WO2011054179A1 - Crystalline form of cladribine and process for preparation thereof - Google Patents
Crystalline form of cladribine and process for preparation thereof Download PDFInfo
- Publication number
- WO2011054179A1 WO2011054179A1 PCT/CN2010/001749 CN2010001749W WO2011054179A1 WO 2011054179 A1 WO2011054179 A1 WO 2011054179A1 CN 2010001749 W CN2010001749 W CN 2010001749W WO 2011054179 A1 WO2011054179 A1 WO 2011054179A1
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- WIPO (PCT)
- Prior art keywords
- cladribine
- crystalline form
- powder
- diffraction pattern
- further characterized
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
Definitions
- 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.
- Cladribine 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:
- 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 (2 ⁇ ).
- 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).
- the crystalline Form I is characterized by a powder X-ray diffraction pattern as shown by at least one of Figs 1-3.
- 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.
- the crystalline Form I may be prepared by a process comprising the steps of:
- 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.
- Another aspect of the present invention is an amorphous form of cladribine.
- the amorphous form is characterized by a powder X-ray diffraction pattern as shown in Figure 8.
- the amorphous form is characterized by infrared absorption spectrum as shown by at least one of Figs. 9-11.
- the amorphous form may be prepared by a process comprising the steps of:
- 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.
- a pharmaceutical composition may be used for treating cancer.
- 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.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Crystalline form of cladribine characterized by a powder X-ray diffraction pattern having a peak at about 26.1° ± 0.2° two-theta (2θ) is disclosed. An amorphous form of cladribine is also disclosed herein. Either of these forms of cladrbine can be incorporated with a pharmaceutically acceptable carrier to form a pharmaceutical composition for treating cancer.
Description
Crystalline form of cladribine and process for preparation thereof
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:
[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), H20 (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)oxolan-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)oxolan-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.
Claims
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25834809P | 2009-11-05 | 2009-11-05 | |
| US61/258,348 | 2009-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011054179A1 true WO2011054179A1 (en) | 2011-05-12 |
Family
ID=43969565
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2010/001749 Ceased WO2011054179A1 (en) | 2009-11-05 | 2010-11-02 | Crystalline form of cladribine and process for preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| TW (1) | TW201117816A (en) |
| WO (1) | WO2011054179A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020052491A1 (en) * | 1999-04-28 | 2002-05-02 | Szepsel Gerszberg | Method for the production of 2-chloro-2' -deoxyadenosine (cladribine) and its 3,5-di-O-p-toluoyl derivative |
-
2010
- 2010-11-02 WO PCT/CN2010/001749 patent/WO2011054179A1/en not_active Ceased
- 2010-11-05 TW TW099138204A patent/TW201117816A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020052491A1 (en) * | 1999-04-28 | 2002-05-02 | Szepsel Gerszberg | Method for the production of 2-chloro-2' -deoxyadenosine (cladribine) and its 3,5-di-O-p-toluoyl derivative |
Non-Patent Citations (2)
| Title |
|---|
| KOELLNER, GERTRAUD ET AL.: "Molecular structure of 2-chloro-2'-deoxyadenosine an agent used in therapy for multiple sclerosis and its unusual crystal packing mode", JOURNAL OF MOLECULAR STRUCTURE, vol. 444, 1998, pages 21 - 27 * |
| WORTHINGTON, VICTORIA L. ET AL.: "The N-7 regioisomer of 2-chloro-2'-deoxyadenosine: synthesis, crystal structure, conformation, and stability", CARBOHYDRATE RESEARCH, vol. 275, 1995, pages 275 - 284 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201117816A (en) | 2011-06-01 |
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