040-1050，1010-1020，965-975，950-960，885-895，860-870，820-830，805-815，750-760，728-735，660-670，615-625，600-610，520-530，465-475，430-440，410-420。
Preferably, the X-ray powder diffraction of Iprazole M crystal formation of the present invention at angle of diffraction 2 θ is: 7.048,9.119、11.763、12.632、14.760、15.812、18.117、19.465、20.187、21.119、22.079、22.733,23.606,24.030,24.413,25.440,27.030,27.808,28.864,31.352 o'clock toolsThere is characteristic peak.
Further preferably, Iprazole M crystal formation of the present invention1H-NMR(CDCl3) data are: 8.30 (d,1H)，7.67(d，1H)，7.50(s，1H)，7.37(m，1H)，7.11(s，2H)，6.68(d，1H)，6.39(s，2H)，4.84(dd，2H)，3.81(s，3H)，2.15(s，3H)。
Still more preferably, its IR (KBr, cm-1) data are: 3422,3190,3100,3060,2963,2936，2888，2835，2560，1733，1631，1580，1519，1476，1432，1410，1388，1356，1337，1293，1270，1255，1215，1162，1111，1089，1044，1014，970，953，891，863，828，810，757，731，663，621，606，521，470，436，412。
The preparation method of Iprazole M crystal formation, comprises the following steps:
1) Iprazole is dissolved in chloroform;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add ethyl acetate, dissolve, stir,Crystallization;
3) crystal is filtered, filter cake washs with ethyl acetate, dry, obtains Iprazole M crystal formation.
More preferably, the preparation method of Iprazole M crystal formation of the present invention, comprises the following steps:
1) 1～2g Iprazole is dissolved in 5～20mL chloroform;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add 5～40mL ethyl acetate, dissolve,Stir crystallization at least 20 minutes;
3) crystal is filtered, filter cake washs with ethyl acetate, and 20～35 DEG C dry, obtains Iprazole M crystalline substanceType.
In the preparation method of Iprazole M crystal formation of the present invention, wherein step 1) in, preferably the amount of chloroform be 5～20mL; More preferably 5～15mL.
In the preparation method of Iprazole M crystal formation of the present invention, wherein step 2) in, the amount of ethyl acetateBe 10～30mL; More preferably 15～25mL. The crystallization time is 0.5～1 hour.
Iprazole novel crystal forms of the present invention, is easy to preparation, the Iprazole M stable crystal form excellence making.
In the present invention, be to adopt this area conventional method, the great first DX-2700 diffractometer in for example Dandong is measured Ai PulaThe X-ray powder diffraction figure of azoles M crystal formation, condition determination is as follows: CuK α, 40kV, 40mV is light source,Step-length is 0.03 °, and sweep speed is 4 °/min, and sweep limits is 5～90 °, under room temperature condition, carries out. AdoptEQUINOX55 FTIS, condition determination: KBr compressing tablet, scope (cm-1)3999.64～400.157, resolution ratio is 2cm-1, scanning times 16 times. Adopt Bruker400M nmr spectrometer,Solvent is CDCl3, content measurement is1HNMR。
Nuclear magnetic resonance hydrogen spectruming determining result shows that Iprazole crystal formation purity prepared by the present invention is high, and impurity content is low,For the clinical better medication source that provides.
The required quantity of solvent of preparation method the present invention relates to is few, low production cost.
The preparation method who the present invention relates to is simple to operate, and reaction condition gentleness is easily controlled.
The preparation method's favorable reproducibility the present invention relates to, acquisition target product crystal formation that can be stable.
Brief description of the drawings:
Fig. 1 is the X-ray powder diffraction figure of Iprazole M crystal formation.
Fig. 2 is the differential scanning calorimeter figure (DSC figure) of Iprazole M crystal formation.
Fig. 3 is infrared spectrum (IR) figure of Iprazole M crystal formation.
Fig. 4 is the nuclear magnetic resonance spectroscopy figure of Iprazole M crystal formation.
Detailed description of the invention:
Embodiment 1: the preparation of Iprazole M crystal formation
1) 1g Iprazole is dissolved in 10mL chloroform;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add 10mL ethyl acetate, dissolve, stirMix crystallization 30min;
3) crystal is filtered, filter cake is washed three times with ethyl acetate, and 28 DEG C dry, obtains off-white color crystalline powder0.756g, productive rate 75.6%.
7.047,9.128 the X-ray powder diffraction of the Iprazole M crystal formation obtaining at angle of diffraction 2 θ is:,11.758、12.637、14.752、15.815、18.119、19.466、20.189、21.121、22.080、22.726、23.614, there is characteristic peak at 24.024,24.415,25.441,27.028,27.811,28.860,31.347 o'clock;Its1H-NMR(CDCl3) data are: 8.33 (d, 1H), 7.63 (d, 1H), 7.45 (s, 1H), 7.31 (m,1H)，7.15(s，2H)，6.66(d，1H)，6.36(s，2H)，4.82(dd，2H)，3.82(s，3H)，2.11(s，3H); Its IR (KBr, cm-1) data are: 3425,3187,3106,3059,2966,2933,2885,2830，2561，1732，1625，1575，1515，1474，1431，1408，1386，1351，1334，1290，1265，1250，1216，1161，1107，1088，1046，1019，971，950，894，865，826，811，752，730，664，620，603，527，468，434，409。
Embodiment 2: the preparation of Iprazole M crystal formation
1) 1g Iprazole is dissolved in 10mL chloroform, dissolves;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add 15mL ethyl acetate, lucifuge is quickDissolve lucifuge stirring and crystallizing 30min after dissolving;
3) crystal is filtered, filter cake is washed three times with ethyl acetate, and 28 DEG C dry. Obtain off-white color crystalline powder0.758g, productive rate 75.8%.
7.050,9.120 the X-ray powder diffraction of the Iprazole M crystal formation obtaining at angle of diffraction 2 θ is:,11.761、12.635、14.757、15.810、18.114、19.461、20.189、21.116、22.074、22.731、23.601, there is characteristic peak at 24.028,24.414,25.439,27.029,27.806,28.861,31.351 o'clock;Its1H-NMR(CDCl3) data are: 8.32 (d, 1H), 7.65 (d, 1H), 7.48 (s, 1H), 7.34 (m,1H)，7.14(s，2H)，6.65(d，1H)，6.37(s，2H)，4.83(dd，2H)，3.80(s，3H)，2.13(s，3H); Its IR (KBr, cm-1) data are: 3426,3187,3104,3057,2964,2932,2884,2831，2562，1730，1629，1578，1516，1475，1430，1407，1385，1354，1336，1291，1266，1252，1214，1160，1108，1086，1045，1018，972，951，890，867，826，810，756，731，660，623，604，524，468，434，410。
Embodiment 3
1) 1g Iprazole is dissolved in 10mL chloroform, lucifuge is dissolved fast;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add 20mL ethyl acetate, lucifuge is quickDissolve lucifuge stirring and crystallizing 45min after dissolving;
3) crystal is filtered, filter cake is washed three times with ethyl acetate, and 28 DEG C dry. Obtain off-white color crystalline powder8.67g, productive rate 86.7%.
7.048,9.119 the X-ray powder diffraction of the Iprazole M crystal formation obtaining at angle of diffraction 2 θ is:,11.763、12.632、14.760、15.812、18.117、19.465、20.187、21.119、22.079、22.733、23.606, there is characteristic peak at 24.030,24.413,25.440,27.030,27.808,28.864,31.352 o'clock;Its1H-NMR(CDCl3) data are: 8.30 (d, 1H), 7.67 (d, 1H), 7.50 (s, 1H), 7.37 (m,1H)，7.11(s，2H)，6.68(d，1H)，6.39(s，2H)，4.84(dd，2H)，3.81(s，3H)，2.15(s，3H); Its IR (KBr, cm-1) data are: 3422,3190,3100,3060,2963,2936,2888,2835，2560，1733，1631，1580，1519，1476，1432，1410，1388，1356，1337，1293，1270，1255，1215，1162，1111，1089，1044，1014，970，953，891，863，828，810，757，731，663，621，606，521，470，436，412。
Embodiment 4
1) 1g Iprazole is dissolved in 20mL chloroform, lucifuge is dissolved fast;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add 20mL ethyl acetate, lucifuge is quickDissolve lucifuge stirring and crystallizing 1h after dissolving;
3) crystal is filtered, filter cake is washed three times with ethyl acetate, and 28 DEG C dry. Obtain off-white color crystalline powder0.789g, productive rate 78.9%.
7.045,9.120 the X-ray powder diffraction of the Iprazole M crystal formation obtaining at angle of diffraction 2 θ is:,11.759、12.630、14.757、15.815、18.124、19.461、20.187、21.124、22.075、22.730、23.604, there is characteristic peak at 24.031,24.415,25.438,27.031,27.805,28.860,31.351 o'clock;Its1H-NMR(CDCl3) data are: 8.34 (d, 1H), 7.65 (d, 1H), 7.51 (s, 1H), 7.35 (m,1H)，7.10(s，2H)，6.67(d，1H)，6.38(s，2H)，4.83(dd，2H)，3.80(s，3H)，2.14(s，3H); Its IR (KBr, cm-1) data are: 3428,3193,3104,3065,2961,2935,2885,2831，2561，1736，1630，1581，1518，1474，1431，1414，1385，1354，1335，1290，1274，1254，1215，1160，1110，1085，1044，1015，974，951，890，864，825，811，758，735，664，620，604，520，473，435，410。
Embodiment 5
1) 1g Iprazole is dissolved in 15mL chloroform, lucifuge is dissolved fast;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add 20mL ethyl acetate, lucifuge is quickDissolve lucifuge stirring and crystallizing 1h after dissolving;
3) crystal is filtered, filter cake is washed three times with ethyl acetate, and 28 DEG C dry. Obtain off-white color crystalline powder0.836g, productive rate 83.6%.
7.039,9.124 the X-ray powder diffraction of the Iprazole M crystal formation obtaining at angle of diffraction 2 θ is:,11.760、12.620、14.754、15.819、18.111、19.460、20.178、21.124、22.069、22.736、23.611, there is characteristic peak at 24.035,24.415,25.444,27.039,27.807,28.866,31.355 o'clock;Its1H-NMR(CDCl3) data are: 8.31 (d, 1H), 7.68 (d, 1H), 7.54 (s, 1H), 7.36 (m,1H)，7.13(s，2H)，6.66(d，1H)，6.38(s，2H)，4.85(dd，2H)，3.80(s，3H)，2.16(s，3H); Its IR (KBr, cm-1) data are: 3424,3189,3104,3062,2968,2937,2885,2836，2562，1734，1630，1580，1519，1471，1430，1411，1385，1354，1338，1291，1272，1254，1212，1160，1110，1087，1045，1010，971，953，890，862，828，812，756，730，660，621，604，520，471，434，411。
The stability experiment of Iprazole M crystal formation of the present invention:
The stability difference of the present invention and Iprazole crystal formation of the prior art is described by contrast experiment below.
The preparation (with reference to patent WO2011071314A2) of comparative example 1 Iprazole crystal form A
10g Ilaprazole Sodium is dissolved in 200mL absolute ethyl alcohol, with the ethanolic solution neutralization containing acetic acid 10%, normal temperatureStir 2h, filter, with the ethanol washing leaching cake of 40mL50%, 40 DEG C of dry 12h, obtain off-white color solid 8.5g,Yield 85%.
The preparation (with reference to patent WO2011071314A2) of comparative example 2 Iprazole crystal form Bs
10g Iprazole is dissolved in the methyl alcohol of 50mL and the mixed solvent of carrene, slowly drips 250mL secondEther, stirring at normal temperature 45min, filter, filter cake washs with ether, 30 DEG C dry 12h, off-white color solid 8.5g,Yield 85%.
The preparation (referenced patent US20110082174) of comparative example 3 Iprazole crystal formation E
10g Iprazole crystal form A is dissolved in the solution of a triethylamine of 700mL methyl alcohol dropping. Solid is with superSonication is dissolved. Membrane filtration is to vial, and bottle covers mouth then in room temperature with the aluminium foil that has 5 aperturesLower evaporation. After 6 days, obtain dirty-green solid, obtain Iprazole crystal formation E.
The preparation (referenced patent US20110082174) of comparative example 4 Iprazole crystal formation F
Get Iprazole crystal form A 10g and be dissolved in 200mL carrene, drip a triethylamine. Solution is with 0.2With evaporating under room temperature after membrane filtration. After approximately 1 day, obtaining slight coloured solid, is Iprazole crystal formation F.
The preparation of comparative example 5 Iprazole crystal formation I
Get Iprazole crystal form A 10g and be dissolved in 200mL methyl alcohol, drip a triethylamine, cold after membrane filtrationFreeze. Approximately 2 days final vacuums filter collects white solid, and this solid is methanol solvate compound. White solid is put intoIn vial, opening is placed in room temperature under vacuum, and after approximately 1 day, obtaining white solid is crystalline form I.
The preparation (referenced patent CN103172618A) of comparative example 6 Iprazole crystal form X
At 25 DEG C, in the single port bottle of 250m1, add l0g Iprazole, add successively 100m1 dichloromethaneAlkane, 100m1 absolute methanol, agitating solution to Iprazole dissolves completely, then solution is transferred to constant pressure funnelIn. Above-mentioned Iprazole mixed solution is slowly added drop-wise in 250m1 ether, in dropping process, controls reaction bodyBe temperature in 2 DEG C of 25 scholars' scope, time for adding is controlled between 25-30min. After dropwising, keep40 minutes crystallizatioies of 25 DEG C of agitating solutions of temperature. Decompress filter, by 150mL ether washing leaching cake, vacuum under room temperatureDry 24 hours, obtain off-white powder, be Iprazole crystal form X, productive rate is 84%.
Get embodiment 3 and obtain off-white color crystalline powder and carry out structural analysis, its result is as follows:
7.048,9.119,11.763,12.632,14.760,15.812 angle of diffraction 2 θ of X-ray powder diffraction are:,18.117、19.465、20.187、21.119、22.079、22.733、23.606、24.030、24.413、25.440、27.030,27.808,28.864,31.352, its X-ray powder diffraction figure as shown in Figure 1;
Its differential scanning calorimeter figure (DSC figure) as shown in Figure 2;
1H-NMR(CDCl3) data are: 8.30 (d, 1H), 7.67 (d, 1H), 7.50 (s, 1H), 7.37 (m,1H)，7.11(s，2H)，6.68(d，1H)，6.39(s，2H)，4.84(dd，2H)，3.81(s，3H)，2.15(s，3H)；
IR(KBr，cm-1) data are: 3422,3190,3100,3060,2963,2936,2888,2835,2560，1733，1631，1580，1519，1476，1432，1410，1388，1356，1337，1293，1270，1255，1215，1162，1111，1089，1044，1014，970，953，891，863，828，810,757,731,663,621,606,521,470,436,412, its infrared spectrum (IR) figure asShown in Fig. 3;
Embodiment 1～2, the results of structural analysis no significant difference of the results of structural analysis of 4-5 and embodiment 3.
Embodiment 6 temperatures involved Factor Experiments.
Get respectively comparative example 1-6 (Iprazole crystal form A, B, E, F, I.X) and the Ai Pu of the embodiment of the present invention 3,5Draw azoles crystal form M at temperature 60 C, under the condition of relative humidity 75%, place 10 days, respectively the 0th, 5,10 daysSampling is observed its outward appearance, color and luster and is measured impurity content, the results detailed in Table 1
Table 1 temperatures involved Factor Experiment result
Result shows, from table 1, and Iprazole A, B, E, F, I, X, the placement 10 of M crystal formation under hot conditionsAfter it, from proterties, see Iprazole A in appearance, B, E, F, I darkens, and Iprazole X and M do not have change substantiallyChange, Iprazole M crystal formation is compared with other Iprazole crystal formations, and Iprazole M crystal formation is transferred in hot conditionsThe content of putting its impurity after 10 days is starkly lower than other Iprazole crystalline forms.
Embodiment 7 high humidity influence factor experiments
Get respectively the Iprazole M of 1g comparative example 1-6 (Iprazole crystal form A, B, E, F, I, X) and embodiment 3,5Crystal formation, placing 10 days containing (25 DEG C, relative humidity 92.5%) in the drier of saturated potassium nitrate solution, distinguishesThe 0th, sampling in 5,10 days, observes its outward appearance, color and luster and measures impurity content, the results detailed in Table 2
Table 2 high humidity influence factor experimental result
Result shows, Iprazole A, B, E, F, I, X, the placement of M crystal formation under super-humid conditions be after 10 days, from proterties,See in appearance Iprazole A, B, E, F, I darkens, Iprazole X, M does not have variation substantially, Iprazole MCrystal formation is compared with other Iprazole crystal formations, and Iprazole M crystal formation is placed its impurity after 10 days under super-humid conditionsObviously low other crystal formation of doing of content.
Embodiment Final 8 influence of light Factor Experiment
Get respectively 1g comparative example 1-6 (Iprazole crystal form A, B, E, F, I, X) and the Iprazole of embodiment 3,5M crystal formation, is to place 10 days in the lighting box of fluorescent lamp of (4500 scholar 500) lx in illumination, respectively the 0th, 5,10It sampling, observes its outward appearance, color and luster and measures impurity content, the results detailed in Table 3
Table 3 high light influence factor experimental result
Result shows, Iprazole A, B, E, F, I, X, the placement of M crystal formation under high light condition be after 10 days, from proterties,See in appearance Iprazole A, B, E, F, I darkens, Iprazole X, M does not have variation substantially, Iprazole MCrystal formation is compared with other Iprazole crystal formations, and Iprazole M crystal formation is placed its impurity after 10 days under high light conditionContent be starkly lower than other Iprazole crystalline forms.
Embodiment 9 Iprazole stable crystal form experiments
Get respectively 1g comparative example 1-6 (Iprazole crystal form A, B, E, F, I, X) and the Iprazole of embodiment 3,5M crystal formation, is placed in clean container, 40 DEG C of temperature, under the condition of relative humidity 75%, places 6 months, theSampling in 6 months, investigates the index such as proterties, impurity content, moisture of Iprazole crystal formation, and experimental result is shown inShown in table 4.
Table 4 Iprazole accelerates experiment in 6 months
Result shows, Iprazole A, and B, E, F, I, X, M crystal formation accelerates after experiment for 6 months, Iprazole M crystal formationCompared with other Iprazole crystal formations, Iprazole M crystal formation proterties there is not variation, clarity and color, water substantiallyIt is all qualified to divide; Iprazole M crystal formation maximum contaminant, total impurities are all significantly less than other Iprazole crystal formations, containAmount is apparently higher than other Iprazole crystal formations.
Iprazole novel crystal forms of the present invention, good stability, has retained all pharmacological properties of Iprazole, in vivoThere is effect identical with existing crystal formation, can be used for treating gastric ulcer, duodenal ulcer and reflux esophagitisAnd application in eliminating pylorus medicine.
Claims (10)
1. Iprazole M crystal formation, its structural formula is:
Its X-ray powder diffraction in the time of angle of diffraction 2 θ: 7.030-7.060,9.100-9.130,11.750-11.770,12.620-12.640,14.750-14.770、15.800-15.820、18.110-18.125、19.450-19.470、20.175-20.195、21.110-21.130、22.070-22.090、22.720-22.740、23.600-23.620、24.020-24.040、24.410-24.420、25.430-25.450、27.020-27.040、27.800-27.815、28.850-28.870, have characteristic peak within the scope of 31.340-31.360.
7.048,9.119,11.763 2. Iprazole M crystal formation according to claim 1, its X-ray powder diffraction at angle of diffraction 2 θ is:,12.632、14.760、15.812、18.117、19.465、20.187、21.119、22.079、22.733、23.606、24.030、24.413、25.440, there is characteristic peak at 27.030,27.808,28.864,31.352 o'clock.
3. Iprazole M crystal formation, its structural formula is:
Its1H-NMR(CDCI3) data are:
8.29-8.34(d，1H)，7.65-7.70(d，1H)，7.45-7.55(s，1H)，7.35-7.40(m，1H)，7.10-7.15(s，2H)，6.65-6.70(d，1H)，6.35-6.45(s，2H)，4.80-4.90(dd，2H)，3.72-3.85(s，3H)，2.10-2.20(s，3H)。
4. Iprazole M crystal formation according to claim 3, its1H-NMR(CDCl3) data are: 8.30 (d, 1H), 7.67 (d, 1H),7.50(s，1H)，7.37(m，1H)，7.11(s，2H)，6.68(d，1H)，6.39(s，2H)，4.84(dd，2H)，3.81(s，3H)，2.15(s，3H)。
5. according to the Iprazole M crystal formation described in claim 1 or 3, its IR (KBr, cm-1) data are: 3415-3425,3185-3195,3095-3105，3055-3065，2960-2970，2930-2940，2885-2895，2830-2840，2555-2565，1730-1740，1625-1635，1575-1585，1515-1525，1470-1480，1430-1440，1405-1415，1380-1390，1350-1360，1330-1340，1290-1300，1265-1275，1250-1260，1210-1220，1160-1170，1110-1120，1085-1095，1040-1050，1010-1020，965-975，950-960，885-895，860-870，820-830，805-815，750-760，728-735，660-670，615-625，600-610，520-530，465-475，430-440，410-420。
6. Iprazole M crystal formation according to claim 5, its IR (KBr, cm-1) data are: 3422,3190,3100,3060,2963,2936，2888，2835，2560，1733，1631，1580，1519，1476，1432，1410，1388，1356，1337，1293， 1270，1255，1215，1162，1111，1089，1044，1014，970，953，891，863，828，810，757，731，663，621，606，521，470，436，412。
7. preparation, according to the method for the Iprazole M crystal formation described in claim 1 or 3, comprises the following steps:
1) 1～2g Iprazole is dissolved in 5～20mL chloroform;
2) by above-mentioned solution 30 DEG C of following evaporated under reduced pressure, after evaporate to dryness, add 5～40mL ethyl acetate, dissolve, stir, crystallization at least 20 minutes;
3) crystal is filtered, filter cake washs with ethyl acetate, and 20～35 DEG C dry, obtains Iprazole M crystal formation.
8. Iprazole M crystal formation preparation method according to claim 7, wherein:
Step 1) in, the amount of chloroform is 5～15mL;
Step 2) in, the amount of ethyl acetate is 10～30mL; The crystallization time is 0.5～1 hour.
9. Iprazole M crystal formation preparation method according to claim 8, wherein:
Described rapid 2), in, the amount of ethyl acetate is 15～25mL.
10. the Iprazole M crystal formation described in claim 1-6 any one claim is at preparation treatment gastric ulcer, duodenal ulcer and anti-fluidityApplication in esophagitis and eliminating pylorus medicine.
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| CN103172618A (en) * | 2013-02-27 | 2013-06-26 | 丽珠医药集团股份有限公司 | Ilaprazole crystal form and preparation method thereof |
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| CN103073536A (en) * | 2013-01-17 | 2013-05-01 | 丽珠医药集团股份有限公司 | Preparation method of ilaprazole |
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