CN109384822B - Epirubicin hydrochloride crystal form and preparation method thereof - Google Patents
Epirubicin hydrochloride crystal form and preparation method thereof Download PDFInfo
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- CN109384822B CN109384822B CN201710686710.8A CN201710686710A CN109384822B CN 109384822 B CN109384822 B CN 109384822B CN 201710686710 A CN201710686710 A CN 201710686710A CN 109384822 B CN109384822 B CN 109384822B
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses an epirubicin hydrochloride crystal form L, wherein X-ray powder diffraction X-RPD expressed by Cu-Kalpha radiation at an angle of 2 theta has characteristic diffraction peaks at 6.78, 9.10, 11.08 and 25.24. In addition, the invention also discloses a preparation method of the crystal form, which comprises the following steps: adding epirubicin hydrochloride into a mixed solvent of alcohol and water, heating to 30-70 ℃, stirring for dissolving, adding a polymer into the solution, cooling for crystallization, separating and drying to obtain the stable epirubicin hydrochloride crystal form L. The crystal form L has high stability, the preparation method is simple, the used organic solvent is less, and a more reliable raw material is provided for preparing other preparations by using epirubicin hydrochloride.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, and particularly relates to an epirubicin hydrochloride crystal form L and a preparation method thereof.
Background
Epirubicin hydrochloride, also known as epirubicin hydrochloride, belongs to the anthracycline class of antibiotics, and has the chemical name: (8S, 10S) -10- [ (3-amino-2, 3, 6-trideoxy-alpha-L-arabinopyranosyl) -O- ] -6, 8, 11-trihydroxy-8-hydroxyacetyl-1-methoxy-7, 8, 9, 10-tetrahydrotetracene-5, 12-dione hydrochloride having the following structural formula:
anthracyclines form one of the largest families of natural bioactive compounds. Some members of this family are clinically effective antineoplastic agents. For example, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and carminomycin. These compounds have been shown to be useful in bone marrow transplantation, stem cell transplantation, breast cancer therapy, acute lymphocytic and non-lymphocytic leukemia, chronic lymphocytic leukemia, non-hodgkin's lymphoma, and other solid tumors. Among them, epirubicin hydrochloride has been shown clinically to have minimal toxic side effects on the heart and bone marrow during treatment. With the advent of liposomes, the greater the demand for epirubicin hydrochloride starting material, epirubicin hydrochloride is becoming increasingly important in the treatment of cancer for humans.
Epirubicin is an isomer of doxorubicin and acts by intercalating directly between DNA base pairs, interfering with the transcription process, preventing the formation of mRNA, and thereby inhibiting the synthesis of DNA and RNA. In addition, epirubicin hydrochloride also has an inhibitory effect on topoisomerase II, is a cell cycle nonspecific drug, and is effective on various transplanted tumors. Compared to doxorubicin, the therapeutic effect was equal or slightly higher, but the toxicity to the heart was less.
There are various methods known in the art to prepare epirubicin hydrochloride. However, amorphous epirubicin hydrochloride (prepared, for example, as described in U.S. patent 4861870) is generally considered unsuitable for pharmaceutical use due to its pronounced deliquescence and chemical instability during storage, with accumulation of the aglycon doxorubicin ketone.
Epirubicin hydrochloride has been reported in two crystalline forms, the XRD pattern of said type i epirubicin hydrochloride in patent US4, 861, 870 shows to produce a single strong signal around 24.6; the XRD pattern of epirubicin hydrochloride type ii described in patent CN102171232A shows multiple strong signals at 5.2, 9.2, 13.7, 15.5, 19.2, 21.1, 22, 22.5, 23.6, 24.1, 25.8, 27.7, 29.8, and these two forms show stability in the more amorphous state. However, it has been found experimentally that the stability of both forms decreases after a few months of storage, resulting in a form which is less safe to use in the preparation of the formulated product. Therefore, it is necessary to provide an epirubicin hydrochloride crystal form with high purity and higher stability, so as to provide more abundant raw materials for preparing preparation products.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a crystal form L of epirubicin hydrochloride, and the crystal form has higher purity and stability than two crystal forms reported in the prior art. In addition, the invention also provides a preparation method for obtaining the epirubicin hydrochloride crystal form L by adopting polymer heterogeneous nucleation.
The invention provides a stable crystalline form L of epirubicin hydrochloride, wherein X-ray powder diffraction X-RPD expressed by 2 theta angle by using Cu-Kalpha radiation has characteristic diffraction peaks at 2 theta (6.78), 9.10, 11.08 and 25.24.
Preferably, the epirubicin hydrochloride of the crystal form L has characteristic diffraction peaks at 2 theta of 6.78, 9.10, 9.44, 11.08, 18.44, 20.98, 22.38, 25.24, 27.63 and 33.93 by X-ray powder diffraction using Cu-Kalpha radiation and expressed by 2 theta angles.
Preferably, the epirubicin hydrochloride form L has characteristic diffraction peaks at 2 theta of 6.78, 9.10, 9.44, 11.08, 13.67, 15.38, 16.47, 18.44, 19.85, 20.98, 21.31, 22.38, 25.24, 27.63, 29.46, 29.67, 31.72 and 33.93 by X-ray powder diffraction expressed by 2 theta angle using Cu-K alpha radiation.
In a preferred embodiment of the present invention, the epirubicin hydrochloride form L has an X-ray powder diffraction pattern as shown in figure 1.
The second aspect of the invention provides a preparation method of epirubicin hydrochloride crystal form L.
In the preparation method of the epirubicin hydrochloride crystal form L provided by the invention, the source and the form of epirubicin hydrochloride are not further limited, and the epirubicin hydrochloride crystal form L can be chemically synthesized and biologically fermented.
A process for preparing the crystalline form, comprising the steps of:
(a) providing a mixed solvent of alcohol and water;
(b) adding epirubicin hydrochloride into the mixed solvent in the step (a), heating to the dissolving temperature of 30-70 ℃, and stirring for dissolving;
(c) adding a polymer into the solution obtained in the step (b) for cooling and crystallization;
(d) and (c) separating and drying the crystals precipitated in the step (c) to obtain the epirubicin hydrochloride crystal form L.
Among them, it is preferable that the alcohol in the step (a) is 1-propanol, isopropanol or ethanol; ethanol is preferred.
Preferably, the volume percentage of water in the mixed solvent of alcohol and water in the step (a) is 8-20%.
Preferably, the mass-to-volume ratio m/v of epirubicin hydrochloride to the mixed solvent in the step (b) is 1: 5-15, preferably 1: 6-13; wherein the mass is in g and the volume is in ml.
Preferably, the dissolving temperature in the step (b) is 55-65 ℃, and the stirring is carried out for 0.5-2 hours after dissolving.
Preferably, the polymer of step (c) is poly (butylene-terephthalate), an ethylene/vinyl acetate copolymer, wherein the vinyl acetate content is 28%, polyvinyl chloride, wherein the chlorine content is 25% by weight, vulcanized polyphenylene or nylon 11; preference is given to poly (butylene-terephthalate), ethylene/vinyl acetate copolymers having a vinyl acetate content of 28%, or polyvinyl chloride having a chlorine content of 25% by weight.
Preferably, the mass ratio of the added polymer to the epirubicin hydrochloride in the step (c) is 1: 40-100, preferably 1: 60-80.
Preferably, in the cooling and crystallization process in the step (c), after the addition of the polymer is finished, the temperature is reduced to 5-10 ℃ at a speed of 10-20 ℃/h, and the mixture is stirred at the temperature for 5-10 h.
Preferably, in the step (d), the crystal precipitated in the system is separated and dried by a conventional method in the art, and the separation is performed by a conventional method such as filtration, centrifugation, etc.; alternatively, the solid is washed with a suitable solvent, such as diethyl ether and the like. The drying can be carried out by using a conventional method in the field such as air-blast drying and reduced pressure drying, and the drying temperature is 20-40 ℃.
The melting point of form L is about 210 c as determined by a melting point apparatus.
The polymer is added in the preparation method, and the influence of the added polymer on the crystallization process of the medicament mainly has two modes, one mode is that heterogeneous nucleation is formed by the interaction between the functional group on the surface of the polymer and the functional group of the medicament; the other is the influence of the topological structure of the surface of the polymer on the nucleation, and the invention mainly takes the first influence as the main factor.
The polymers adopted by the invention are all insoluble in water, and can be filtered in the preparation process when epirubicin hydrochloride crystal form L is used as a raw material to prepare preparation products such as powder injection or water injection preparations, so that the quality and the medication safety of the final product are not influenced.
Compared with the prior art, the invention has obvious technical advantages. The epirubicin hydrochloride crystal form L provided by the invention has good chemical stability and crystal form purity, is easy for large-scale preparation, and is beneficial to transportation and storage; meanwhile, the invention provides a method for preparing epirubicin hydrochloride crystal form L, which has the advantages of high yield, simple operation, less used organic solvent, suitability for large-scale production and wide application prospect.
Drawings
FIG. 1: an X-ray powder diffraction pattern of epirubicin hydrochloride form L.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the examples are for illustrative purposes only and are not intended to limit the invention, so that simple modifications of the invention in its process context are within the scope of the invention as claimed.
Example 1
Adding 10.0g epirubicin hydrochloride (HPLC purity 98.0%) into a mixed solvent of 63ml ethanol and 7ml water, heating to 65 ℃, and stirring for 1h under the condition of heat preservation; adding 0.13g of ethylene/vinyl acetate copolymer (the content of vinyl acetate is 28%) into the solution, cooling the system to 5 ℃ at the speed of 10 ℃/h, and stirring for 10h under heat preservation; and filtering to collect a solid, washing the solid with 20ml of ether, and drying for 16h at 20-40 ℃ under vacuum to obtain 9.68g of L-type epirubicin hydrochloride crystals with the purity of 99.8 percent by HPLC.
Example 2
Adding 10.0g epirubicin hydrochloride (HPLC purity is 98.0%) into a mixed solvent of 76ml isopropanol and 14ml water, heating to 60 ℃, and stirring for 0.5h under heat preservation; adding 0.14g of polyvinyl chloride into the system, cooling to 7 ℃ at the speed of 17 ℃/h, and stirring for 8h under heat preservation; the solid was collected by filtration, washed with 20ml of ether and dried under vacuum at 20-40 ℃ for 16h to give 8.86g of epirubicin hydrochloride form, with HPLC purity of 99.6%.
Example 3
Adding 10.0g epirubicin hydrochloride (HPLC purity is 98.0%) into a mixed solvent of 104ml 1-propanol and 26ml water, heating to 55 ℃, and stirring for 1h under heat preservation; adding 0.16g of poly (butylene-terephthalate) into the system, cooling to 10 ℃ at the speed of 15 ℃/h, and stirring for 8h under the condition of heat preservation; the solid was collected by filtration, washed with 25ml of ether and dried under vacuum at 20-40 ℃ for 16h to give 6.81g of epirubicin hydrochloride form, with HPLC purity of 99.7%.
Example 4
Adding 10.0g epirubicin hydrochloride (HPLC purity is 98.0%) into a mixed solvent of 63ml ethanol and 7ml water, heating to 65 ℃, and stirring for 1h under the condition of heat preservation; adding 0.14g of vulcanized polyphenylene into the system, cooling to 5 ℃ at the speed of 10 ℃/h, and stirring for 10h under heat preservation; the solid was collected by filtration, washed with 20ml of ether and dried under vacuum at 20-40 ℃ for 16h to give 9.68g of epirubicin hydrochloride form, with an HPLC purity of 99.4%.
Example 5
Adding 10.0g epirubicin hydrochloride (HPLC purity is 98.0%) into a mixed solvent of 63ml ethanol and 7ml water, heating to 65 ℃, and stirring for 1h under the condition of heat preservation; adding 0.15g of nylon 11 into the system, cooling to 5 ℃ at the speed of 10 ℃/h, and stirring for 10h under heat preservation; the solid was collected by filtration, washed with 20ml of ether and dried under vacuum at 20-40 ℃ for 16h to give 9.69g of epirubicin hydrochloride form, with HPLC purity of 99.2%.
Example 6
Adding 10.0g epirubicin hydrochloride (HPLC purity is 98.0%) into a mixed solvent of 64ml ethanol and 16ml water, heating to 30 ℃, and stirring for 2h under heat preservation; adding 0.1g of poly (butylene-terephthalate) into the system, cooling to 5 ℃ at the speed of 10 ℃/h, preserving heat and stirring for 10 h; the solid was collected by filtration, washed with 20ml of ether and dried under vacuum at 20-40 ℃ for 16h to give 9.14g of epirubicin hydrochloride form, with HPLC purity of 99.3%.
Example 7
Adding 10.0g epirubicin hydrochloride (HPLC purity is 98.0%) into a mixed solvent of 92ml isopropanol and 8ml water, heating to 70 ℃, and stirring for 0.5h under heat preservation; adding 0.25g of polyvinyl chloride into the system, cooling to 7 ℃ at the speed of 20 ℃/h, and stirring for 8h under heat preservation; the solid was collected by filtration, washed with 20ml of ether and dried under vacuum at 20-40 ℃ for 16h to give 9.44g of epirubicin hydrochloride form, with HPLC purity of 99.1%.
Example 8
Adding 10.0g epirubicin hydrochloride (HPLC purity is 98.0%) into a mixed solvent of 90ml 1-propanol and 10ml water, heating to 50 ℃, and stirring for 1h under heat preservation; adding 0.16g of ethylene/vinyl acetate copolymer and 28% of vinyl acetate into the system, cooling to 10 ℃ at the speed of 15 ℃/h, and stirring for 8h under heat preservation; the solid was collected by filtration, washed with 25ml of ether and dried under vacuum at 20-40 ℃ for 16h to give 9.32g of epirubicin hydrochloride form, with an HPLC purity of 99.3%.
Comparative example 1
10.0g epirubicin hydrochloride (HPLC purity 98.0%) was added to water pH3.5 and evaporated at low pressure at 40 ℃ until the solution became gel; 300ml of acetone is added to the system, the solid is collected by filtration, washed with 50ml of acetone and dried in vacuum for 16 hours, yielding 9.60g of epirubicin hydrochloride type I crystals with an HPLC purity of 99.0%.
Comparative example 2
Adding 10.0g of epirubicin hydrochloride (HPLC purity is 98.0%) into an ethanol-water mixed solution with the pH of 3-4, evaporating at the low pressure at 40 ℃ until the solution becomes a gel state, adding 12 times of 1-propanol into the residual solution, stirring for 3 hours, filtering to collect solids, washing with 10ml of acetone, and drying at room temperature to obtain 9.00g of type II epirubicin hydrochloride crystals with the HPLC purity of 99.4%.
Stability test
The epirubicin hydrochloride crystal L sample prepared in the example is weighed and placed at 40 ℃, and the stability of the sample placed for 1 month, 2 months, 3 months and 6 months is examined. And the results of stability tests were compared with the samples of type I and type II crystals obtained in the prior art using the epirubicin hydrochloride crystal L obtained in example 1, and the results are detailed in Table 1.
The specific stability investigation method can be according to the method in the second part, appendix XIX C of the 2010 version of Chinese pharmacopoeia; the purity of the sample can be measured by HPLC, which is described in appendix V D of the second part of the pharmacopoeia 2010.
Table 1 stability test results
Note: is anhydrous and solvent-free
As can be seen from the above table, the epirubicin hydrochloride crystal form I in the comparative example 1 has greatly reduced content and increased content of impurity doxorubicin ketone and total impurities along with the prolonging of the standing time. In contrast, in comparative example 2, the epirubicin hydrochloride form II has relatively poor stability although it degrades slowly. After the epirubicin hydrochloride crystal form L is placed for 6 months, the epirubicin hydrochloride crystal form L has good stability. The L-type epirubicin hydrochloride contains trace polymer, so the content is measured to be low, but the polymer can be removed in the preparation process and the quality of the final product cannot be influenced. As can be seen from the Doxorubicin and Total miscellaneous data in Table 1, the stability of the L-type epirubicin hydrochloride is superior to that of the I-type and II-type epirubicin hydrochloride.
Claims (14)
1. A crystalline form L of epirubicin hydrochloride characterized by an X-ray powder diffraction X-RPD expressed in degrees 2 Θ using Cu-ka radiation having characteristic diffraction peaks at 2 Θ ═ 6.78, 9.10, 9.44, 11.08, 18.44, 20.98, 22.38, 25.24, 27.63, 33.93.
2. A crystalline form L of epirubicin hydrochloride according to claim 1 characterized by X-ray powder diffraction at 2 Θ angles using Cu-ka radiation having characteristic diffraction peaks at 2 Θ ═ 6.78, 9.10, 9.44, 11.08, 13.67, 15.38, 16.47, 18.44, 19.85, 20.98, 21.31, 22.38, 25.24, 27.63, 29.46, 29.67, 31.72, 33.93.
3. A process for preparing the crystalline form L of claim 1 or 2, comprising the steps of:
(a) providing a mixed solvent of alcohol and water;
(b) adding epirubicin hydrochloride into the mixed solvent in the step (a), heating to the dissolving temperature of 30-70 ℃, and stirring for dissolving;
(c) adding a polymer into the solution obtained in the step (b) for cooling and crystallization;
(d) and (c) separating and drying the crystals precipitated in the step (c) to obtain the epirubicin hydrochloride crystal form L.
4. The process of claim 3, wherein the alcohol in step (a) is 1-propanol, isopropanol or ethanol.
5. The process of claim 3, wherein the alcohol in step (a) is ethanol.
6. The method of claim 3, wherein the mixed solvent of alcohol and water in step (a) contains 8% to 20% by volume of water.
7. The method according to claim 3, wherein the mass-to-volume ratio m/v of epirubicin hydrochloride to the mixed solvent in step (b) is 1: 5-15; wherein the mass is in g and the volume is in ml.
8. The method according to claim 3, wherein the mass-to-volume ratio m/v of epirubicin hydrochloride to the mixed solvent in step (b) is 1: 6-13; wherein the mass is in g and the volume is in ml.
9. The method according to claim 3, wherein the dissolving temperature in the step (b) is 55-65 ℃, and the stirring is carried out for 0.5-2 hours after the dissolution.
10. The method of claim 3, wherein the polymer of step (c) is polybutylene terephthalate, ethylene/vinyl acetate copolymer, polyvinyl chloride, vulcanized polyphenylene, or nylon 11; wherein the vinyl acetate content of the ethylene/vinyl acetate copolymer is 28 percent, and the chlorine content of the polyvinyl chloride is 25 percent by weight.
11. The method according to claim 3, wherein the polymer of step (c) is polybutylene terephthalate or polyvinyl chloride; wherein the vinyl acetate content is 28 percent, and the chlorine content in the polyvinyl chloride is 25 percent by weight.
12. The method according to claim 3, wherein the mass ratio of the polymer in the step (c) to the epirubicin hydrochloride is 1: 40-100.
13. The method according to claim 3, wherein the mass ratio of the polymer in the step (c) to the epirubicin hydrochloride is 1: 60-80.
14. The method according to claim 3, wherein in the cooling crystallization process in the step (c), the temperature is reduced to 5-10 ℃ at a speed of 10-20 ℃/h after the polymer is added, and the mixture is stirred at the temperature for 5-10 h.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102120750A (en) * | 2011-01-30 | 2011-07-13 | 山东新时代药业有限公司 | Epirubicin hydrochloride purification method |
| TW201143777A (en) * | 2010-03-24 | 2011-12-16 | Dong A Pharm Co Ltd | Novel crystal forms of Epirubicin hydrochloride |
| CN103827129A (en) * | 2011-05-31 | 2014-05-28 | 贺利氏贵金属有限责任两合公司 | Crystallization of epirubicin hydrochloride |
| CN104861014A (en) * | 2015-06-03 | 2015-08-26 | 道中道（菏泽）制药有限公司 | Preparing method of epirubicin hydrochloride crystals |
| CN105713055A (en) * | 2009-09-08 | 2016-06-29 | 尼德制药股份有限公司 | Crystalline 4'-epidaunorubicin hydrochloride |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105713055A (en) * | 2009-09-08 | 2016-06-29 | 尼德制药股份有限公司 | Crystalline 4'-epidaunorubicin hydrochloride |
| TW201143777A (en) * | 2010-03-24 | 2011-12-16 | Dong A Pharm Co Ltd | Novel crystal forms of Epirubicin hydrochloride |
| CN102120750A (en) * | 2011-01-30 | 2011-07-13 | 山东新时代药业有限公司 | Epirubicin hydrochloride purification method |
| CN103827129A (en) * | 2011-05-31 | 2014-05-28 | 贺利氏贵金属有限责任两合公司 | Crystallization of epirubicin hydrochloride |
| CN104861014A (en) * | 2015-06-03 | 2015-08-26 | 道中道（菏泽）制药有限公司 | Preparing method of epirubicin hydrochloride crystals |
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