CN101781333B - Adefovir dipivoxil crystal form and preparation method thereof - Google Patents
Adefovir dipivoxil crystal form and preparation method thereof Download PDFInfo
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- CN101781333B CN101781333B CN 201010108877 CN201010108877A CN101781333B CN 101781333 B CN101781333 B CN 101781333B CN 201010108877 CN201010108877 CN 201010108877 CN 201010108877 A CN201010108877 A CN 201010108877A CN 101781333 B CN101781333 B CN 101781333B
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Abstract
The invention discloses an adefovir dipivoxil crystal form and a preparation method thereof. Cu-Ka radiation is used by the adefovir dipivoxil crystal form clear characteristic absorption peaks are generated through X-ray powder diffraction shown by 2 theta and interplanar spacing (value d), and the angle 2 theta and interplanar spacing (value d) of the absorption peaks are as follows: about 8.76(10.11), about 13.69(6.47), about 15.44(5.74), about 15.84(5.60), about 17.60(5.04), about 19.74(4.50), about 20.22(4.39), about 21.02(4.22) and about 21.73 (4.09), which is shown by angle 2 theta and interplanar spacing (value d). The preparation process of adefovir dipivoxil of the invention is simple, the new adefovir dipivoxil crystal form with good stability is prepared; and the residual solvent in the crystal form is less than 5000ppm, thus fully conforming to the concentration limit of pharmaceutical residual solvent guidline of the International Conference on Harmonization (ICH).
Description
(1) technical field
The present invention relates to crystal formation of a kind of ucleosides medicinal compound adefovir ester and preparation method thereof.
(2) background technology
Adefovir ester is a kind of novel HBV-DNA AG14361, is novel antiviral.Adefovir ester is the precursor medicine of Adefovir, changes into rapidly in vivo Adefovir, and Adefovir can mix the viral DNA chain with adenylic acid (AMP) competitiveness, suppress archaeal dna polymerase, stop the synthetic of DNA chain, and copying of virus is suppressed, bring into play the effect of anti-HIV, HBV and simplexvirus.
The different crystal forms of same medicine often has different physico-chemical properties as stability and solubleness etc.The polymorphous research of medicine has epochmaking meaning to the stability in assurance pharmaceutical production storage process and the safety and effectiveness in clinical use.Which kind of crystallographic system the crystal formation of medicine belongs to, which kind of lattice structure is relevant with drug molecular structure, and cooling when crystallisation process solvent for use kind, strength of solution, crystallization during simultaneously also with preparation, velocity of evaporation, drying means etc. all have relation.At present existing numerous bibliographical informations about adefovir dipivoxil crystal form and preparation method thereof.
Chinese patent CN 1995048 discloses a kind of adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof, preparation technology is simple for this crystal formation, carbonates solvent relative environmental protection used, industrial production cost is lower, it has obvious restraining effect to HBV-DNA, has good stable crystal form and scale operation and the required performance of preparation preparation.The present invention adopts the furnace drying method different from CN 1995048, obtains a new crystal.The new crystal adefovir ester residual solvent for preparing by the method is low, content is high, good stability.
(3) summary of the invention
First technical problem that the present invention will solve is to provide a kind of crystal formation with adefovir ester of good stability, and in this crystal formation, contained residual solvent less than 5000ppm, meets ICH to the concentration limit of drug residue solvent governing principle.
Adefovir dipivoxil crystal form of the present invention uses the Cu-Ka radiation, with the X-ray powder art diffraction of 2 θ angles and spacing d value representation, following characteristic peak is arranged:
| Peak number | 2 θ (degree) | |
| 1 | Approximately 8.76 | Approximately 10.11 |
| 2 | Approximately 13.69 | Approximately 6.47 |
| 3 | Approximately 15.44 | Approximately 5.74 |
| 4 | Approximately 15.84 | Approximately 5.60 |
| 5 | Approximately 17.60 | Approximately 5.04 |
| 6 | Approximately 19.74 | Approximately 4.50 |
| 7 | Approximately 20.22 | Approximately 4.39 |
| 8 | Approximately 21.02 | Approximately 4.22 |
| 9 | Approximately 21.73 | Approximately 4.09 |
Further, described adefovir dipivoxil crystal form is surveyed infrared absorption spectrum at about 3363cm with the KBr pressed disc method
-1, about 3284cm
-1, about 3161cm
-1, about 1757cm
-1, about 1658cm
-1, about 1600cm
-1, about 1253cm
-1There is charateristic avsorption band at the place.
Adefovir dipivoxil crystal form of the present invention has satisfactory stability.(40 ± 2 ℃ of temperature under the accelerated stability condition, humidity 75% ± 5%RH) was placed after 6 months, samples contg is in 99.5% left and right, converted product is mainly adefovir (AD) monoester, content is in 0.37% left and right, the adefovir (AD) monoester intermediates that to be adefovir ester transform to Adefovir is also the precursor medicine of Adefovir.And the contained residual solvent of described adefovir dipivoxil crystal form meets ICH to the concentration limit of the governing principle of drug residue solvent less than 5000ppm.
Second technical problem that the present invention will solve is to provide a kind of preparation method of above-mentioned adefovir dipivoxil crystal form, and the method technique is simple, and is environmentally friendly, is more suitable in suitability for industrialized production.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of method for preparing adefovir dipivoxil crystal form comprises the steps:
(1) adefovir ester is dissolved in the carbonates solvent of C3～C7;
(2) crystallization;
(3) step (2) gained solid vacuum-drying 30～100 hours under 30～80 ℃, 0～10KPa condition gets the adefovir dipivoxil crystal thing.
Further, the carbonates solvent of C3～C7 of the present invention is preferably methylcarbonate, diethyl carbonate, Methyl ethyl carbonate or carbonic acid diisopropyl ester.Methylcarbonate more preferably.
Further, described step (2) specifically adopts following method to carry out crystallization: control recrystallization temperature at 0～50 ℃, placement or stirred crystallization until crystallisate separate out fully.The preferred recrystallization temperature of controlling is at 0～20 ℃.
Further, described step (2) specifically adopts following method to carry out crystallization: decompression or normal pressure solvent evaporated crystallization under 30～80 ℃.Preferably reduce pressure or normal pressure solvent evaporated crystallization under 50～70 ℃.
Further, preferred steps of the present invention (3) obtains the adefovir dipivoxil crystal thing carrying out drying under following condition: vacuum-drying is 40～60 hours under 55～65 ℃, 0～10KPa condition.
The adefovir dipivoxil crystal form that the present invention makes has a good application prospect in the preparation hepatitis B virus resisting medicine.
Compared with prior art, the preparation technology of adefovir dipivoxil crystal form of the present invention is simple, main by controlling drying conditions, extend time of drying, obtained the new crystal of adefovir ester, this adefovir dipivoxil crystal form good stability, contained residual solvent meet ICH to the concentration limit of the governing principle of drug residue solvent less than 5000ppm.
(4) description of drawings
Fig. 1 is the X-ray powder diffraction spectrogram of a kind of adefovir dipivoxil crystal form of the present invention.
Fig. 2 is the infrared absorpting light spectra of a kind of adefovir dipivoxil crystal form of the present invention.
(5) embodiment
Below with concrete exemplifying embodiment explanation technical scheme of the present invention, but protection scope of the present invention is not limited to this:
The preparation of embodiment 1 adefovir dipivoxil crystal form
20g adefovir ester crude product is dissolved in the methylcarbonate of 50 ℃ of 200ml, stir molten clear, the solution (0 ℃) in ice-water bath that then will be dissolved with adefovir ester is cooling, and stirring and crystallizing, separate out to no longer including solid simultaneously, filter, the gained solid materials is placed in vacuum drying oven, and vacuum-drying is 40 hours under 60 ℃, 5KPa condition, obtains adefovir dipivoxil crystal thing 19.0g, adopt HPLC to detect, content is 99.8%; Adopt GC to detect, the residual carbon dimethyl phthalate is 80ppm.The Cu-Ka radiation, approximately 8.76 (10.11), approximately 13.69 (6.47), approximately 15.44 (5.74), approximately 15.84 (5.60), approximately 17.60 (5.04), approximately 19.74 (4.50), approximately 20.22 (4.39), approximately 21.02 (4.22), approximately 21.73 (4.09) the obvious characteristic absorption peak being arranged, see accompanying drawing 1 with the X-ray powder diffraction of 2 θ angles and spacing (d value) expression for details.Infrared absorption spectrum (KBr compressing tablet) is at about 3363cm
-1, 3284cm
-1, 3161cm
-1, 1757cm
-1, 1658cm
-1, 1600cm
-1, 1253cm
-1There is charateristic avsorption band at the place, sees accompanying drawing 2 for details.
The preparation of embodiment 2 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the methylcarbonate of 50 ℃ of 200ml, stirs molten clear.50 ℃ of lower stirring and crystallizing, separate out to no longer including solid, filter, the gained solid materials is placed in vacuum drying oven, and vacuum-drying is 40 hours under 60 ℃, 10KPa condition, obtains adefovir dipivoxil crystal thing 18.5g, adopts HPLC to detect, and content is 99.6%; Adopt GC to detect, the residual carbon dimethyl phthalate is 218ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 3 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the diethyl carbonate of 200ml50 ℃, stirs molten clear.(0 ℃) is cooling in ice-water bath, places crystallization, separates out to no longer including solid, filters, the gained solid materials is placed in vacuum drying oven, and in 60 ℃, under the 5Kpa condition, vacuum-drying is 50 hours, obtain adefovir dipivoxil crystal thing 17g, adopt HPLC to detect, content is 99.6%; Adopt GC to detect, the residual carbon diethyl phthalate is 600ppm (GC).Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 4 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the Methyl ethyl carbonate of 200ml50 ℃ of preheating, stir molten clear, the solution (0 ℃) in ice-water bath that then will be dissolved with adefovir ester is cooling, the while stirring and crystallizing, and solid to be no longer included is separated out, filter, the gained solid materials is placed in vacuum drying oven, and in 60 ℃, under the 2Kpa condition, vacuum-drying is 50 hours, obtain adefovir dipivoxil crystal thing 18.2g, adopt HPLC detection level 99.6%; Adopt GC to detect, residual Methyl ethyl carbonate is 500ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 5 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the carbonic acid diisopropyl ester of 200ml50 ℃ of preheating, stir molten clearly, then be placed in ice-water bath (0 ℃) cooling, simultaneously stirring and crystallizing, separate out to no longer including solid, filter, the gained solid materials is placed in vacuum drying oven, in 60 ℃, under the 5Kpa condition, vacuum-drying is 60 hours, obtain adefovir dipivoxil crystal thing 18.6g, adopt HPLC to detect, content 99.5%; Residual carbonic acid diisopropyl ester is 450ppm (GC).Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 6 adefovir dipivoxil crystal forms
In methylcarbonate with 20g adefovir ester crude product and 50 ℃ of preheatings of 200ml, stir molten clear.The solvent (0 ℃) in ice-water bath that is dissolved with adefovir ester is cooling, the while stirring and crystallizing, solid to be no longer included is separated out, filter, the gained solid materials is placed in vacuum drying oven, in 30 ℃, 5Kpa vacuum-drying 100 hours, obtains adefovir dipivoxil crystal thing 19.1g, adopt HPLC to detect, content is 99.5%; Adopt GC to detect, the residual carbon dimethyl phthalate is 4005ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 7 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the methylcarbonate of 50 ℃ of preheatings of 200ml, stirs molten clear.Then be placed in ice-water bath (0 ℃) cooling, stirring and crystallizing, separate out to no longer including solid simultaneously, filter, the gained solid materials was placed in vacuum drying oven, in 80 ℃, 5Kpa vacuum-drying 30 hours, obtain adefovir dipivoxil crystal thing 19.0g, adopt HPLC to detect, content is 99.0%; Adopt GC to detect, the residual carbon dimethyl phthalate is 20ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 8 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the methylcarbonate of 50 ℃ of preheatings of 200ml, stirs molten clear.At 80 ℃ of evaporated under reduced pressure solvent crystallizatioies, steam to no longer including solvent, the gained solid materials is placed in vacuum drying oven, in 60 ℃, 5Kpa vacuum-drying 40 hours, obtains adefovir dipivoxil crystal thing 19.9g, adopts HPLC to detect, and content is 99.6%; Adopt GC to detect, the residual carbon dimethyl phthalate is 68ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 9 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the diethyl carbonate of 50 ℃ of preheatings of 200ml, stirs molten clear.At 80 ℃ of normal pressure solvent evaporated crystallizatioies, steam to no longer including solvent, the gained solid materials is placed in vacuum drying oven, in 60 ℃, 5Kpa vacuum-drying 40 hours, obtains adefovir dipivoxil crystal thing 20.0g, adopts HPLC to detect, and content is 99.2%; Adopt GC to detect, the residual carbon diethyl phthalate is 280ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 10 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the methylcarbonate of 50 ℃ of preheatings of 200ml, stirs molten clear.At 60 ℃ of normal pressure solvent evaporated crystallizatioies, steam to no longer including solvent, the gained solid materials is placed in vacuum drying oven, in 60 ℃, 10Kpa vacuum-drying 40 hours, obtains adefovir dipivoxil crystal thing 19.8g, adopts HPLC to detect, and content is 99.7%; Adopt GC to detect, the residual carbon dimethyl phthalate is 560ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The preparation of embodiment 11 adefovir dipivoxil crystal forms
20g adefovir ester crude product is dissolved in the diethyl carbonate of 50 ℃ of preheatings of 200ml, stirs molten clear.At 30 ℃ of normal pressure solvent evaporated crystallizatioies, steam to no longer including solvent, the gained solid materials is placed in vacuum drying oven, in 60 ℃, 5Kpa vacuum-drying 40 hours, obtains adefovir dipivoxil crystal thing 19.9g, adopts HPLC to detect, and content is 99.1%; Adopt GC to detect, the residual carbon diethyl phthalate is 800ppm.Gained adefovir dipivoxil crystal form XRD figure is composed, infared spectrum is consistent with accompanying drawing 1 and accompanying drawing 2 respectively.
The stability study of embodiment 12 adefovir dipivoxil crystal forms
Adopt method provided by the present invention to prepare adefovir dipivoxil crystal form, carry out stability study.(40 ± 2 ℃ of temperature, humidity 75% ± 5%RH) was placed 6 months, carried out Liquid Detection respectively at the 0th month, January, February, March, April, May, June under the accelerated stability condition.Test-results is presented under the accelerated stability test condition and places after 6 months, and samples contg is 99.5%, and result shows that this stable crystal form is good.
Stability data sees the following form 1:
Table 1
Claims (10)
1. adefovir dipivoxil crystal form is characterized in that: described adefovir dipivoxil crystal form uses the Cu-Ka radiation, and is as shown below with the X-ray powder diffraction spectrogram of 2 θ angles and spacing d value representation:
2. adefovir dipivoxil crystal form as claimed in claim 1 is characterized in that described adefovir dipivoxil crystal form surveys infrared absorption spectrum at about 3363cm with the KBr pressed disc method
-1, about 3284cm
-1, about 3161cm
-1, about 1757cm
-1, about 1658cm
-1, about 1600cm
-1, about 1253cm
-1There is charateristic avsorption band at the place.
3. a method for preparing adefovir dipivoxil crystal form as claimed in claim 1, is characterized in that described method comprises the steps:
(1) adefovir ester is dissolved in the carbonate solvent of C3～C7;
(2) crystallization;
(3) step (2) gained solid vacuum-drying 30～100 hours under 30～80 ℃, 0～10KPa condition gets the adefovir dipivoxil crystal thing.
4. the preparation method of adefovir dipivoxil crystal form as claimed in claim 3 is characterized in that in described step (2), recrystallization temperature is controlled at 0～50 ℃, placement or stirred crystallization until crystallisate separate out fully.
5. the preparation method of adefovir dipivoxil crystal form as claimed in claim 4 is characterized in that in described step (2), recrystallization temperature is controlled at 0～20 ℃, placement or stirred crystallization until crystallisate separate out fully.
6. the preparation method of adefovir dipivoxil crystal form as claimed in claim 3, is characterized in that described step (2) reduces pressure or normal pressure solvent evaporated crystallization under 30～80 ℃.
7. the preparation method of adefovir dipivoxil crystal form as claimed in claim 6, is characterized in that described step (2) reduces pressure or normal pressure solvent evaporated crystallization under 50～70 ℃.
8. as the preparation method of the described adefovir dipivoxil crystal form of one of claim 3～7, the carbonate solvent that it is characterized in that described C3～C7 is methylcarbonate, diethyl carbonate, Methyl ethyl carbonate or carbonic acid diisopropyl ester.
9. as the preparation method of the described adefovir dipivoxil crystal form of one of claim 3～7, it is characterized in that described step (3) obtains the adefovir dipivoxil crystal thing carrying out drying under following condition: vacuum-drying is 40～60 hours under 55～65 ℃, 0～10KPa condition.
10. as the preparation method of the described adefovir dipivoxil crystal form of one of claim 3～7, the carbonate solvent that it is characterized in that described C3～C7 is methylcarbonate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0647649A1 (en) * | 1992-06-23 | 1995-04-12 | Yamanouchi Pharmaceutical Co. Ltd. | Novel crystal of monohydrate of heterocyclic bis(phosphonic acid) derivative |
| CN1995048A (en) * | 2006-12-14 | 2007-07-11 | 浙江车头制药有限公司 | Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof |
| CN101139363A (en) * | 2007-09-05 | 2008-03-12 | 福建广生堂药业有限公司 | M-crystal system of adefovir dipivoxil ester and preparation method and medicine application |
| CN101357930A (en) * | 2008-09-09 | 2009-02-04 | 珠海联邦制药股份有限公司 | Adefovir dipivoxil preparation method |
-
2010
- 2010-02-10 CN CN 201010108877 patent/CN101781333B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0647649A1 (en) * | 1992-06-23 | 1995-04-12 | Yamanouchi Pharmaceutical Co. Ltd. | Novel crystal of monohydrate of heterocyclic bis(phosphonic acid) derivative |
| CN1995048A (en) * | 2006-12-14 | 2007-07-11 | 浙江车头制药有限公司 | Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof |
| CN101139363A (en) * | 2007-09-05 | 2008-03-12 | 福建广生堂药业有限公司 | M-crystal system of adefovir dipivoxil ester and preparation method and medicine application |
| CN101357930A (en) * | 2008-09-09 | 2009-02-04 | 珠海联邦制药股份有限公司 | Adefovir dipivoxil preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 蒋晔等.阿德福韦酯的合成.《中国医药工业杂志》.2007,第38卷(第1期),第6页左栏最后1段，右栏第1-2段. * |
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