CN105646498A

CN105646498A - Crystal form F of ibrutinib and preparation method

Info

Publication number: CN105646498A
Application number: CN201610114027.2A
Authority: CN
Inventors: 孙霖
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-03-01
Filing date: 2016-03-01
Publication date: 2016-06-08

Abstract

The invention discloses a crystal form F of ibrutinib. The crystal form F is characterized in that X-ray powder diffraction (X-RPD) which adopts Cu-Kalpha radiation and is represented with a 2theta angle has diffraction peaks in positions at angles of 3.7 degrees plus or minus 0.2 degrees, 6.7 degrees plus or minus 0.2 degrees, 13.2 degrees plus or minus 0.2 degrees, 16.1 degrees plus or minus 0.2 degrees, 19.1 degrees plus or minus 0.2 degrees, 20.0 degrees plus or minus 0.2 degrees, 23.8 degrees plus or minus 0.2 degrees and 24.6 degrees plus or minus 0.2 degrees. Related solvents in a preparation process of the crystal form F are cheap, the conditions are mild, the operation is simple, good controllability and reproducibility are realized, further, the prepared crystal form has great stability, the HPLC (high performance liquid chromatography) purity is higher than 99%, and the phenomenon of crystal transformation can be avoided; besides, the solubility is high, the dissolubility is good, and the bioavailability is high.

Description

According to Shandong for Buddhist nun crystal formation F and preparation method

Technical field

The present invention relates to medicinal chemistry art, in particular it relates to according to Shandong for the crystal formation of Buddhist nun, and the preparation method of crystal formation and purposes.

Background technology

It is the pioneering new drug of a kind of oral bruton's tyrosine kinase (BTK) inhibitor for Buddhist nun (Ibrutinib) according to Shandong, by Pharmacyclics company of the U.S. and Johson & Johnson's joint research and development, commodity are called Imbruvica, its chemical name is: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, structural formula is as follows:

According to Shandong for Buddhist nun by with target protein Btk activity site cysteine residue (Cys-481) optionally covalent bond, irreversibility ground suppress BTK, thus effectively stop tumor move to the lymphoid tissue being adapted to tumor growth environment from B cell. In November, 2013, FDA (Food and Drug Adminstration) (FDA) ratifies its listing, for treating a kind of rare aggressive leukemia lymphoma mantle cell (MCL), in July, 2014, FDA ratified its treatment for chronic lymphocytic leukemia (CLL).

The patent WO2013/184572 of Pharmacyclics company of U.S. application in 2013 discloses the six kinds of crystal formations replacing Buddhist nun according to Shandong, wherein crystal formation D is methyl isobutyl ketone solvent compound, crystal formation E is toluene solvate, and crystal formation D is Methanol Solvate, is all not suitable for pharmaceutical formulation. In its excess-three kind crystal formation, reporting crystal form B hygroscopicity according to WO2013/184572 relatively larger, crystal form A is not easy moisture absorption by contrast, it does not have the stability of report crystal C and solubility data. Therefore, in six kinds of crystal formations, only crystal form A is suitable for pharmaceutical formulation, and the crystal form A of its report has three kinds of preparation methoies: method one is will to be suspended in the organic solvent of 10 times of volumes for Buddhist nun's amorphous article according to Shandong, heat in an oscillator to 50 DEG C, vibrate 1 hour, add the organic solvent of 30 times of volumes, be again heated to 50 DEG C and vibrate 1 hour, then it is cooled to 0 DEG C with the speed of 0.1 DEG C/min, filtering, the solid obtained is crystal form A, and filtrate also obtains crystal form A by pin hole slow evaporation. This kind of method complex operation, and because consumption of organic solvent is 40 times, so the product yield that is filtrated to get of first time is low, although and from filtrate, also can obtain product, but consuming time oversize; Method two is will to be suspended in the organic solvent of 1-10 times of volume for Buddhist nun's amorphous article according to Shandong, and then sealed reaction bottle seals 5 days in curing chamber, is filtrated to get crystal form A.This kind of method is same consuming time long and it needs to special installation; Method three is will to replace Buddhist nun's heating for dissolving in the methanol of 10 times of volumes according to Shandong, add water, then heat up under insulation, is subsequently cooled to room temperature and continues stirring 16 hours, obtaining crystal form A, and yield is 80%. The complex operation of this kind of method, has intensification repeatedly and cooling in operation, the bad control of production process.

Suzhou crystalline substance cloud CN104327085A discloses another crystal form A (hereinafter referred to crystal form A '), the preparation method of its report has three kinds: method one, to replace Buddhist nun's dissolving crude product in the mixed solution of isopropanol and normal heptane according to Shandong, at room temperature stirring with the speed of 750 turns per minute and obtain crystal form A ', such high-revolving stirring industrializing implementation is highly difficult; Method two, will according to Shandong for Buddhist nun's dissolving crude product in the mixed solvent of isopropanol and normal heptane, and drop to 5 DEG C with the cooling rate of 0.1 DEG C/min from 50 DEG C and obtain crystal form A, so accurate cooling rate is difficult to control; Method three, according to Shandong for Buddhist nun's dissolving crude product in acetone, will be slow added into normal heptane, and stirring obtains crystal form A in 1 day under the rotating speed of 1000 turns per minute, and the rotating speed that this method ratio method one requires is higher, and industrialization is more difficult to realize. And have been reported discovery when repeating these methods, and poor reproducibility, somewhat control bad to obtain crystal form A disclosed in WO2013/184572. Additionally, existing dosage form water solublity is little, oral organism-absorbing availability is relatively low.

Therefore, this area needs the crystal formation that research and development are new badly, it is desirable to preparation method is simple, and Heat stability is good, hygroscopicity is low, is produced on a large scale.

Summary of the invention

For above-mentioned prior art Problems existing, the present invention provides a kind of novel crystal forms F according to Shandong for Buddhist nun, and preparation method is simply controlled, is produced on a large scale, Heat stability is good, and dissolubility is high and dissolution is good, and bioavailability is high.

Crystal formation F according to Shandong for Buddhist nun of the present invention, it is characterized in that, use Cu-K �� radiation, the X-ray powder diffraction (X-RPD) represented with 2 �� angles at 3.7 �� 0.2 ��, 6.7 �� 0.2 ��, 13.2 �� 0.2 ��, 16.1 �� 0.2 ��, 19.1 �� 0.2 ��, 20.0 �� 0.2 ��, 23.8 �� 0.2 ��, there is diffraction maximum at 24.6 �� 0.2 �� of places.

Further, described crystal formation F, use Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles at 3.7 �� 0.2 ��, 6.7 �� 0.2 ��, 11.6 �� 0.2 ��, 13.2 �� 0.2 ��, 16.1 �� 0.2 ��, 19.1 �� 0.2 ��, 20.0 �� 0.2 ��, 23.8 �� 0.2 ��, 24.6 �� 0.2 ��, 26.2 �� 0.2 ��, 27.8 �� 0.2 ��, 28.1 �� 0.2 ��, there is diffraction maximum at 31.8 �� 0.2 �� of places.

The preparation method of described crystal formation: replacing Buddhist nun's amorphous article to add in the mixed solution of isopropanol and methanol according to Shandong, stir 10 hours, add water, continue stirring 2 hours, filter, vacuum drying obtains crystal F.

The described ratio replacing Buddhist nun and mixed solution according to Shandong is 1g:10ml. The volume ratio of described isopropanol and methanol is 2:1. The addition volume of described water is with the volume of mixed solution. Described vacuum drying temperature is 40 degree.

The present invention also provides for a kind of pharmaceutical composition, including described crystal formation F and pharmaceutically acceptable excipient.

The present invention also provides for a kind of pharmaceutical composition, including the combination of described crystal formation F and the second pharmacological active substance.

Solvent involved by crystal formation preparation process of the present invention is cheap, and mild condition is simple to operate, has good controllability and reproducibility, and the crystal formation prepared has fabulous stability, HPLC high purity more than 99%, does not have and turns brilliant phenomenon.Additionally, dissolubility is high and dissolution is good, bioavailability is high.

Accompanying drawing explanation

Fig. 1 is the X-RPD collection of illustrative plates of crystal formation F of the present invention.

Detailed description of the invention

Below in conjunction with specific embodiment, the present invention is expanded on further. Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention. The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition. Experiment material used in following example and reagent all can obtain from commercially available channel if no special instructions.

Embodiment 1

Buddhist nun amorphous article 10g is replaced to add in the mixed solution (volume ratio of isopropanol and methanol is 2:1) of 100ml isopropanol and methanol according to Shandong, heating makes dissolving to backflow, stir 10 hours after dissolving, add water 100ml, stirs 2 hours, filters, 40 DEG C of vacuum dryings obtain crystal F, using Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles is as it is shown in figure 1, HPLC purity is for 99.90%.

Mensuration about the crystal formation of embodiment 1 preparation:

1. stability test

Example 1 prepare when being placed on 35 DEG C according to Shandong for Buddhist nun's crystal formation F sample, investigate and placing the stability of 1 month, 3 months, 6 months, result of the test is in Table 1. (method of concrete study on the stability is referred to the method for 2010 editions second annex XIXC of Chinese Pharmacopoeia; Purity detecting HPLC method, it is possible to reference to the method for 2010 editions second annex VD of Chinese Pharmacopoeia)

Table 1 replaces the stability test result of Buddhist nun crystal formation F according to Shandong

	Purity %	Crystal formation
			1 month	99.90	Same Fig. 1
3 months	99.89	Same Fig. 1
			6 months	99.88	Same Fig. 1

2. solubility test

Measure the medium (phosphate buffer of water, 0.01mol/LHCl solution and pH6.8) of 10ml respectively in cillin bottle, add excessive Shandong for Buddhist nun crystal formation F, cillin bottle is sealed and puts 37 DEG C of constant temperature water baths stirrings 1 hour, through 0.45 ��m of membrane filtration, taking subsequent filtrate and measure absorbance respectively at the wavelength place of 284nm, result is in Table 2.

(�� g/ml) is compared for Buddhist nun crystal formation F dissolubility in different medium in table 2 Shandong

	Water	0.01mol/L HCl solution	The phosphate buffer of pH6.8
				Buddhist nun crystal formation F is replaced in Shandong	11.63	9.97	7.75

3. dissolution determination

For Buddhist nun crystal formation F, Shandong being crossed 80 mesh sieves, weighs powder 10mg after sieving, according to two annex XC the second method (paddle method) devices of " Chinese Pharmacopoeia " version in 2010, dissolution medium is 500ml water respectively, rotating speed 100rpm, temperature 37 DEG C. Respectively at 10,15,30,45,60,90min sample 3ml, and fluid infusion 3ml in time, 0.22 ��m of filter membrane crossed by sample, and sample introduction, in HPLC, calculates dissolution. Result is in Table 3.

Buddhist nun crystal formation F dissolution percentage amounts/% in water is replaced in table 3 Shandong

Time (min)	Buddhist nun crystal formation F is replaced in Shandong
		10	16.98
15	24.92
		30	38.31
45	42.16
		60	46.38
90	47.11

Claims

1. the crystal formation F of Buddhist nun is replaced according to Shandong, it is characterized in that, use Cu-K �� radiation, the X-ray powder diffraction (X-RPD) represented with 2 �� angles at 3.7 �� 0.2 ��, 6.7 �� 0.2 ��, 13.2 �� 0.2 ��, 16.1 �� 0.2 ��, 19.1 �� 0.2 ��, 20.0 �� 0.2 ��, 23.8 �� 0.2 ��, there is diffraction maximum at 24.6 �� 0.2 �� of places.

2. the crystal formation F according to Shandong for Buddhist nun according to claim 1, it is characterised in that use Cu-K �� radiation, the X-ray powder diffraction represented with 2 �� angles at 3.7 �� 0.2 ��, 6.7 �� 0.2 ��, 11.6 �� 0.2 ��, 13.2 �� 0.2 ��, 16.1 �� 0.2 ��, 19.1 �� 0.2 ��, 20.0 �� 0.2 ��, 23.8 �� 0.2 ��, 24.6 �� 0.2 ��, 26.2 �� 0.2 ��, 27.8 �� 0.2 ��, 28.1 �� 0.2 ��, there is diffraction maximum at 31.8 �� 0.2 �� of places.

3. the preparation method replacing the crystal formation F of Buddhist nun according to Shandong, it is characterised in that replace Buddhist nun's amorphous article to add in the mixed solution of isopropanol and methanol according to Shandong, stir 10 hours, add water, continues stirring 2 hours, and filtration, vacuum drying obtains crystal F.

4. method according to claim 3, it is characterised in that the described ratio replacing Buddhist nun and mixed solution according to Shandong is 1g:10ml.

5. method according to claim 3, it is characterised in that the volume ratio of described isopropanol and methanol is 2:1.

6. method according to claim 3, it is characterised in that the addition volume of described water is with the volume of mixed solution.

7. method according to claim 3, it is characterised in that described vacuum drying temperature is 40 degree.

8. a pharmaceutical composition, including crystal formation F described in claim 1 and pharmaceutically acceptable excipient.

9. a pharmaceutical composition, including the combination of crystal formation F and the second pharmacological active substance described in claim 1.