CN105315260A - Topiroxostat monohydrate crystal form and preparation method thereof - Google Patents
Topiroxostat monohydrate crystal form and preparation method thereof Download PDFInfo
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- CN105315260A CN105315260A CN201410366563.2A CN201410366563A CN105315260A CN 105315260 A CN105315260 A CN 105315260A CN 201410366563 A CN201410366563 A CN 201410366563A CN 105315260 A CN105315260 A CN 105315260A
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Abstract
The invention relates to a topiroxostat monohydrate crystal form and a preparation method thereof. The invention provides a topiroxostat novel crystal form which has characteristic peaks at 8.12, 16.38, 24.71, and 33.18 in an X-ray powder diffraction pattern represented by 2theta diffraction angle. The crystal form also contains one molecule of crystal water. The novel crystal form has stable thermodynamic property and good solubility. The crystal form is more suitable to be applied in pharmaceutical preparations.
Description
Technical field
The present invention relates to medicine new crystal, specifically 5-(2-cyano group-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole monohydrate crystal form, his monohydrate of general Tobe department by name, and preparation method thereof, and the pharmaceutical composition containing his monohydrate crystal form of Tobe department.
Background technology
His (Topiroxostat) chemical name: 5-(2-cyano group-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazoles of Tobe department, structural formula by shown in lower formula I,
Tobe department he jointly researched and developed by Japan three and chemistry institute and Japanese fuji medicine Co., Ltd., be used for the treatment of gout, hyperuricemia clinically.
CN02819276 and CN200480021322 describes his preparation method of Tobe department.In the embodiment 12 of CN02819276, disclose 5-(2-cyano group-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, it has and suppresses the effect of xanthine oxidase activity, can treat the medicine that uric acid produces the gout that the hyperuricemia of hyperfunction type and hyperuricemia cause.
In the embodiment 3 of CN200480021322, disclose the preparation method of 5-(2-cyano group-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazoles.
Whether in CN02819276 and CN200480021322, all with no specific disclosure of Tobe department, he is crystallization or noncrystalline, also with no specific disclosure of existing in the form of hydrates.
Summary of the invention
Same medicine, due to the difference of condition during crystallization, can generate complete different types of crystal, be called as the paramorphism of medicine.Different crystal forms due to same medicine often causes medicine in significant differences such as physico-chemical property and biological effectiveness such as outward appearance, solubleness, fusing point, density, thus affects medicine stability, the performance of the curative effects such as bioavailability.
We are studied his character of compound of Tobe department, have studied the multiple recrystallization solvent or mixed solvent with opposed polarity, be intended to find that polytropism is with or without possibility, the object of the invention is to provide thermodynamically stable being more suitable for carry out commercial mass production and be easier to storage and processing, be suitable for his crystallized form of Tobe department of pharmaceutical preparation.
In the present inventor's process that he studies to Tobe department, he has heteromorphism to have unexpectedly discovered that Tobe department, and the crystallization method under adopting the different solvent of various polarity to carry out different condition, obtains different crystal formations.Specifically obtain his 3 kinds of crystal formations of Tobe department, be defined as crystal form A respectively, crystal form B and crystal C, and surprisingly, crystal C has more favourable character.
Object of the present invention provides a kind of his new crystal of Tobe department be more suitable for for pharmaceutical preparation, i.e. crystal C.
His crystal C of Tobe department is monohydrate, containing 6.8% water.The formula I compound appearance character of crystal C, solvability are all better than crystal form A and crystal form B, and crystal C is at room temperature thermodynamically stable, are easier to storage and processing, are particularly suitable for pharmaceutical preparation.
His crystal C of Tobe department of the present invention, it contains the crystal water being no less than 1 molecule, says further, and it contains the crystal water of 1 molecule, and thermogravimetric analysis (TGA) test confirms the existence of stoichiometric monohydrate.When TGA test displays temperature reaches 116 DEG C, the weight loss of sample is about 6.76%, is equivalent to a part crystal water; Its means of differential scanning calorimetry (DSC) tests absorption peak has an endotherm(ic)peak at 114-132 DEG C, and TGA and DSC test result is consistent.
His crystal C of above-mentioned Tobe department, its DSC test curve has endotherm(ic)peak at about 131 and 330 DEG C respectively.
His crystal C of Tobe department, in the X-ray powder diffraction pattern represented with 2 θ diffraction angle, 2 θ about 8.12,14.99,16.38,24.71,25.31,27.68, there is charateristic avsorption band at 33.18 places.In the present invention, the mensuration of 2 θ diffraction angle adopts CuK α light source, and precision is ± 0.2 degree.Therefore, 2 θ values of said determination have allowed certain reasonably limit of error, and its limit of error is ± 0.2 degree.
Thermogram SDTQ600V8.0 Differential Scanning Calorimeter, and obtain with SDTQ600V8.0 thermogravimetric analyzer.X-ray powder diffraction pattern obtains on D/Max-RC instrument, test condition: anode tube Cu target, emitting voltage 45KV, transmitter current 300mA, sweep velocity 4 °/point, step-length 0.02 °, sweep limit 4 ° ~ 60 °.Nuclear magnetic spectrum adopts INOVA-400 nuclear magnetic resonance spectrometer to obtain.
His crystal C thermodynamic property of Tobe department of the present invention is stable; Appearance character, solvability are obviously better than crystal form A or crystal form B, are particularly suitable for pharmaceutical preparation.
1. outward appearance compares
| Crystal form A | Crystal form B | Crystal C |
| Off-white color is to light yellow crystalline powder | White crystalline powder | White crystalline powder |
2. solvability compares (unit: μ g/ml)
3. thermodynamic stability
Crystal C high temperature (60 DEG C) influence factor test-results
| Time | Proterties | Moisture (%) | Content (%) | Related substance (%) |
| 0 day | White crystalline powder | 6.82 | 100.04 | 0.065 |
| 5 days | White crystalline powder | 6.80 | 100.02 | 0.068 |
| 10 days | White crystalline powder | 6.80 | 100.03 | 0.068 |
Crystal C high humidity (90% ± 5%) influence factor test-results
| Time | Proterties | Moisture (%) | Content (%) | Related substance (%) |
| 0 day | White crystalline powder | 6.82 | 100.04 | 0.065 |
| 5 days | White crystalline powder | 6.87 | 100.01 | 0.065 |
| 10 days | White crystalline powder | 6.85 | 100.00 | 0.067 |
This product is placed 10 days under high temperature, super-humid conditions, and outward appearance, moisture, content and related substance have no significant change, and this product Thermodynamically stable is described.
Another object of the present invention is to provide the preparation method of his crystal C of Tobe department.
The preparation method of his crystal C of Tobe department of the present invention, its process comprises: Tobe department he add in the mixed solvent of acid reagent and water, reflux is dissolved completely to solid, cooling crystallization, filter, dry overnight at room temperature.Acid reagent wherein comprises organic acid or mineral acid, and organic acid comprises formic acid, acetic acid, oxalic acid, phenylformic acid or tartrate; Mineral acid comprises hydrochloric acid or sulfuric acid, and mineral acid refers to that concentration is hydrochloric acid or the 1mol/L aqueous sulfuric acid of 1mol/L further.
The volume ratio of organic acid and water in the scope of 2:1-1:2, such as 2 parts of formic acid and 1 part of water, 1 part of formic acid and 1 part of water or 1 part of formic acid and 2 parts of water; The volume ratio of mineral acid and water in the scope of 2:1-1:2, such as 2 parts of 1mol/L aqueous hydrochloric acids and 1 part of water, 1 part of 1mol/L aqueous hydrochloric acid and 1 part of water or 1 part of 1mol/L aqueous hydrochloric acid and 2 parts of water.
The present invention also provides a kind of pharmaceutical composition, and it contains his crystal C and pharmaceutically acceptable carrier of Tobe department.Described pharmaceutical composition is oral preparations, such as tablet, hard capsule, soft capsule, suspensoid or granule etc.
The present invention has following beneficial effect: crystal C has very high thermodynamic stability, and appearance character and solvability are better than other A crystal formation or B crystal form, are suitable for useful in preparing drug formulations, are particularly suitable for preparing solid orally ingestible.
Accompanying drawing explanation
The X-ray powder diffraction of Fig. 1 crystal form A
The X-ray powder diffraction of Fig. 2 crystal form B
The X-ray powder diffraction of Fig. 3 crystal C
The DSC collection of illustrative plates of Fig. 4 crystal form A
The DSC collection of illustrative plates of Fig. 5 crystal C
The TGA collection of illustrative plates (TG (crystal form A)) of Fig. 6 crystal form A
The TGA collection of illustrative plates (TG (crystal C)) of Fig. 7 crystal C
Fig. 8 crystal form A, B, C make the dissolution rate releasing curve diagram of tablet
Embodiment
The method that the present invention prepares various polymorphs body comprises multiple, and its representative instance is as described below.
Embodiment 1: the preparation of his crystal form A of Tobe department
Preparation method is with reference to 5-(2-cyano group-4-pyridyl)-3-(4-pyridyl)-1 in CN02819276 embodiment 12, the method of 2,4-triazole, his crude product of obtained Tobe department, by recrystallizing methanol, obtain light yellow crystalline powder (A crystallization).
1H-NMR(DMSO)δ8.00(dd,2H),8.01(dd,1H),8.30～8.31(dd,1H),8.53(dd,1H),8.79～8.80(dd,2H),8.91～8.92(dd,1H),15.41(br,1H)
Embodiment 2: the preparation of his crystal form B of Tobe department
5 grams of his crude products of Tobe department are joined in reaction vessel, 30mlN is added in reaction vessel, dinethylformamide (DMF) and 30ml ethanol, reaction system is heated to 80 degree, insulated and stirred 19 hours, is cooled to room temperature, filters, dry at room temperature over night, obtains white crystalline powder (B crystallization).
1H-NMR(DMSO)δ8.00(dd,2H),8.02(dd,1H),8.32(dd,1H),8.55(dd,1H),8.79(dd,2H),8.91～8.92(dd,1H),15.43(br,1H)
Embodiment 3: the preparation of his crystal C of Tobe department
5 grams of his crude products of Tobe department are added in reaction vessel, in reaction vessel, adds 40ml formic acid and 20ml water, reaction system is heated to backflow, insulated and stirred 30 minutes, naturally cools to room temperature, filters, dry at room temperature over night, obtains white crystalline powder (C crystallization).
1H-NMR(DMSO)δ4.37(br,2H),8.09～8.10(dd,2H),8.29(dd,1H),8.30(dd,1H),8.52(dd,1H),8.82～8.84(dd,2H),8.91～8.92(dd,1H),15.47(br,1H)
Water ratio (%): theoretical value 6.77
Measured value (thermogravimetric analysis TGA) 6.76
Moisture determination (Ka Er-Fei Xiu aquametry): 6.74
Embodiment 4:
5 grams of his crude products of Tobe department are added in reaction vessel, in reaction vessel, adds 40ml acetic acid and 40ml water, reaction system is heated to backflow, insulated and stirred 30 minutes, naturally cools to room temperature, filters, dry at room temperature over night, obtains white crystalline powder (C crystallization).
Moisture determination (%): 6.82
Embodiment 5:
5 grams of his crude products of Tobe department are added in reaction vessel, 40ml aqueous hydrochloric acid (1mol/L) and 80ml water is added in reaction vessel, reaction system is heated to backflow, insulated and stirred 30 minutes, naturally cool to room temperature, filter, dry at room temperature over night, obtains white crystalline powder (C crystallization).
Moisture determination (%): 6.88
X-ray powder diffraction analysis data
Embodiment 6: the preparation of his crystal C tablet of Tobe department
The mixing of his crystal C of Tobe department of the present invention, lactose, croscarmellose sodium, with the hydroxypropylcellulose aqueous solution for tackiness agent wet granular, cross 22 mesh sieves, 60 DEG C of forced air dryings, add Magnesium Stearate and mix, compressing tablet.
Embodiment 7:
According to method described in embodiment 6, by his crystal form A, crystal form B and crystal C of Tobe department compressing tablet respectively, be under the condition of pH3.5 phosphate buffered saline buffer in release medium, stripping method carries out according to 2010 editions Chinese Pharmacopoeia appendix C X dissolution methods second method (paddle method), rotating speed is per minute 50 turns, adopts high-efficient liquid phase technique (HPLC method) to carry out the mensuration of dissolution rate, test 6 altogether to test tablet, each sampling time point dissolution results sees the following form, and Dissolution profiles is shown in Fig. 8.
Dissolution rate (%) test data table
| Time (min) | 5 | 10 | 15 | 20 | 30 | 45 | 60 |
| Crystal form A (%) | 35 | 52 | 65 | 75 | 85 | 90 | 93 |
| Crystal form B (%) | 25 | 40 | 51 | 56 | 61 | 65 | 67 |
| Crystal C (%) | 47 | 68 | 78 | 85 | 90 | 95 | 97 |
Crystal C is more conducive to prepare solid orally ingestible.
Claims (8)
1. a Tobe department he---5-(2-cyano group-4-pyridyl)-3-(4-pyridyl)-1,2, the crystal formation of 4-triazole, it is characterized in that, in the X-ray powder diffraction pattern represented with 2 θ diffraction angle, 2 θ have characteristic peak at 8.12,14.99,16.38,24.71,25.31,27.68,33.18 ± 0.2 (degree) place, and the crystal water containing 1 molecule.
2. the crystal formation of his monohydrate of Tobe department according to claim 1, is characterized in that, the X-ray powder diffraction pattern represented with 2 θ diffraction angle has characteristic peak as shown in Figure 3.
3. the crystal formation of his monohydrate of Tobe department according to claim 1, it is characterized in that the first endotherm(ic)peak of its dsc differential thermogram is at about 131 DEG C, the second endotherm(ic)peak is at about 330 DEG C.
4. prepare a method for his monohydrate crystal form of Tobe department described in claim 1, its concrete method comprises the steps:
(1) Tobe department he add in the mixed solvent of acid reagent and water, acid reagent wherein comprises organic acid or mineral acid, the volume ratio of acid reagent and water in the scope of 2:1 ~ 1:2, and
(2) system reflux is dissolved completely to solid, cooling crystallization, filter, drying at room temperature, obtain his monohydrate of Tobe department.
5. preparation method according to claim 4, is characterized in that described organic acid is selected from formic acid, acetic acid, oxalic acid, phenylformic acid or tartrate.
6. preparation method according to claim 4, is characterized in that described mineral acid is selected from 1mol/L aqueous hydrochloric acid or 1mol/L aqueous sulfuric acid.
7. preparation method according to claim 4, is characterized in that the preferred 1:1 of the volume ratio of described acid reagent and water.
8. the pharmaceutical composition containing his monohydrate crystal form of Tobe department described in claim 1, is characterized in that containing his monohydrate crystal form and pharmaceutically acceptable carrier of Tobe department according to claim 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250183A (en) * | 2016-12-29 | 2018-07-06 | 北京诚济制药有限公司 | A kind of preparation method of the Topiroxostat of high-purity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561340A (en) * | 2002-01-28 | 2005-01-05 | 株式会社富士药品 | Novel 1,2,4-triazole compound |
| CN1826335A (en) * | 2003-07-24 | 2006-08-30 | 株式会社富士药品 | Process for producing 1,2,4-triazole compound and intermediate therefor |
| WO2014017515A1 (en) * | 2012-07-25 | 2014-01-30 | 株式会社富士薬品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
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- 2014-07-29 CN CN201410366563.2A patent/CN105315260A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561340A (en) * | 2002-01-28 | 2005-01-05 | 株式会社富士药品 | Novel 1,2,4-triazole compound |
| CN1826335A (en) * | 2003-07-24 | 2006-08-30 | 株式会社富士药品 | Process for producing 1,2,4-triazole compound and intermediate therefor |
| WO2014017515A1 (en) * | 2012-07-25 | 2014-01-30 | 株式会社富士薬品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250183A (en) * | 2016-12-29 | 2018-07-06 | 北京诚济制药有限公司 | A kind of preparation method of the Topiroxostat of high-purity |
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