ZHANG, Xiaoheng (Changmao Town, Lianyungang City Guannan County, Jiangsu, CN)
SCINOPHARM (KUNSHAN) BIOCHEMICAL TECHNOLOGY CO., LTD. (No. 88, Weiye RoadKunshan, Jiangsu 0, 215300, CN)
HENSCHKE, Julian, Paul (1006 Greenhill Road, Summertown, Australia SA 5141, 5141, AU)
ZHANG, Xiaoheng (Changmao Town, Lianyungang City Guannan County, Jiangsu, CN)
CHEN, Chentung (No. 1, Nan-ke 8th Road Tainan Science-based, Industrial Park, Shan-hu, Tainan County Taiwan, Taiwan, CN)
| CLAIMS What is claimed is: 1. Crystalline Form I of cladribine characterized by a powder X-ray diffraction pattern having a peak at about 26.1 ± 0.2° two-theta (2Θ). 2. The crystalline Form I according to claim 1 further characterized by peaks in the powder X-ray diffraction pattern at about 10.4, 11.1 , 15.8, 16.2, 23.5, 28.5, 31.4, 33.0 ± 0.2° two-theta(29). 3. The crystalline form according to claim 1 further characterized by a powder X-ray diffraction pattern as shown by at least one of Figs 1-3. 4. The crystalline form according to claim 1 further characterized by infrared absorption spectrum as shown by at least one of Figs. 4-6. 5. The crystalline Form I according to claim 1 further characterized by a DSC curve as shown on Fig. 7. 6. An amorphous form of cladribine. 7. The amorphous form of cladribine according to claim 6 further characterized by a powder X-ray diffraction pattern as shown in Figure 8. 8. The amorphous form according to claim 7 further characterized by infrared absorption spectrum as shown by at least one of Figs. 9- 1. 9. A pharmaceutical composition comprising crystalline Form I of claim 1 and a pharmaceutically acceptable carrier. 10. A method of treating cancer suffered by a mammalian subject comprising administering the subject an effective amount of the pharmaceutical composition of claim 9. 11. A pharmaceutical composition comprising amorphous form of cladribine of claim 6 and a pharmaceutically acceptable carrier. 12. A method of treating cancer suffered by a mammalian subject comprising administering the subject an effective amount of the pharmaceutical composition of claim 11. |
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0001] The present application relates to crystalline form and amorphous form of
5-(6-amino-2-chloro-purin-9-yl)-2-(hydroxymethyl)oxolan-3 -ol (also known as cladribine), process of making thereof, and pharmaceutical composition containing crystlaline or amorphous form of cladribine.
2. Description of the related arts
[0002] Cladribine (leustatin) is an anti-cancer agent. It can be used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and multiple sclerosis. Its chemical name is 5-(6-amino-2-chloro-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol or 2-chlorodeoxyadenosine (2CDA). Its chemical structure is:
SUMMARY OF THE INVENTION
[0003] We have obtained crystalline and amorphous forms of cladribine that exhibit unique properties.
[0004] One aspect of the present application is crystalline Form I of cladribine characterized by a powder X-ray diffraction pattern having a peak at about 26.1 ± 0.2° two-theta (2Θ). Preferably, the crystalline Form I is further characterized by peaks in the powder X-ray diffraction pattern at about 10.4, 11.1 , 15.8, 16.2, 23.5, 28.5, 31.4, 33.0 ± 0.2° two-theta(20). More preferably, the crystalline Form I is characterized by a powder X-ray diffraction pattern as shown by at least one of Figs 1-3. In accordance with another preferred embodiment, the crystalline Form I is characterized by infrared absorption spectrum as shown by at least one of Figs. 4-6. In accordance with yet another embodiment of the present application, the crystalline Form I is characterized by a DSC curve as shown on Fig. 7.
[0005] The crystalline Form I may be prepared by a process comprising the steps of:
a) dissolving crude cladribine in an organic solvent or a mixture of organic solvent and water under heating;
b) cooling the resulting solution; and
c) separating and drying the resulting solid under reduced pressure to obtain crystalline form I of cladribine.
[0006] Alternatively, the crystalline Form I may also be prepared by a process comprising the steps of: a') dissolving crude cladribine in an organic solvent under heating;, b') adding an antisolvent; and c') separating and drying the resulting solid to obtain crystalline form I of cladribine. [0007] Another aspect of the present invention is an amorphous form of cladribine.
Preferably, the amorphous form is characterized by a powder X-ray diffraction pattern as shown in Figure 8. In accordance with another preferred embodiment of the present application, the amorphous form is characterized by infrared absorption spectrum as shown by at least one of Figs. 9-11.
[0008] The amorphous form may be prepared by a process comprising the steps of:
i) dissolving crude cladribine in a protic solvent;
ii) cooling the resulting solution; and
ii) lyophilizing the resulting solid under reduced pressure to obtain amorphous form of cladribine.
[0009] The crystalline Form I and amorphous form of cladribine may be individually or together incorporated with a pharmaceutically acceptable carrier to form a pharmaceutical composition. Such a pharmaceutical composition may be used for treating cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] In the drawings:
Figs. 1-3 show characteristic X-ray powder diffraction pattern of Form I of cladribine in accordance with an embodiment of the present invention.
Figs. 4-6 show infrared diffuse-reflectance pattern of Form I of cladribine in accordance with an embodiment of the present invention.
Fig. 7 shows DSC pattern of Form I of cladribine in accordance with an embodiment of the present invention.
Fig. 8 shows characteristic X-ray powder diffraction pattern of amorphous cladribine in accordance with an embodiment of the present invention.
Figs. 9-11 show infrared diffuse-reflectance pattern of amorphous cladribine in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0011] The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
Example 1 : Preparation of Crystalline Form I of Cladribine
[0012] Crude Cladribine (70 g), H 2 0 (350 mL), MeOH (350 ml_) and 29% MeONa/MeOH solution (0.17 g) were charged into a flask with stirring. The mixture was stirred and heated to reflux at 75 to 80°C until the mixture turned clear. The mixture was stirred for 3 h, and then the solution was filtered to remove the precipitates at 75 to 80 °C. The mixture was stirred and heated to reflux until the mixture turned clear again. The filtrate was stirred and cooled. Crystals started to form at 45°C. The slurry was stirred for 2 h at the cloudy point. The slurry was cooled slowly at a rate of 5°C/0.5 h. The slurry was stirred at 10-20°C for 4-8 h, and then filtered. The filter cake was washed with MeOH (50 mLx3) and dried at 50°C in vacuum for 6 h to give 62.7 g of Cladribine crystalline form I (99.9%, by HPLC).
Example 2: Preparation of Crystalline Form I of Cladribine
[0013] Crystalline of
(2R,3S,5R)-5-(6-amino-2-chloropurin-9-yl)-2-(hydroxymethyl)o xolan-3-ol (300 mg) was dissolved in methanol, ethanol, DMSO or DMAC at 60°C, following by dropwise adding antisolvent of EA, heptane or cyclohexane. The resulting solid was filtrated and dried at 40°C under ambient pressure. After analyzing by XRD, form I was obtained.
Example 3: Preparation of Amorphous form of Cladribine [0014] Crystalline of
(2R,3S,5R)-5-(6-amino-2-chloropurin-9-yl)-2-(hydroxymethyl)o xolan-3-ol (100 mg) was dissolved in water (10 ml) at 60°C. The clear solution was slowly cooled to 25°C and then filtrated. The resulting solution was further cooled by dry ice for one hour and subsequently subjected to the lyophilizer (EYELA FDU-830) under reduced pressure. After 24 hours drying, the powder X-ray analysis showed that the resulting solid was in amorphous form.
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