WO2015051738A1

WO2015051738A1 - Tofacitinib citrate

Info

Publication number: WO2015051738A1
Application number: PCT/CN2014/088145
Authority: WO
Inventors: Xin LEI; Jin'an PENG; Zhen Guo
Original assignee: Sunshine Lake Pharma Co., Ltd.
Priority date: 2013-10-08
Filing date: 2014-10-08
Publication date: 2015-04-16
Also published as: CN105873931B; CN105873931A

Abstract

Crystalline particle of tofacitinib citrate, process for the preparation of a crystalline particle of tofacitinib citrate, pharmaceutical composition, substantially pure amorphous form of tofacitinib citrate, process for preparing the substantially pure amorphous form of tofacitinib citrate, and use of the crystalline particle of tofacitinib citrate, and the pharmaceutical composition are provided.

Description

TOFACITINIB CITRATE

This application claims priority to and benefits of Chinese Patent Application Serial No. 201310464169. 8, filed with the State Intellectual Property Office of P. R. China on October 08, 2013, the entire content of which is incorporated herein by reference.

FIELD

The present disclosure relates to medical filed, particularly to tofacitinib citrate, more particularly to crystalline particle of tofacitinib citrate, process for the preparation of a crystalline particle of tofacitinib citrate, pharmaceutical composition, and use of the crystalline particle of tofacitinib citrate.

BACKGROUND

Tofacitinib citrate, also known as

3- [ (3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino] piperidin-1-yl] -3-oxoprop anenitrile with a formula (I) as follow:

PCT publication WO2003048162 discloses a novel crystalline form of Tofacitinib citrate and preparation method thereof, the crystalline particles prepared by the method of WO2003048162 has a large particle size, and the color of the crystalline particle will become darker after placed for a period of time, therefore the crystalline particle of Tofacitinib citrate disclosed in WO2003048162 may be unstable, thus dose not conform to the requirement of active pharmaceutical ingredient.

It is well recognized that preparation of a solid dosage form with a reproducible composition requires that all the dry ingredients have a good flow property. In cases, where the active ingredient has a good flow property, the solid dosage form such as tablets can be prepared by direct compression. Usually small particle size of the active substance is cohesive or has a poor flow property, therefore, the skilled person in the art regard the small particle size of the active substance as not suitable for direct compression.

Then, there is always a need in the art for tofacitinib citrate with a desirable particle size distribution having a good flow property, and better dissolution and solubility property.

SUMMARY

Embodiments of the present disclosure seek to solve at least one of the problems existing in the prior art to at least some extent, or to provide a consumer with a useful commercial choice.

The disclosure then, inter alia, comprises the following alone or in combination:

According to embodiments of a first broad aspect of the present disclosure, there is provided a crystalline particle of tofacitinib citrate having a median particle size of less than about 40 μm.

Inventors of present disclosures surprisingly find that the crystalline particle of tofacitinib citrate disclosed herein has good flow properties, compressibility and formability, then crystalline particle of tofacitinib citrate disclosed herein, as an active ingredient, is suitable for direct compression in the formulation process, thus the granulation step can be avoided. The pharmaceutical composition comprising tofacitinib citrate having a median particle size of less than 40 μm provided herein may have a good dissolution rate in vitro, in different dissolution medium, the mean dissolution rate may be above 75％within 5 min and above 90％within 30 min. Therefore, the pharmaceutical composition provided in the present invention may have a better dissolution and solubility property.

In some embodiments, the crystalline particle disclosed herein has a median particle size in the range of about 3 μm to about 30 μm.

In some embodiments, the crystalline particle disclosed herein has the median particle size in the range of about 3 μm to about 15 μm.

In some embodiments, the crystalline particle disclosed herein has the median particle size in the range of about 3 μm to about 10 μm.

In some embodiments, the crystalline particle disclosed herein has the median particle size in the range of about 5 μm to about 10 μm.

In some embodiments, the crystalline particle of tofacitinib citrate shows at least one characteristic peak expressed in degrees two-theta at about 5.7, about 17.3, about 18.7, about 20.2 and about 20.5 in an x-ray powder diffraction pattern.

In some embodiments, the crystalline particle of tofacitinib citrate shows an X-ray powder diffraction pattern substantially as depicted in Fig. 1.

In another aspect, provided herein is a crystalline particle of tofacitinib citrate having a particle size of less than about 40 μm.

Inventors of present disclosure surprisingly find that the crystalline particle of tofacitinib citrate disclosed herein has good flow properties, compressibility and formability, then crystalline particle of tofacitinib citrate disclosed herein, as an active ingredient, is suitable for direct compression in the formulation process, thus the granulation step can be avoided. The pharmaceutical composition comprising tofacitinib citrate having a median particle size of less than 40 μm provided herein may have a good dissolution rate in vitro, in different dissolution medium, the mean of dissolution rate may be above 75％within 5 min and above 90％within 30 min. Therefore, the pharmaceutical composition provided in the present invention may have a better dissolution and solubility property.

In some embodiments, the crystalline particle disclosed herein has a particle size in the range of about 3 μm to about 30 μm.

In some embodiments, the crystalline particle disclosed herein has the particle size in the range of about 3 μm to about 15 μm.

In some embodiments, the crystalline particle disclosed herein has the particle size in the range of about 3 μm to about 10 μm.

In some embodiments, the crystalline particle disclosed herein has the particle size in the range of about 5 μm to about 10 μm.

In another aspect, provided herein is a process for the preparation of a crystalline particle of tofacitinib citrate, comprising: providing a solution comprising a tofacitinib citrate and a solvent at a first temperature, reducing a temperature of the solution from the first temperature to a second temperature to form the crystalline particle of tofacitinib citrate.

The inventors of present disclosure find that using the process for the preparation of a crystalline particle of tofacitinib citrate described above, a crystalline particle of tofacitinib citrate having a particle size or a median particle size less than about 40μm will be obtained. And inventors of present disclosures surprisingly find that the crystalline particle of tofacitinib citrate disclosed herein has good flow properties, compressibility and formability, then crystalline particle of tofacitinib citrate disclosed herein, as an active ingredient, is suitable for direct compression in the formulation process, thus the granulation step can be avoided. The pharmaceutical composition comprising tofacitinib citrate having a median particle size of less than 40 μm provided herein may have a good dissolution rate in vitro, in different dissolution medium, the mean dissolution rate may be above 75％within 5 min and above 90％within 30 min. Therefore, the pharmaceutical composition provided in the present invention may have a better dissolution and solubility property.

In some embodiments, the process disclosed herein further comprises a step of isolating the crystalline particle of tofacitinib citrate.

In some embodiments, the solvent is at least one selected from a group consisting of water, alcohol, ketone, DMSO, DMF, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran and toluene.

In some embodiments, the alcohol is at least one selected from a group consisting of methanol, ethanol, isopropanol, n-butyl alcohol, isobutyl alcohol and n-amyl alcohol.

In some embodiments, the ketone is at least one selected from a group consisting of acetone, butanone and 4-methyl-2-pentanone.

In some embodiments, the solvent is at least one selected from a group consisting of water, methanol, ethanol, isopropyl alcohol and acetone.

In some embodiments, 1.0 gram of tofacitinib citrate dissolves in the solvent with a volume 10 mL to 26 mL.

In some embodiments, preferably the volume of the solvent is 16 mL.

In some embodiments, the solvent comprises alcohol and water, and a volume ratio of alcohol to water is 10∶1 to 10∶10.

In some embodiments, preferably the volume ratio of alcohol to water is 10∶6.

In some embodiments, the first temperature is in the range from about room temperature to a refluxing temperature of the solvent.

In some embodiments, the first temperature is about 5℃ to about 30℃ lower than the refluxing temperature of the solvent.

In some embodiments, the first temperature is about 5℃ lower than the refluxing temperature of the solvent.

In some embodiments, the first temperature is about 10℃ lower than the refluxing temperature of the solvent.

In some embodiments, the first temperature is about 15℃ lower than the refluxing temperature of the solvent.

In some embodiments, the first temperature is about 20℃ lower than the refluxing temperature of the solvent.

In some embodiments, the first temperature is about 25℃ lower than the refluxing temperature of the solvent.

In some embodiments, the first temperature is about 30℃ lower than the refluxing temperature of the solvent.

In some embodiments, the first temperature is the refluxing temperature of the solvent.

In some embodiments, the second temperature is about 20℃ to 100℃ lower than the first temperature.

In some embodiments, the second temperature is about 20℃ lower than the first temperature.

In some embodiments, the second temperature is about 30℃ lower than the first temperature.

In some embodiments, the second temperature is about 40℃ lower than the first temperature.

In some embodiments, the second temperature is about 50℃ lower than the first temperature.

In some embodiments, the second temperature is about 60℃ lower than the first temperature.

In some embodiments, the second temperature is about 70℃ lower than the first temperature.

In some embodiments, the second temperature is about 80℃ lower than the first temperature.

In some embodiments, the second temperature is about 90℃ lower than the first temperature.

In some embodiments, the first temperature is in the range from about 50℃ to a refluxing temperature of the solvent, and the second temperature is in the range from about -5℃ to 50℃.

In some embodiments, the first temperature is the refluxing temperature of the solvent, and the second temperature is in the range from about 0℃ to about 40℃.

In some embodiments, the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by the following steps: (1) reducing the temperature of the solution by about 5 to about 20℃, (2) standing the solution of step (1) for about 1 hour to about 300 hours, (3) repeating the steps (1) and (2) until the temperature of the solution reaches the second temperature.

In some embodiments, stand the solution of step (1) for about 1 hour to about 50 hours in the step (2) .

In some embodiments, stand the solution of step (1) for about 1 hour to about 5 hours in the step (2) .

In some embodiments, the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by reducing the temperature of the solution at a rate of about 1 to about 20℃/hour.

In some embodiments, the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by reducing the temperature of the solution at a rate of about 5 to about 10℃/hour.

In some embodiments, the process disclosed herein further comprises standing the solution of tofacitinib citrate at the second temperature for at least 30 minutes.

In some embodiments, the process disclosed herein further comprises standing the solution of tofacitinib citrate at the second temperature for about 1 to about 24 hours.

In some embodiments, the crystalline particle is formed under a condition of stirring at about 100 rpm to about 500 rpm.

In some embodiments, the crystalline particle is formed under a condition of stirring at 200 rpm to 400 rpm.

In some embodiments, the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by the step:

(i) maintaining the solution at the first temperature for a first predetermined time；

(ii) reducing the temperature of the solution from the first temperature to a third temperature lower than the second temperature, and maintaining the solution at the third temperature for a second predetermined time； and

(iii) reducing the temperature of the solution from the third temperature to the second temperature, and maintaining the solution at the third temperature for a third predetermined time.

Then, the inventors of present disclosure surprisingly find that the property of the obtained crystal will be significantly improved.

In some embodiments, the first temperature is in a range of 50℃ to the refluxing temperature of the solvent, the third temperature is in a range of 50℃ to 15℃, the second temperature is a temperature in a range of -5℃ to 20℃. Then, the inventors of present disclosure surprisingly find that the property of the obtained crystal will be significantly improved.

In some embodiments, the first temperature is the refluxing temperature of the solvent, the third temperature is in a range of 40℃ to 30℃, the second temperature is in a range of 0℃ to 10℃. Then, the inventors of present disclosure surprisingly find that the property of the obtained crystal will be significantly improved.

In some embodiments, each of the first and second predetermined times is at least 30 min. Then, the inventors of present disclosure surprisingly find that the property of the obtained crystal will be significantly improved.

In some embodiments, each of the first and second predetermined times is in a range of 1 to 24 hours, and the third predetermined time is at least 1 hour. Then, the inventors of present disclosure surprisingly find that the property of the obtained crystal will be significantly improved.

In another aspect, provided herein is a pharmaceutical composition, comprising tofacitinib citrate having a median particle size of less than 40 μm. The pharmaceutical composition comprising tofacitinib citrate having a median particle size of less than 40 μm provided herein may have a good dissolution rate in vitro, in different dissolution medium, the mean dissolution rate may be above 75％within 5 min and above 90％within 30 min. Therefore, the pharmaceutical composition provided in the present invention may have a better dissolution and solubility property.

In some embodiments, the pharmaceutical composition is in a form such as tablets, capsules, pills , powder or granule, etc.

In some embodiments, the pharmaceutical composition is in a form a tablet.

In some embodiments, the tablet of the pharmaceutical composition is prepared by direct compression.

In some embodiments, the pharmaceutical composition further comprises an excipient being at least one selected from a group consisting of a filler, disintegrate, a small amount of lubricant, colorant and sweeteners, etc.

In some embodiments, the filler is at least one selected from a group consisting of microcrystalline cellulose, sorbitol, mannitol, lactose, starch, modified starch, sucrose, glucose, calcium phosphate, silicate, calcium sulfate and calcium carbonate.

In some embodiments, the filler is at least one selected from a group consisting of lactose monohydrate FLOWLAC100 and microcrystalline cellulose.

In some embodiments, the content of the filler is 30 to 92wt％based on the total weight of the pharmaceutical composition.

In some embodiments, the disintegrate is at least one selected from a group consisting of croscarmellose sodium, calcium carbonate, potato starch, tapioca starch, alginate, silicate, sodium carbonate, dry starch, carboxymethyl starch sodium, L-HPC and crospolyvinylpyrrolidone.

In some embodiments, the disintegrate is croscarmellose sodium.

In some embodiments, the content of the disintegrant is 2.0 to 10.0wt％. based on the total weight of the pharmaceutical composition.

In some embodiments, the content of the disintegrant is 3wt％.

In some embodiments, the lubricant is at least one selected from a group consisting of stearic acid metal salt, stearic acid, wax, hydrogenated vegetable oil, talcum powder or colloidal silica.

In some embodiments, the stearic acid metal salt is at least one selected from a group consisting of magnesium stearate, calcium stearate and stearic acid.

In some embodiments, the stearic acid metal salt is lubricant magnesium stearate.

In some embodiments, the content of the magnesium stearate is 0.25wt％to 2.5wt％.

In some embodiments, the content of the magnesium stearate is 1.5wt％.

In some embodiments, the excipient being at least one selected from a group consisting of microcrystalline cellulose, croscarmellose sodium, lactose monohydrate and magnesium stearate.

In another aspect, provided herein is a pharmaceutical composition, comprising tofacitinib citrate having a particle size of less than 40 μm. The pharmaceutical composition comprising tofacitinib citrate having a particle size of less than 40 μm provided herein may have a good dissolution rate in vitro, in different dissolution medium, the mean dissolution rate may be above 75％within 5 min and above 90％within 30 min. Therefore, the pharmaceutical composition provided in the present invention may have a better dissolution and solubility property.

In some embodiments, the pharmaceutical composition is in a form such as tablet, capsule, pill, powder or granule, etc.

In some embodiments, the pharmaceutical composition is in a form a tablet.

In some embodiments, the disintegrate is croscarmellose sodium.

In some embodiments, the content of the disintegrant is 3wt％.

In some embodiments, lubricant magnesium stearate.

In some embodiments, the content of the magnesium stearate is 1.5wt％.

In another aspect, provided herein is use of the crystalline particle of tofacitinib citrate above-mentation, or the pharmaceutical composition above-mentation in the preparation of a medicament preventing or treating a disorder or disease.

In some embodiments, the disorder or disease comprises at least one selected form a group consisting of organ transplant rejection, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and a complication induced by at least one selected from a group consisting of diabetes, cancer, asthma, atopic dermatitis, autoimmue thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer disease and leukemia.

In another aspect, provided herein is a method of preventing or treating a disorder or disease comprising administering the crystalline particle of tofacitinib citrate above-mentation, or the pharmaceutical composition above-mentation to a subject.

Any embodiment disclosed herein can be combined with other embodiments as long as they are not contradictory to one another, even though the embodiments are described under different aspects of the invention. In addition, any technical feature in one embodiment can be applied to the corresponding technical feature in other embodiment as long as they are not contradictory to one another, even though the embodiments are described under different aspects of the invention.

The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limiting in nature. These aspects and other aspects and embodiments are described more fully below.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects and advantages of embodiments of the present disclosure will become apparent and more readily appreciated from the following descriptions made with reference to the accompanying drawings, in which:

Fig. 1 depicts the X-ray powder diffraction diagram of the crystalline particles of tofacitinib citrate have a median particle size (D50) of less than 40 μm according to one embodiment of present disclosure.

Fig. 2 depicts the differential scanning calorimetry (DSC) profile of the crystalline particles of tofacitinib citrate have a median particle size (D50) of less than 40 μm according to one embodiment of present disclosure.

DETAILED DESCRIPTION

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified methods and may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting which will be limited only by the appended claims.

All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. However, publications mentioned herein are cited for the purpose of describing and disclosing the protocols, and reagents which are reported in the publications and which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

Definition

Otherwise stated, the following definitions may be use throughout the disclosure.

As used herein, the term “crystalline form” of a compound refers to a unique ordered arrangement and/or conformations of molecules in the crystal lattice of the compound.

The term “median particle size” , which is also designated as the D50 value of the integral volume distribution, is defined in the context of the invention as the particle size at which 50 volume ％of the particles have a particle size that is smaller than the D50 value and, consequently, 50 volume ％of the particles have a particle size that is larger than the D50 value, as determined by laser diffraction at 3.0 bar dispersive pressure in Malvern Mastersizer 2000.

The term "μm" refers to "micrometer" which is l x 10^-6 meter.

The term "crystalline particles" means any combination of single crystals, aggregates and agglomerates.

As used herein, the term “room temperature” refers to a temperature from about 18℃ to about 35℃ or a temperature from about 20℃ to about 24℃ or a temperature at about 22℃.

As used herein, the term “over night” refers to a period of from about 13 hours to about 24 hours, or from about 16 hours to about 24 hours.

As used herein, “refluxing temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

As used herein, “direct compression” means that the solid unit dosage form is prepared by compression of a simple mixture of the active ingredient and excipients, without the active ingredient having been subjected to an intermediate granulation process in order to embed it in a larger particle and improve its fluidity properties.

In the following description, all numbers disclosed herein are approximate values, regardless whether the word “about” is used in connection therewith. The value of each number may differ by 1％, 2％, 5％, 7％, 8％, 10％, 15％or 20％. Therefore, whenever a number having a value N is disclosed, any number having the value N+/-1％, N+/-2％, N+/-3％, N+/-5％, N+/-7％, N+/-8％, N+/-10％, N+/-15％or 20 N+/-20％is specifically disclosed, wherein “+/-” refers to plus or minus. Whenever a numerical range with a lower limit, RL, and an upper limit, RU, is disclosed, any number falling within the range is specifically disclosed. In particular, the following numbers within the range are specifically disclosed: R＝RL+k* (RU-RL) , wherein k is a variable ranging from 1wt％to 100％with a 1％increment, i. e. , k is 1％, 2％, 3％, 4％, 5％, . . . , 50％, 51％, 52％, ..., 95％, 96％, 97％, 98％, 99％, or 100％. Moreover, any numerical range defined by two R numbers as defined above is also specifically disclosed.

EXAMPLES

The embodiments of the present disclosure firstly disclose tofacitinib citrate having a median particle size of less than 40 μm. Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way is obvious to the skilled in this art and is deemed to included in the present invention. Numeric ranges are inclusive of the numbers defining the range. Furthermore, numeric ranges are provided so that the range of values is recited in addition to the individual values within the recited range being specifically recited in the absence of the range.

N- ( (3R4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2, 3-d] pyrimidin-4-amine was prepared by the process disclosed in WO2007012953.

Example A

Preparation of tofacitinib citrate

To a round-bottomed flask fitted with an hydrogen source, was added 10％hydroxide palladium supported on carbon (0.56 g) , methanol (20 ml) , acetic acid (0.5 g) and N- ( (3R, 4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2, 3-d] pyrimidin-4-amine (2.8 g) , firstly nitrogen was bubbled into the flask, and then hydrogen (1atm) was bubbled into the flask. The resulting mixture was heated to 50℃ for about 6 h, after the reaction was completed, the reaction product was filtered to remove the solid content, and then was concentrated. Then the resulting mass was added with ethanol (20 ml) , 1, 8-Diazabicyclo [5.4.0] undec-7-ene (3.8 g) and ethyl cyanoacetate (3.7 g) , then stirred the resulting mixture at room temperature for about 6 hours. Then citric acid (3.5 g) , water (18 ml) was added directly without working-up, stirred at room temperature, precipitated out, the solid was filtered to obtain tofacitinib citrate. The median particle size D50 of the resulting tofacitinib citrate is 56.973 μm, D10 is 17.348 μm, D90 is 225.26 μm as determined by laser diffraction at 3.0 bar dispersive pressure in Malvern Mastersizer 2000 with a sampling rate 50％.

Example 1

preparation of crystalline form A of tofacitinib citrate

Tofacitinib citrate (10 g, as prepared by Example A) , ethanol (100 ml) and water (60 ml) were added to a round flask to form a mixture, the mixture was heated to reflux and stirred with a stirring rate 300 rpm to form a solution, the solution was stirred at the reflux temperature for 1 hour, then the solution was cooled to 40℃, after keeping at 40℃ for 1 hour, the mixture was cooled to 10℃, maintaining at 10℃ for 2 hours, filtered and dried in vacuum at 45℃ for 10 hours to obtain the Tofacitinib citrate crystals 9.52 g. And an X-ray powder diffraction of the resulting Tofacitinib citrate crystals depicted as Fig. 1 was obtained.

The resulting Tofacitinib citrate crystals have the following particle size distribution:

the median particle size D50 is 5.816 μm, 10％volume-％of the particles D10 is 1.837 μm, and 90％volume-％of the particles D90 is 16.782 μm as determined by laser diffraction at 3.0 bar dispersive pressure in Malvern Mastersizer 2000 with a sampling rate 50％.

Example 2

preparation of crystalline form A of tofacitinib citrate

Tofacitinib citrate (1.0 g, as prepared by Example A) was dissolved in 55 ml methanol at 65℃ with stirring to form a solution. The temperature of the solution was reduced to 40℃ and kept at 40℃ for 2 hours, the temperature was reduced to 15℃ and kept for 1 hour. The obtained crystal was filtered out, dried in vacuum at 55℃ for 12 hours, XRPD of the obtained crystal (Fig. 2) shows the dry product is form A, yield is 91.1％, purity (HPLC) is 99.5％.

the median particle size D50 is 11.2 μm detected by laser diffraction at 3.0 bar dispersive pressure in Malvern Mastersizer 2000 with a sampling rate 50％.

Example 3

Preparation of crystalline form A of tofacitinib citrate

Tofacitinib citrate (1.0 g, as prepared by Example A) was dissolved in a mixture of isopropyl alcohol and water (20 ml , 1∶1, v/v) at 83℃ with a stirring rate 300 rpm. The temperature was reduced to 45℃ and kept for 0.5 hour, then the temperature was reduced to 10℃ and maintained for 10℃ 1 hour. The obtained crystal was precipitate out, filtered, and then the solid was dried in vacuum at 55 ℃ for 12 hours, yield 88.9％, HPLC purity (area) is 99.1％, mean particle size D50 is 9.2 μm as determined by laser diffraction at 3.0 bar dispersive pressure in Malvern Mastersizer 2000 with a sampling rate 50％.

Example 4

Preparation of crystalline form A of tofacitinib citrate

Dissolving tofacitinib citrate (1.0 g, as prepared by Example A) in a mixture of acetone (10 ml) and water (10 ml) to form a solution at 65℃. The solution was stirred slowly and the temperature was reduced to 30℃, and was kept at 15℃ for 1 hour, the temperature was reduced to 0℃ and maintained at 0℃ for 2 hours, the obtained solid was filtered out and dried in vacuum at 55℃ for 12 hours, XRPD of the obtained solid (Fig. 1) shows the dry product is form A, yield is 93.2％, High performance liquid chromatography (HPLC) purity is 99.3％.

Example 5

Preparing Tablet

Tablet was prepared by direct compression of tofacitinib citrate crystalline particle prepared by Example 1 to Example 4 using the composition as follows.

Tablet ingredient	Wt. ％
Tablet ingredient	Wt. ％	tofacitinib citrate	5.00
microcrystalline cellulose	55.00	tofacitinib citrate	5.00
microcrystalline cellulose	55.00	lactose monohydrate	35.00
croscarmellose sodium	3.00	lactose monohydrate	35.00
croscarmellose sodium	3.00	magnesium stearate	2.00
Total percent	100.0	magnesium stearate	2.00

Crystalline particles of tofacitinib citrate, microcrystalline cellulose (PH102) and lactose monohydrate (Flowlac 100) were sieved through 810 μm screen and blended at 10 rpm for 30 min in a 200 liter HZD 600T mixer. Croscarmellose Sodium (XL) was added and blending continued for 5 min. Magnesium stearate was sieved through 30mesh (600 μm) screen and added and blending continued for 5 min. 50 kg of the final mixture was tabletted (121, 800 tablets/hour) on a Korsch XL 400 tablet press fitted with round Φ8 mm punches. Tablet core weight was set to 200 mg.The nominal yield was 250,000 tablets. The tablet press was run until the mixture level was just above the forced feeder, i. e. the tabletting was continued as long as possible in order to identify possible segregation tendencies in the last quantities of mixture. The tablets produced had satisfactory technical properties. The tablets were coated by Opadry Y-1-7000 coating suspension using BGB-75D coating machine and reached the target weight increase value of 3％.

Example 6

The test of the dissolution rate

The dissolution rate of the tablet 5 mg prepared by Example 5 in the following dissolution medium: 0.1N hydrochloric acid, pH4.5 acetate buffer or pH6.8 phosphate buffer with paddle method. Testing 3 batches tablet (n＝3) , 9 experiments in total in each dissolution medium. The mean dissolution rate is listed in tables 1 to 3.

Table 1

Table 2

Table 3

Instrument and condition:

X-ray powder diffraction

The X-ray data were collected on a PANalytical Empyrean diffractometer, the X-ray data was collected over a 2 theta range of 3° to 40°, the step size is 0.0168°, scan rate 10s/step, using CuK. alpha radiation (

) . The sample was rotated continuously in order to reduce the impact of preferred orientation.

Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) experiments were performed in a TA Instruments^TM model Q2000. The weight of the sample was measured in an aluminum pan accurately and recorded, and transferred to the DSC. The instrument was purged with nitrogen gas. Data were collected between 40 and 300 ℃ at 10 ℃/min heating rate. The plot was made with the endothermic peaks.

Those illustrative embodiments herein are used to help understand the method and core ideas about this present invention. In should be noted that many adaptation and modifications may be made without departing from the scope of the appended claims in accordance with the common general knowledge of those of ordinary skilled in the art.

Reference throughout this specification to “an embodiment, ” “some embodiments, ” “one embodiment” , “another example, ” “an example, ” “aspecific example, ” or “some examples, ” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as “in some embodiments, ” “in one embodiment” , “in an embodiment” , “in another example, ” “in an example, ” “in a specific example, ” or “in some examples, ” in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples.

Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

Claims

A crystalline particle of tofacitinib citrate having a median particle size of less than about 40 μm.
The crystalline particle of claim 1, wherein the median particle size is in the range of about 3 μm to about 30 μm.
The crystalline particle of claim 2, wherein the median particle size is in the range of about 3 μm to about 15 μm.
The crystalline particle of claim 2, wherein the median particle size is in the range of about 3 μm to about 10 μm.
The crystalline particle of claim 2, wherein the median particle size is in the range of about 5 μm to about 10 μm.
The crystalline particle of any one of claims 1 to 5, wherein the crystalline particle of tofacitinib citrate shows at least one characteristic peak expressed in degrees two-theta at about 5.7, about 17.3, about 18.7, about 20.2 and about 20.5 in an x-ray powder diffraction pattern.
The crystalline particle of any one of claims 1 to 5, wherein the crystalline particle of tofacitinib citrate shows an X-ray powder diffraction pattern substantially as depicted in Fig. 1.
A crystalline particle of tofacitinib citrate having a particle size of less than about 40 μm.
The crystalline particle of claim 8, wherein the particle size is in the range of about 3 μm to about 30 μm.
The crystalline particle of claim 9, wherein the particle size is in the range of about 3 μm to about 15 μm.
The crystalline particle of claim 9, wherein the particle size is in the range of about 3 μm to about 10 μm.
The crystalline particle of claim 9, wherein the particle size is in the range of about 5 μm to about 10 μm.
The crystalline particle of any one of claims 9 to 12, wherein the crystalline particle of tofacitinib citrate shows at least one characteristic peak expressed in degrees two-theta at about 5.7, about 17.3, about 18.7, about 20.2 and about 20.5 in an x-ray powder diffraction pattern.
The crystalline particle of any one of claims 9 to 12, wherein the crystalline particle of tofacitinib citrate shows an X-ray powder diffraction pattern substantially as depicted in Fig. 1.
A process for the preparation of a crystalline particle of tofacitinib citrate, comprising:

(1) providing a solution comprising a tofacitinib citrate and a solvent at a first temperature；

(2) reducing a temperature of the solution from the first temperature to a second temperature to form the crystalline particle of tofacitinib citrate.
The process of claim 15, further comprising a step of isolating the crystalline particle of tofacitinib citrate.
The process of claim 15, wherein the solvent is at least one selected from a group consisting of water, alcohol, ketone, DMSO, DMF, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran and toluene.
The process of claim 17, wherein the alcohol is at least one selected from a group consisting of methanol, ethanol, isopropanol, n-butyl alcohol, isobutyl alcohol and n-amyl alcohol.
The process of claim 18, wherein the ketone is at least one selected from a group consisting of acetone, butanone and 4-methyl-2-pentanone.
The process of claim 15, wherein the solvent is at least one selected from a group consisting of water, methanol, ethanol, isopropyl alcohol and acetone.
The process of claim 15, wherein 1.0 gram of tofacitinib citrate dissolves in the solvent with a volume 10 mL to 26 mL.
The process of claim of 21, wherein the volume of the solvent is 16 mL.
The process of claim 15, wherein the solvent comprises alcohol and water, and a volume ration of alcohol to water is 10: 1 to 10: 10.
The process of claim 23, wherein the volume ration of alcohol to water is 10: 6.
The process of claim 15, wherein the first temperature is in the range from about room temperature to a refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is about 5 ℃ to about 30 ℃ lower than the refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is about 5 ℃ lower than the refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is about 10 ℃ lower than the refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is about 15 ℃ lower than the refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is about 20 ℃ lower than the refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is about 25 ℃ lower than the refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is about 30 ℃ lower than the refluxing temperature of the solvent.
The process of claim 25, wherein the first temperature is the refluxing temperature of the solvent.
The process of claim 15, wherein the second temperature is about 20 ℃ to 100 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 20 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 30 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 40 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 50 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 60 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 70 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 80 ℃ lower than the first temperature.
The process of claim 34, wherein the second temperature is about 90 ℃ lower than the first temperature.
The process of claim 15, wherein the first temperature is in the range from about 50 ℃ to a refluxing temperature of the solvent, and the second temperature is in the range from about -5 ℃ to 50 ℃.
The process of claim 43, wherein the first temperature is the refluxing temperature of the solvent, and the second temperature is in the range from about 0 ℃ to about 40 ℃.
The process of claim 15, wherein the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by the following steps:

(1) reducing the temperature of the solution by about 5 to about 20 ℃,

(2) standing the solution of step (1) for about 1 hour to about 300 hours,

(3) repeating the steps (1) and (2) until the temperature of the solution reaches the second temperature.
The process of claim 45, wherein in the step (2) , stand the solution of step (1) for about 1 hour to about 50 hours.
The process of claim 45, wherein in the step (2) , stand the solution of step (1) for about 1 hour to about 5 hours.
The process of claim 15, wherein the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by reducing the temperature of the solution at a rate of about 1 to about 20 ℃/hour.
The process of claim 48, wherein the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by reducing the temperature of the solution at a rate of about 5 to about 10 ℃/hour.
The process of claim 15, further comprising standing the solution of tofacitinib citrate at the second temperature for at least 30 minutes.
The process of claim 15, further comprising standing the solution of tofacitinib citrate at the second temperature for about 1 to about 24 hours.
The process of any one of claims 15 to 51, wherein the crystalline particle is formed under a condition of stirring at about 100 rpm to about 500 rpm.
The process of claim 52, wherein the crystalline particle is formed under a condition of stirring at 200 rpm to 400 rpm.
The process of claim 15, wherein the step of reducing a temperature of the solution from the first temperature to a second temperature is performed by the step:

(i) maintaining the solution at the first temperature for a first predetermined time；

(ii) reducing the temperature of the solution from the first temperature to a third temperature lower than the second temperature, and maintaining the solution at the third temperature for a second predetermined time； and

(iii) reducing the temperature of the solution from the third temperature to the second temperature, and maintaining the solution at the third temperature for a third predetermined time.
The process of claim 54, wherein the first temperature is in a range of 50℃ to the refluxing temperature of the solvent, the third temperature is in a range of 50℃ to 15℃, the second temperature is a temperature is in a range of -5℃ to 20℃.
The process of claim 54, wherein the first temperature is the refluxing temperature of the solvent, the third temperature is in a range of 40℃ to 30℃, the second temperature is in a range of 0℃ to 10℃.
The process of claim 54, wherein each of the first and second predetermined times is at least 30 min.
The process of claim 57, wherein each of the first and second predetermined times is in a range of 1 to 24 hours, and the third predetermined time is at least 1 hour.
A pharmaceutical composition, comprising tofacitinib citrate having a median particle size of less than 40 μm.
The pharmaceutical composition according to claim 59, wherein the pharmaceutical composition is in a form of tablet, capsule, pill, powder or granule.
The pharmaceutical composition according to claim 60, wherein the tablet is prepared by direct compression.
The pharmaceutical composition of any one of claims 59 to 61, further comprising an excipient being at least one selected from a group consisting of a filler, disintegrate, a small amount of lubricant, colorant and sweeteners.
The pharmaceutical composition of claim 62, wherein the filler is at least one selected from a group consisting of microcrystalline cellulose, sorbitol, mannitol, lactose, starch, modified starch, sucrose, glucose, calcium phosphate, silicate, calcium sulfate and calcium carbonate.
The pharmaceutical composition of claim 63, wherein the filler is at least one selected from a group consisting of lactose monohydrate FLOWLAC100 and microcrystalline cellulose.
The pharmaceutical composition of claim 62, wherein the content of the filler is 30 to 92wt％ based on the total weight of the pharmaceutical composition.
The pharmaceutical composition of claim 62, wherein the disintegrate is at least one selected from a group consisting of croscarmellose sodium, calcium carbonate, potato starch, tapioca starch, alginate, silicate, sodium carbonate, dry starch, carboxymethyl starch sodium, L-HPC and crospolyvinylpyrrolidone.
The pharmaceutical composition of claim 66, wherein the disintegrate is croscarmellose sodium.
The pharmaceutical composition of claim 62, wherein the content of the disintegrant is 2.0 to 10.0wt％. based on the total weight of the pharmaceutical composition.
The pharmaceutical composition of claim 68, wherein the content of the disintegrant is 3wt％.
The pharmaceutical composition of claim 62, wherein the lubricant is at least one selected from a group consisting of stearic acid metal salt, stearic acid, wax, hydrogenated vegetable oil, talcum powder or colloidal silica.
The pharmaceutical composition of claim 70, wherein the stearic acid metal salt is at least one selected from a group consisting of magnesium stearate, calcium stearate and stearic acid.
The pharmaceutical composition of claim 71, wherein the lubricant is magnesium stearate.
The pharmaceutical composition of claim 72, wherein the content of the magnesium stearate is 0.25wt％ to 2.5wt％.
The pharmaceutical composition of claim 73, wherein the content of the magnesium stearate is 1.5wt％.
The pharmaceutical composition of claim 62 , wherein the excipient being at least one selected from a group consisting of microcrystalline cellulose, croscarmellose sodium, lactose monohydrate and magnesium stearate.
A pharmaceutical composition, comprising tofacitinib citrate having a particle size of less than 40 μm.
Use of the crystalline particle of tofacitinib citrate of any one of claims 1 to 14, the pharmaceutical composition of any one of claims 59 to 76 in the preparation of a medicament preventing or treating a disorder or disease.
The use of claim 77, wherein the disorder or disease comprises at least one selected form a group consisting of organ transplant rejection, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and a complication induced by at least one selected from a group consisting of diabetes, cancer, asthma, atopic dermatitis, autoimmue thyroid disease, ulcerative colitis, Crohn′s disease, Alzheimer disease and leukemia.
A method of preventing or treating a disorder or disease comprising administering the crystalline particle of tofacitinib citrate of any one of claims 1 to 14, the pharmaceutical composition of any one of claims 59 to 76 to a subject.
The method of claim 79, wherein the disorder or disease comprises at least one selected form a group consisting of organ transplant rejection, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and a complication induced by at least one selected from a group consisting of diabetes, cancer, asthma, atopic dermatitis, autoimmue thyroid disease, ulcerative colitis, Crohn′s disease, Alzheimer disease and leukemia.