CN102268042A - Minodronate crystalform II and preparation method thereof - Google Patents
Minodronate crystalform II and preparation method thereof Download PDFInfo
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- CN102268042A CN102268042A CN2011101459745A CN201110145974A CN102268042A CN 102268042 A CN102268042 A CN 102268042A CN 2011101459745 A CN2011101459745 A CN 2011101459745A CN 201110145974 A CN201110145974 A CN 201110145974A CN 102268042 A CN102268042 A CN 102268042A
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- minodronic acid
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- minodronic
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- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 229950011129 minodronic acid Drugs 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 23
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 3
- 239000013078 crystal Substances 0.000 claims description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000002329 infrared spectrum Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 238000002156 mixing Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000002075 main ingredient Substances 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 108010011485 Aspartame Proteins 0.000 description 4
- 241000220223 Fragaria Species 0.000 description 4
- 235000016623 Fragaria vesca Nutrition 0.000 description 4
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 4
- 229960003438 aspartame Drugs 0.000 description 4
- 235000010357 aspartame Nutrition 0.000 description 4
- 239000000605 aspartame Substances 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 206010013786 Dry skin Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011122 softwood Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- 235000020985 whole grains Nutrition 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- -1 phosphonic acids monohydrates Chemical class 0.000 description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008398 formation water Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to the field of synthesis of medicines, in particular to a minodronate crystalform II and a preparation method thereof. The minodronate crystalform II is characterized in that an X-ray powder diffraction pattern has characteristic peaks when a reflection angle 2theta is close to 10.32, 11.16, 13.14, 15.02, 15.72, 17.44, 20.28, 20.72, 21.46, 22.30, 23.48, 25.64, 26.48, 28.80, 30.14, 32.30, 34.58, 35.50 and 36.34. The minodronate crystalform II has high solubility and dissolution rate.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to crystal form II of a kind of minodronic acid and preparation method thereof.
Background technology
Minodronic acid (Minodronic Acid), its chemistry is by name: [1-hydroxyl-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] two phosphonic acids monohydrates, its anti-bone resorption activity is high 100～1000 times than Sodium Pamidronate, and the osteolysis effect that energy antagonism myelomatosis and tumour cause, the clinical osteoporosis that is used for the treatment of.
The crystallization method of the minodronic acid of bibliographical information all adopts in water and methanol system and carries out at present.The contriver is according to the preparation method of patent US4990503 report, obtains the known crystal formation I of minodronic acid by the recrystallization method that adopts water and methyl alcohol, and powder x-ray diffraction Fig. 2 θ of this crystal formation is near 9.60,10.40, and 12.18,13.96,15.84,16.50,17.32,18.42,19.10,20.42,23.20,24.22,24.98,26.62,27.92,29.12,31.06,33.40,36.04,36.62, locate to have characteristic peak for 38.88,42.10,43.78 °.See Fig. 1.The infrared spectrogram of this crystal formation I 3393,3262,2919,2850,1658,1529,1414,1344,1277,1187,1093,1015,989,961,929,893,754,556,511,433cm
-1There is charateristic avsorption band at the place, sees Fig. 2.
But shortcomings such as there is poor solubility in minodronic acid crystal formation I, and bioavailability is low, and the solvent for use amount is big in the crystalline process, and environmental protection pressure is big, and the cost height is unfavorable for suitability for industrialized production.Therefore, it is good to seek a kind of solubleness, and the minodronic acid new crystal that bioavailability is high is very necessary.
Summary of the invention
The invention discloses a kind of good stability, have the minodronic acid new crystal of good solubility and dissolution rate, be i.e. minodronic acid crystal form II, and the method and the medicinal compositions thereof that prepare crystal form II.
The present invention is by changing recrystallization solvent and method, it is unexpected that the discovery minodronic acid exist another crystal form II, crystal form II improves greatly than the solubleness of crystal formation I, and the flowability of crystal form II and quality are better than crystal formation I, the more important thing is that the crystal form II dissolution rate is significantly improved than crystal formation I.The crystal form II preparation is simple, and the solvent usage quantity is few, and cost is low, has obvious superiority aspect industrialization.
Reflection angle 2 θ of the X-ray powder diffraction figure of minodronic acid crystal form II of the present invention are near 10.32,11.16, and 13.14,15.02,15.72,17.44,20.28,20.72,21.46,22.30,23.48,25.64,26.48,28.80,30.14,32.30, locate to have characteristic peak for 34.58,35.50 and 36.34 °.It has the x ray diffration pattern x as Fig. 3.
Its infrared spectrum is near 3100,1474,1454,1424,1402,1382,1327,1137,1100,1043,969,813,497cm
-1The place has charateristic avsorption band.See Fig. 4.
The preparation method of minodronic acid crystal form II of the present invention is as follows: after minodronic acid is used the hydrochloric acid heating for dissolving, drip methyl alcohol, reflux, when muddiness appears in solution, stop to drip methyl alcohol, crystallisation by cooling promptly.
The preferred 6mol/L of concentration of hydrochloric acid wherein, the consumption of hydrochloric acid are preferably 2～10 times of weight of minodronic acid, more preferably 3 times.Preferred 40～90 ℃ of Heating temperature; More preferably 60 ℃.
The invention also discloses a kind of pharmaceutical composition, it contains minodronic acid crystal form II of the present invention and pharmaceutically acceptable carrier.This pharmaceutical composition can exist with forms such as tablets, capsule, granule, oral liquid, syrup, dispersible tablet, fast disintegrating tablet, instant, slow releasing tablet, controlled release tablet, minodronic acid crystal form II and suitable thinner, tackiness agent, disintegrating agent, lubricant, glidant (also can add suitable correctives) are through mixing, granulate, make tablet behind the compressing tablet (but dressing) in case of necessity; Adding thinner, disintegrating agent, lubricant, glidant, tackiness agent are made capsule, granule, dry syrup through mixing, granulation, can etc.; Add the suitable technology of warps such as sweeting agent, correctives, water and make oral liquid.Using the minodronic acid crystal form II to make various oral preparations makes absorption apparently higher than crystal formation I because of the dissolving out capability of raw material is good.
The present invention is by carrying out recrystallization with concentrated hydrochloric acid as solvent, the crystal form II that obtains than use water as crystal formation I that solvent obtains have dissolution rate height, water absorbability little, stablize advantages of higher, simple to operate, the solvent usage quantity is few, cost is low, has obvious superiority aspect industrialization.
Below by the contrast experiment superiority of the present invention is described:
Minodronic acid crystal formation I: water as solvent makes.
Minodronic acid crystal form II of the present invention: 6mol/L hydrochloric acid makes as solvent.
1, the water absorbability of minodronic acid different crystal forms is measured and comparative tests
Table 1 was placed 24 hours under humidity 75% and 92.5% condition, each crystal formation water absorbability
Conclusion: crystal formation I is water absorbability slightly, and the crystal form II water absorbability is little.
2, the stable contrast experiment of minodronic acid different crystal forms
Under condition of storage 1:40 ℃/relative humidity 75% condition, store 3 and 6 months at sealed state
Under condition of storage 2:40 ℃/relative humidity 75% condition, store 1 and 3 months at the non-tight state
Comparative result such as following table:
Table 2 stability test
Get I, II crystal respectively, every kind of crystal each minute gets and places numbering I in right amount
1, II
1I
2, II
2I
3, II
3Plate in split (condition of storage 1:4500lx ± 500lx illumination, condition of storage 2:60 ℃ high temperature, condition of storage 3: relative humidity 92.5% high humidity) carry out the minodronic acid stability test under the following condition.Measurement result is shown in table 3～5.
Table 3 strong illumination study on the stability (4500lx ± 500lx)
Table 4 high temperature experiment study on the stability (60 ± 2 ℃)
Table 5 high humidity experiment study on the stability (RH90 ± 5%)
Conclusion: confirm that through infrared spectra and X-ray powder diffraction analysis infrared spectra and the X-ray powder diffraction of crystal formation I, II all do not change, and prove that it still keeps original crystal formation.Crystal form II is stable better than crystal formation I, is convenient to store.
3, the solubleness simultaneous test of minodronic acid in different solvents
Table 6 solubility test
| Solvent | I crystal formation (g/ml) | II crystal formation (g/ml) |
| |
1∶10000 | 1∶10000 |
| |
1∶8000～10000 | 1∶1000～3000 |
| 1mol/ |
1∶30～60 | 1∶10～30 |
Conclusion: crystal form II is better than crystal formation I solvability, is convenient to preparation and uses.
Description of drawings:
Fig. 1 is the powder x-ray diffraction figure of minodronic acid crystal formation I;
Fig. 2 is the infrared spectrogram of minodronic acid crystal formation I;
Fig. 3 is the powder x-ray diffraction figure of minodronic acid crystal form II of the present invention;
Fig. 4 is the infrared spectrogram of minodronic acid crystal form II of the present invention.
Embodiment
The preparation of minodronic acid crystal form II
Minodronic acid crude product 2g, 6mol/L hydrochloric acid 6ml are added in the three-necked bottle, be warming up to 60 ℃, stir moltenly entirely, slowly drip methyl alcohol, and keep reflux state, treated that turbid phenomenon promptly stops to drip methyl alcohol slightly, be cooled to 0 ℃ and stir 2h, put the cold analysis crystalline substance, filter, in 80 ℃ of forced air dryings, get crystal form II sample 1.72g.Its x-ray diffraction pattern is seen Fig. 3, and infrared spectrum is seen Fig. 4.
Embodiment 2
Minodronic acid crystal form II tablet
The label prescription:
| The supplementary material title | Consumption |
| The minodronic acid crystal form II | 1.0g |
| Microcrystalline Cellulose | 36.0g |
| Lactose | 66.0g |
| Polyvinylpolypyrrolidone | 6.0g |
| Magnesium Stearate | 1.0g |
| Water | About 40ml |
| Make 1000 |
Coating fluid prescription:
| The supplementary material title | Consumption |
| Opadry 81W680000 | 36.0g |
| Water | 200ml |
Label preparation technology:
Cross behind 80 mesh sieves supplementary material standby respectively; Main ingredient and polyvinylpolypyrrolidone, Microcrystalline Cellulose, lactose are mixed by the equivalent incremental method; Water, is granulated through 24 mesh sieves above-mentioned mixing fine powders system softwood as wetting agent, about 2 hours of 60 ℃ of dryings, the control particle moisture content≤whole grain of 3%, 24 mesh sieve, mixing; Get above particle, add the Magnesium Stearate of recipe quantity, mixing is surveyed intermediate content, is the stamping of 6.5mm scrobicula with diameter, and Hardness Control is at 5～10kg/mm
2
Art for coating:
Under whipped state, the Opadry 81W680000 of recipe quantity is slowly added in the prescription water gaging, in 5 minutes, add and continue stir about 45min, make to mix, get final product; Label is put in the coating pan, and adjusting rotating speed is that per minute 30 changes, and the hot blast of blast temperature about 55 ℃ sprays into coating liquid, after sheet heavily increases about 3%, gets final product.
Embodiment 3
Minodronic acid crystal form II capsule
Prescription:
| The supplementary material title | Consumption |
| The minodronic acid crystal form II | 1.0g |
| Starch | 36.0g |
| Lactose | 66.0g |
| Magnesium Stearate | 1.0g |
| Water | About 40ml |
| Make 1000 |
Preparation technology:
Cross behind 80 mesh sieves supplementary material standby respectively; Main ingredient and starch, lactose are mixed by the equivalent incremental method; Water, is granulated through 24 mesh sieves above-mentioned mixing fine powders system softwood as wetting agent, about 2 hours of 60 ℃ of dryings, the control particle moisture content≤whole grain of 3%, 24 mesh sieve, mixing; Get above particle, add the Magnesium Stearate of recipe quantity, mixing is surveyed intermediate content, is filled in capsule No. 4, gets final product.
Embodiment 4
Minodronic acid crystal form II granule
Prescription:
| The supplementary material title | Consumption |
| The minodronic acid crystal form II | 1.0g |
| Sucrose | 180.0g |
| Lactose | 328.0g |
| Magnesium Stearate | 1.0g |
| Water | About 40ml |
| Make 1000 bags |
Preparation technology:
Cross behind 80 mesh sieves supplementary material standby respectively; Main ingredient and starch, lactose are mixed by the equivalent incremental method; Water, is granulated through 24 mesh sieves above-mentioned mixing fine powders system softwood as wetting agent, about 2 hours of 60 ℃ of dryings, the control particle moisture content≤whole grain of 3%, 24 mesh sieve, mixing; Get above particle, add the Magnesium Stearate of recipe quantity, mixing is surveyed intermediate content, and pack gets final product.
Embodiment 5
Minodronic acid crystal form II oral liquid
Prescription:
| The supplementary material title | Consumption |
| The minodronic acid crystal form II | 1.0g |
| Aspartame | 18.0g |
| Strawberry flavour | 2.0g |
| Sodium Citrate | 50.0g |
| Water for injection | Add to 5000ml |
| |
Preparation technology:
Main ingredient and aspartame, strawberry flavour, Sodium Citrate are dissolved in existing system water for injection, and dissolving is filtered, and surveys intermediate content, and can gets final product.
Embodiment 6
Minodronic acid crystal form II syrup
Prescription:
| The supplementary material title | Consumption |
| The minodronic acid crystal form II | 1.0g |
| Sucrose | 700.0g |
| Aspartame | 18.0g |
| Strawberry flavour | 2.0g |
| Sodium Citrate | 50.0g |
| Water for injection | Add to 1000ml |
| |
Preparation technology:
Main ingredient and aspartame, sucrose, strawberry flavour, Sodium Citrate are dissolved in existing system water for injection, and dissolving is filtered, and surveys intermediate content, and can gets final product.
Embodiment 7
Determination of dissolution rate: get each 6 or 6 or 6 bags of tablet, capsule and granules that embodiment 2,3,4,5,6 makes respectively; according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method); with pH6.8 phosphate buffered saline buffer 900ml is dissolution medium; rotating speed is that per minute 50 changes, and operation in accordance with the law is in the time of 45 minutes; it is an amount of to get solution; filter, get subsequent filtrate, measure according to the method under the assay item.It is an amount of to get the minodronic acid reference substance according to other, and precision claims fixed, adds the also quantitative dilution of pH6.8 phosphate buffered saline buffer dissolving and makes the solution that contains 1 μ g among every 1ml approximately, measures with method, calculates stripping quantity.Change crystal formation I into by embodiment 2 methods general minodronic acid crystal form II wherein and prepare tablet as a comparison case.Test-results is as follows
The average stripping quantity of table 7 tablet, capsule and granule (%) (N=6)
The dissolution rate comparison test of table 7 as can be seen, the dissolution rate of minodronic acid crystal form II preparation reflects indirectly that obviously than the dissolution rate height of minodronic acid crystal formation I preparation the intravital absorption of people is faster.
Claims (9)
1. minodronic acid crystal form II is characterized in that: reflection angle 2 θ of the X-ray powder diffraction figure of this crystal formation are near 10.32,11.16, and 13.14,15.02,15.72,17.44,20.28,20.72,21.46,22.30,23.48,25.64,26.48,28.80,30.14,32.30, locate to have characteristic peak for 34.58,35.50 and 36.34 °.
2. the minodronic acid crystal form II of claim 1, its x-ray diffraction pattern such as Fig. 3.
3. the minodronic acid crystal form II of claim 1, its infrared spectrum be near 3100,1474, and 1454,1424,1402,1382,1327,1137,1100,1043,969,813 and 497cm
-1The place has charateristic avsorption band.
4. the preparation method of the minodronic acid crystal form II of a claim 1 comprises: with minodronic acid with the hydrochloric acid heating for dissolving after, drip methyl alcohol, reflux, when solution occurs stopping to drip methyl alcohol when muddy, crystallisation by cooling is promptly.
5. the preparation method of claim 4, concentration of hydrochloric acid wherein is 6mol/L, and the consumption of hydrochloric acid is 2～10 times of weight of minodronic acid, and Heating temperature is 40～90 ℃.
6. pharmaceutical composition wherein contains the minodronic acid crystal form II and the pharmaceutically acceptable carrier of claim 1.
7. the pharmaceutical composition of claim 1 wherein contains minodronic acid crystal form II 0.1mg～20mg in the unit dosage.
8. the pharmaceutical composition of claim 7 wherein contains minodronic acid crystal form II 1mg in the unit dosage.
9. the minodronic acid crystal form II of claim 1 is used to prepare the purposes of the medicine for the treatment of osteoporosis.
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|---|---|---|---|
| CN201110145974.5A CN102268042B (en) | 2011-06-01 | 2011-06-01 | Minodronate crystalform II and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584897A (en) * | 2012-02-08 | 2012-07-18 | 安徽省新星药物开发有限责任公司 | Refining method for minodronic acid |
| CN106831873A (en) * | 2017-01-17 | 2017-06-13 | 成都归合科技有限公司 | A kind of technique for preparing high-purity minodronic acid |
| JP2018519360A (en) * | 2015-06-12 | 2018-07-19 | ポリクリスタリン・ソチエタ・ア・レスポンサビリタ・リミタータＰｏｌｙＣｒｙｓｔａｌＬｉｎｅ Ｓ．ｒ．ｌ． | A new crystal form of minodronic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040590A (en) * | 1988-08-12 | 1990-03-21 | 山之内制药株式会社 | Heterocyclic ring di-phosphonic acid derivatives |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584897A (en) * | 2012-02-08 | 2012-07-18 | 安徽省新星药物开发有限责任公司 | Refining method for minodronic acid |
| CN102584897B (en) * | 2012-02-08 | 2014-07-30 | 安徽省新星药物开发有限责任公司 | Refining method for minodronic acid |
| JP2018519360A (en) * | 2015-06-12 | 2018-07-19 | ポリクリスタリン・ソチエタ・ア・レスポンサビリタ・リミタータＰｏｌｙＣｒｙｓｔａｌＬｉｎｅ Ｓ．ｒ．ｌ． | A new crystal form of minodronic acid |
| CN106831873A (en) * | 2017-01-17 | 2017-06-13 | 成都归合科技有限公司 | A kind of technique for preparing high-purity minodronic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102268042B (en) | 2014-06-25 |
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