CN103910760A - New crystal form of Minodronic acid and preparation method - Google Patents
New crystal form of Minodronic acid and preparation method Download PDFInfo
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- CN103910760A CN103910760A CN201210591216.0A CN201210591216A CN103910760A CN 103910760 A CN103910760 A CN 103910760A CN 201210591216 A CN201210591216 A CN 201210591216A CN 103910760 A CN103910760 A CN 103910760A
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Abstract
Belonging to the technical field of pharmaceutical chemistry, the invention in particular relates to a new crystal form G of 1-hydroxy-2[(imidazo[1, 2-a]pyridine-3yl)]calcium folinate-1, 1-diphosphonic acid hydrate (minodronic acid hydrate) and a preparation method thereof. The invention further provides the X-ray powder diffraction (XRPD) characteristic absorption peak, infrared absorption peak and differential scanning calorimetry (DSC) analysis data of the crystal form. The reflection angle 2theta of the crystal form's X-ray powder diffraction pattern have characteristic absorption peaks at the sites of about 8.96, 10.33, 11.68, 14.89, 15.37, 16.37, 17.95, 18.50, 19.05, 21.44, 22.22, 25.08, 25.63 and 27.27 degrees. The invention also relates to a preparation method of the crystal form.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to new crystal G of a kind of minodronic acid hydrate (Minodronic Acid Hydrate) and preparation method thereof.
Technical background
Minodronic acid (Minodronic Acid), its chemistry is by name: 1-hydroxyl-2[(imidazo [1,2-a] pyridine-3 base)] sub-acetic acid-1, the two phosphonic acids of 1-.
Minodronic acid is in Yamanouchi Pharma. Co., Ltd. in 2009 and ONO Pharmaceutical Co., Ltd. (Ono) first in Japan's this product of having gone on the market, and trade(brand)name is respectively Bonoteo and Recalbon.Minodronic acid, by suppressing farnesyl pyrophosphate (FPP) synthase activity in osteoclast, suppresses the bone resorption of osteoclast, reduces bone conversion, plays the osteoporotic effect of control.
Minodronic acid has multiple crystal formation, and U.S. Pat 005480875A has recorded the preparation method by the A that relates to this compound, the B of Japanese Yamanouchi drugmaker invention, C, D, E, F.Wherein, crystal A, B exist with the form of sodium salt; Crystal C is without hydrate, and it adds methanol solvate to separate out and obtain under aqueous hydrochloric acid heating condition; Crystal D, E are monohydrate, and crystal F is crystal formation D dry anhydride obtaining after 3 hours at 150 ℃.The II crystal formation and the preparation method that relate to this compound that are invented by Hefei Yigong Medicine Co., Ltd. in Chinese patent application (201110145974.5), are recorded: by after minodronic acid hydrochloric acid heating for dissolving, drip methyl alcohol, reflux, in the time there is muddiness in solution, stop dripping methyl alcohol, crystallisation by cooling obtains.The inventor is in research minodronic acid hydrate process, also there is a kind of crystal formation in unexpected discovery minodronic acid hydrate, this crystal formation is different from any in the disclosed 6 kinds of crystal formations of US005480875A, is also different from disclosed crystal form II in patent (application number is 201110145974.5).
Summary of the invention
The object of this invention is to provide the crystal formation that a kind of minodronic acid is new.The heat analysis data of this crystal formation and dry rear income analysis data show at normal temperature storage condition stability inferior better.
New crystal of the present invention, names the type into G, and its powder x-ray diffraction (XRPD) charateristic avsorption band (2 θ) value is about 8.96,10.33,11.68,14.89,15.37,16.37,17.95,18.50,19.05,21.44,22.22,25.08,25.63 and 27.27.In the present invention, the mensuration of 2 θ values is used Cu/K-α 1 light source, precision is ± 0.02o, therefore, " approximately " in above-mentioned " powder x-ray diffraction (XRPD) charateristic avsorption band (2 θ) value of crystal formation is about " should be defined as 2 θ ± 0.02, represent that 2 above-mentioned got θ values have allowed certain reasonably limit of error, its limit of error is ± 0.02.
This crystal formation through infrared analysis in about wave number approximately 3128,3049,3005,1257,1229,855,774,671,624,594cm
-1place has and itself and other crystal formation can be distinguished to the charateristic avsorption band coming.
This crystal formation shows that through thermogravimetric analysis dehydration weight is 8.644%, differential scanning calorimetric analysis shows that dehydration temperature is about 106.6 ℃, the crystal A, the B that are obviously different from other crystal formations of current bibliographical information: U.S. Pat 005480875A record exist with the form of sodium salt, crystal C is without hydrate, crystal F is crystal formation D dry anhydride obtaining after 3 hours at 150 ℃, and these four kinds of crystal formations are all without comparability; Crystal D, E dehydration temperature are respectively 135 ℃-149 ℃ and 160 ℃-170 ℃, and are monohydrate, and dehydration weight is all about 5.30%.
Another object of the present invention is the preparation method who discloses a kind of new crystal of minodronic acid.The method is simple to operate, has avoided the pollution that uses organic solvent to produce product, environmental protection more, and the concentration of hydrochloric acid using is low, and lower to equipment corrosion, cost is low simultaneously, has obvious superiority aspect industrialization.
The preparation method of minodronic acid crystal formation G of the present invention, its process comprises: minodronic acid is dissolved in the 0.6-1.0mol/L hydrochloric acid that mass volume ratio (g/mL) is 1:30-50, heating for dissolving, put and in cryostat, stir slowly crystallization, cryostat temperature is 0 ± 2 ℃, filter, drying under reduced pressure 4 hours, obtains G N-type waferN at 50 ± 2 ℃.
The preferred 1mol/L of above-mentioned concentration of hydrochloric acid, the mass volume ratio of minodronic acid and hydrochloric acid is preferably 1:37.5, obtains crystal formation constant under this condition, but yield is obviously higher.
Accompanying drawing explanation
Fig. 1 is the G crystal formation powder x-ray diffraction figure of minodronic acid.
Fig. 2 is the G crystal formation infrared absorpting light spectra of minodronic acid.
Fig. 3 is the G crystal formation thermogravimetric analysis figure of minodronic acid.
Fig. 4 is the G crystal formation differential scanning calorimetric thermogram of minodronic acid.
Embodiment
In conjunction with embodiment, the invention will be further described, makes professional and technical personnel in the field can better understand the present invention.
Embodiment 1
Minodronic acid 1.0g, 1mol/L hydrochloric acid 37.5mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystalline powder 0.9g.Measure its powder x-ray diffraction figure and data, infrared spectrogram, thermogravimetric analysis figure and differential scanning figure, according to powder x-ray diffraction figure (see figure 1) charateristic avsorption band 2 θ values 8.96,10.33,11.68,14.89,15.37,16.37,17.95,18.50,19.05,21.44,22.22,25.08,25.63 and 27.27o), infrared spectrogram (is shown in Fig. 2,3128,3049,3005,1257,1229,855,774,671,624,594cm
-1), thermogravimetric analysis figure (see figure 3) and differential scanning calorimetric thermogram (see figure 4), that obviously obtain is crystal formation G.
Embodiment 2
Minodronic acid 1.0g, 0.8mol/L hydrochloric acid 37.5mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.8g.
Embodiment 3
Minodronic acid 1.0g, 0.6mol/L hydrochloric acid 37.5mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred, filter, filtrate is placed in 0 ± 2 ℃ of cryostat, stirs slowly insulation crystallization, filters, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.6g.
Embodiment 4
Minodronic acid 1.0g, 1mol/L hydrochloric acid 30mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred, filter, filtrate is placed in 0 ± 2 ℃ of cryostat, stirs slowly insulation crystallization, filters, and in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtains crystal formation G crystalline powder 0.7g.
Embodiment 5
Minodronic acid 1.0g, 1mol/L hydrochloric acid 35mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.8g.
Embodiment 6
Minodronic acid 1.0g, 1mol/L hydrochloric acid 40mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.7g.
Embodiment 7
Minodronic acid 1.0g, 1mol/L hydrochloric acid 45mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.6g.
Embodiment 8
Minodronic acid 1.0g, 1mol/L hydrochloric acid 50mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.4g.
Embodiment 9
Minodronic acid 1.0g, 0.8mol/L hydrochloric acid 50mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.4g.
Embodiment 10
Minodronic acid 1.0g, 0.8mol/L hydrochloric acid 45mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.6g.
Embodiment 11
Minodronic acid 1.0g, 0.8mol/L hydrochloric acid 40mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.8g.
Embodiment 12
Minodronic acid 1.0g, 0.8mol/L hydrochloric acid 35mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.7g.
Embodiment 13
Minodronic acid 1.0g, 0.8mol/L hydrochloric acid 30mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred, filter, filtrate is placed in 0 ± 2 ℃ of cryostat, stirs slowly insulation crystallization, filters, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.5g.
Embodiment 14
Minodronic acid 1.0g, 0.6mol/L hydrochloric acid 50mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.7g.
Embodiment 15
Minodronic acid 1.0g, 0.6mol/L hydrochloric acid 45mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.6g.
Embodiment 16
Minodronic acid 1.0g, 0.6mol/L hydrochloric acid 40mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred to dissolving, treat that raw material dissolves completely, stop heating, withdraw from oil bath, be placed in 0 ± 2 ℃ of cryostat, slowly stir insulation crystallization, filter, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.6g.
Embodiment 17
Minodronic acid 1.0g, 0.6mol/L hydrochloric acid 35mL are joined in three-necked bottle, filter in 110 ± 2 ℃ of oil bath heated and stirred, filtrate is placed in 0 ± 2 ℃ of cryostat, stirs slowly insulation crystallization, filters, and in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtains crystal formation G crystalline powder 0.5g.
Embodiment 18
Minodronic acid 1.0g, 0.6mol/L hydrochloric acid 30mL are joined in three-necked bottle, in 110 ± 2 ℃ of oil bath heated and stirred, filter, filtrate is placed in 0 ± 2 ℃ of cryostat, stirs slowly insulation crystallization, filters, in 50 ± 2 ℃ of vacuum-dryings 4 hours, obtain crystal formation G crystalline powder 0.4g.
The G crystal formation powder x-ray diffraction analyzing and testing of embodiment 19 minodronic acids
1, testing conditions
Measuring unit: Institute of Analysis of the Chinese Academy of Sciences
Instrument: DX-1000 type X-ray diffractometer
Test condition: Cu target/graphite monochromator, room temperature, precision is ± 0.02o that sweep velocity is 0.06o/s, pipe pressure: 40KV, pipe stream: 25mA
2, detected result is in table one
Table one
| Sequence number | 2 θ values |
| 1 | 8.959 |
| 2 | 10.328 |
| 3 | 11.684 |
| 4 | 14.296 |
| 5 | 14.892 |
| 6 | 15.370 |
| 7 | 15.987 |
| 8 | 16.373 |
| 9 | 17.079 |
| 10 | 17.946 |
| 11 | 18.503 |
| 12 | 19.046 |
| 13 | 20.181 |
| 14 | 20.521 |
| 15 | 20.775 |
| 16 | 21.438 |
| 17 | 22.219 |
| 18 | 23.595 |
| 19 | 25.084 |
| 20 | 25.633 |
| 21 | 26.416 |
| 22 | 27.265 |
| 23 | 27.708 |
| 24 | 28.328 |
| 25 | 29.934 |
| 26 | 30.446 |
3, interpretation of result
Through the data analysis of XRPD detected result, characteristic peak (2 θ) value of the crystal formation G that the present invention obtains is being about 8.96,10.33,11.68,14.89,15.37,16.37,17.95,18.50,19.05,21.44,22.22,25.08, before 25.63 and 27.27 places are obviously different from, other crystal formations of report, are a kind of new crystal.
Claims (8)
1. a crystal formation G for minodronic acid, reflection angle 2 θ of the powder x-ray diffraction figure of this crystal formation are being about 8.96,10.33,11.68,14.89,15.37,16.37,17.95,18.50,19.05,21.44,22.22,25.08,25.63 and 27.27o place have charateristic avsorption band.
2. crystal formation G as claimed in claim 1, is characterized in that its infared spectrum wave number is approximately 3128,3049,3005,1257,1229,855,774,671,624,594cm
-1place has charateristic avsorption band.
3. crystal formation G as claimed in claim 1, is characterized in that its thermogravimetric analysis figure shows that dehydration weight is 8.64%.
4. crystal formation G as claimed in claim 1, is characterized in that its differential scanning calorimetric thermogram shows that dehydration temperature is 106.6 ℃.
5. prepare the method for minodronic acid crystal formation G described in claim 1 for one kind: minodronic acid is dissolved in the 0.6-1.0mol/L aqueous hydrochloric acid that mass ratio (g/mL) is 1:30-1:50, heating for dissolving is (if there is not molten thing, filter), solution is put and in cryostat, is stirred slowly crystallization, cryostat temperature is-2-2 ℃, filter, drying under reduced pressure 4 hours, obtains G N-type waferN at 50 ℃.
6. the method for minodronic acid crystal formation G as claimed in claim 5, is characterized in that cryostat temperature is 0-2 ℃.
7. the method for minodronic acid crystal formation G as claimed in claim 5, is characterized in that aqueous hydrochloric acid is 1.0mol/L.
8. the method for minodronic acid crystal formation G as claimed in claim 5, is characterized in that minodronic acid is dissolved in the 1.0mol/L aqueous hydrochloric acid that mass ratio is 1:37.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016198117A1 (en) * | 2015-06-12 | 2016-12-15 | Polycrystalline S.R.L. | New crystal forms of minodronic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153585A (en) * | 2011-02-24 | 2011-08-17 | 北京欧克兰医药技术开发中心 | Synthesis method of minodronate midbody and synthesis of minodronate |
| 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 |
-
2012
- 2012-12-31 CN CN201210591216.0A patent/CN103910760A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153585A (en) * | 2011-02-24 | 2011-08-17 | 北京欧克兰医药技术开发中心 | Synthesis method of minodronate midbody and synthesis of minodronate |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016198117A1 (en) * | 2015-06-12 | 2016-12-15 | Polycrystalline S.R.L. | New crystal forms of 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 |
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Application publication date: 20140709 |