WO2022161507A1 - Crystal form of brepocitinib tosylate, and preparation method and use therefor - Google Patents

Abstract

Provided are a crystal form of Brepocitinib tosylate, and a preparation method, pharmaceutical composition, and use therefor.

Description

Crystal form of Brepocitinib tosylate and its preparation method and use

Citations to Related Applications

This disclosure requires all of the invention patent application with application number 202110134561.0 submitted to the State Intellectual Property Office of the People's Republic of China on February 1, 2021 and the application number 202210110391.7 submitted to the State Intellectual Property Office of the People's Republic of China on January 29, 2022 is incorporated by reference into this disclosure in its entirety.

field

The present disclosure generally relates to the field of medicinal chemistry. In particular, the present disclosure relates to crystalline forms of brepocitinib tosylate and methods for their preparation and uses.

background

Brepocitinib, with the development code PF-06700841, is a selective tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1) inhibitor developed by Pfizer for the treatment of psoriasis and atopic dermatitis (AD). Topical therapy, as well as psoriasis, psoriatic arthritis (PA), inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), vitiligo (eg active non-segmental Vitiligo), systemic lupus erythematosus (SLE), aplastic anemia (AA) and hidradenitis suppurativa (HS), etc. The chemical name for Brepocitinib is: [(1S)-2,2-difluorocyclopropanyl]-[(1R,5S)-3-[2-[(1-methylpyrazol-4-yl)amino]pyrimidine -4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone, its structural formula is shown in the following formula (I):

At present, the free state of brepocitinib disclosed in WO2020165788A1 has been found to have problems such as high hygroscopicity, easy deliquescence, and easy gelation through research by the present inventors. Further, using a solid form with high hygroscopicity will lead to many problems after preparation, such as: opening, bottle opening stability; preparation process requirements are extremely high; affecting dissolution, it is easy to cause impurities to increase; large; and poor liquidity.

Therefore, there is still a need in the art to develop brepocitinib salts and crystalline forms thereof with good physicochemical properties.

Overview

The purpose of the present disclosure is to provide the crystal form 1 of brepocitinib tosylate and its preparation method, pharmaceutical composition and use.

In certain embodiments, the brepocitinib tosylate form 1 of the present disclosure has at least one of the following advantages over known brepocitinib free forms or brepocitinib tosylate amorphous or other crystalline forms of brepocitinib tosylate : High purity and content, better stability, further reduced hygroscopicity, good particle size distribution, better solubility, meeting medicinal requirements, stable storage, and simple preparation method.

In certain embodiments, the crystalline form 1 of brepocitinib tosylate of the present disclosure has good druggability, is suitable for industrial production, is more conducive to preparation into a preparation product, and the prepared product is easy to store, stable in preparation, good in quality, and in dissolution. It has a better degree and is suitable for industrial production.

In one aspect, the present disclosure provides an X-ray powder diffraction pattern of brepocitinib tosylate Form 1, expressed at 2θ angles, having the following characteristic diffraction peaks: 6.3°±0.2°, 9.4°±0.2°, 18.7°±0.2 °, 19.2°±0.2° and 22.6°±0.2°.

In certain embodiments, the X-ray powder diffraction pattern of the crystalline form at 2θ angle further has at least one of the following characteristic diffraction peaks: 14.7°±0.2°, 16.8°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.6°±0.2°.

In certain embodiments, the X-ray powder diffraction pattern of the crystalline form at 2θ angle further has at least 3 characteristic diffraction peaks as follows: 14.7°±0.2°, 16.8°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 21.6°±0.2°.

In certain embodiments, the X-ray powder diffraction pattern of the crystalline form at 2θ angle further has at least one of the following characteristic diffraction peaks: 13.5°±0.2°, 14.2°±0.2°, 21.2°±0.2°, 24.9°±0.2°, 27.1°±0.2°.

In certain embodiments, the X-ray powder diffraction pattern of the crystalline form at 2θ angle further has at least 3 characteristic diffraction peaks as follows: 13.5°±0.2°, 14.2°±0.2°, 21.2°±0.2°, 24.9°±0.2°, 27.1°±0.2°.

In certain embodiments, the crystalline form has characteristic peaks and their relative intensities in an X-ray powder diffraction pattern expressed at 2θ angle as follows:

In certain embodiments, the brepocitinib tosylate form 1 has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1 .

In certain embodiments, the Fourier transform infrared spectrum (FT-IR) of the brepocitinib tosylate form 1 is at 654±2 cm ⁻¹ , 682±2 cm ⁻¹ , 774±2 cm ⁻¹ , 820±2 cm ^-1 , 876±2cm ^-1 , 960±2cm ^-1 , 980±2cm ^-1 , 1009±2cm ^-1 , 1032±2cm ^-1 , 1086±2cm ^-1 , 1121±2cm ^-1 , 1156±2cm ^-1 , 1216±2cm ^-1 , 1234±2cm ^-1 , 1254±2cm ^-1 , 1273±2cm ^-1 , 1333±2cm ^-1 , 1364±2cm ^-1 , 1398±2cm ^-1 , 1423±2cm ^-1 , 1445 There is a characteristic peak at at least one of ±2 cm ^-1 , 1523 ± 2 cm ^-1 and 1635 ± 2 cm ^-1 .

In certain embodiments, the Fourier transform infrared spectroscopic characterization of the brepocitinib tosylate form 1 is substantially as shown in FIG. 7 .

In certain embodiments, the brepocitinib tosylate salt form 1 is anhydrous.

In certain embodiments, the TGA characterization of the brepocitinib tosylate form 1 is substantially as shown in FIG. 2 , before 100°C, the weight loss is 0.26%, and the decomposition temperature is about 281°C.

In certain embodiments, the DSC characterization of the brepocitinib tosylate crystal form 1 is substantially as shown in FIG. 3 , the Onset value is 281±2°C, and the peak value is 282±2°C.

In certain embodiments, the DVS characterization of the brepocitinib tosylate form 1 is substantially as shown in Figure 4, with a 0.14% weight gain at 25°C between 0% RH and 80% RH.

On the other hand, the present disclosure provides a method for preparing the crystal form, comprising:

The toluenesulfonic acid aqueous solution and the brepocitinib solution are mixed, stirred, and a solid is precipitated to obtain the brepocitinib tosylate crystal form 1.

The order in which the toluenesulfonic acid aqueous solution and the brepocitinib solution are mixed is not limited. In certain embodiments, the aqueous solution of toluenesulfonic acid can be added dropwise to the brepocitinib solution (positive addition). In certain embodiments, the brepocitinib solution can also be added dropwise to the aqueous toluenesulfonic acid solution (back addition).

In certain embodiments, the mixing manner in the preparation method is to drop the aqueous solution of toluenesulfonic acid into the brepocitinib solution.

In certain embodiments, the brepocitinib solution is sonicated in acetonitrile or acetone or isopropanol.

In certain embodiments, the aqueous solution of toluenesulfonic acid is sonicated in water.

In certain embodiments, the stirring means is overnight stirring at room temperature.

In certain embodiments, the solids are separated and dried after being precipitated in the preparation method. The drying method is vacuum drying, and the time is 10-24 hours.

In certain embodiments, the drying operation is performed at room temperature.

In certain embodiments, the brepocitinib tosylate form 1 has at least one of the following beneficial effects:

1. The brepocitinib tosylate crystal form 1 of the present disclosure has good stability. Stable under high humidity conditions, its crystal form remains unchanged for at least 3 weeks.

2. The brepocitinib tosylate crystal form 1 of the present disclosure has extremely low hygroscopicity. 0.14% weight gain between 0%RH-80%RH, no or almost no hygroscopicity, while brepocitinib free state gains 5.0% weight gain between 0%RH-70%RH, has hygroscopicity, and is easy to deliquescence under high humidity conditions .

3. The brepocitinib tosylate crystal form 1 of the present disclosure has better solubility. However, brepocitinib has low solubility in free state and is easy to form a gel in water or under accelerated conditions, which will bring difficulties to the mixing step in the production process, especially it is not suitable for wet granulation, thus limiting the use of water in the production process.

4. The brepocitinib tosylate crystal form 1 of the present disclosure has good chemical stability. Purity and content did not change significantly under long-term (normal temperature, 60%RH), accelerated (40℃, 75%RH), high temperature (50℃), high humidity (normal temperature, 92%RH) and oxidative conditions; however, the free state of brepocitinib Under the same conditions, the content is reduced, that is, the active ingredient is reduced.

5. The tablet prepared by using the brepocitinib tosylate crystal form 1 of the present disclosure has good stability. Under accelerated conditions and under high humidity conditions, the hygroscopic weighing of the tablets of brepocitinib tosylate form 1 did not change much, and there was no change in their appearance; while the tablets prepared with brepocitinib free state were under high humidity conditions. The lower tablets gained significant weight, and were yellowed, tacky, and partially collapsed under accelerated conditions and under high humidity conditions.

6. The brepocitinib tosylate crystal form 1 of the present disclosure has less solvent residue on the surface and high purity.

In yet another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the brepocitinib tosylate crystal form 1 of the present disclosure or the brepocitinib tosylate crystal form obtained by the preparation method of the present disclosure, and at least one pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is selected from the group consisting of tablets, capsules, creams, transdermal patches, ointments, eye drops, lotions and gels.

In certain embodiments, the pharmaceutical composition may contain one or more other pharmaceutically active ingredients.

In certain embodiments, the other pharmaceutically active ingredient is selected from the group consisting of psoriasis drugs, lupus drugs, dermatitis drugs, and the like.

The pharmaceutical compositions provided by the present disclosure can be administered by a number of routes including, but not limited to: oral (enteral) administration, parenteral (injection) administration, rectal administration, topical administration, intradermal administration, intrathecal administration Administration, subcutaneous (SC), intramuscular (IM), sublingual/buccal, ocular, otic, vaginal and intranasal or by inhalation, typically, an effective amount of the Solid form of brepocitinib tosylate form 1. The actual amount of brepocitinib tosylate to be administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. The amount used in the solid form of the salt Form 1.

The compounds of the present disclosure can also be administered directly into the bloodstream, into muscle, or into internal organs. Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. The compounds of the present disclosure may also be applied topically to the skin or mucosa, that is, dermally or transdermally.

The compositions of the present disclosure can take a variety of forms. These include, for example, liquid, semisolid, and solid dosage forms such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic use.

Oral administration of solid dosage forms may, for example, be in discrete units such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure. Oral administration can be in powder or granular form; oral dosage forms are sublingual, eg, lozenges. In such solid dosage forms, the crystalline compound is usually combined with one or more adjuvants. Such capsules or tablets may contain controlled release formulations. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents or may be prepared with enteric coatings. Oral administration can be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (eg, water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring (eg, sweetening) and/or perfuming agents. The present disclosure includes parenteral dosage forms. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal administration, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (ie, sterile injectable aqueous or oleaginous suspensions) can be formulated according to known techniques using suitable dispersing, wetting and/or suspending agents.

The present disclosure encompasses topical dosage forms. "Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. Topical formulations may include crystalline compounds that enhance absorption or penetration of the active ingredient through the skin or other affected area. When administering the crystalline compounds of the present disclosure by transdermal devices, administration will be accomplished using patches, either of the reservoir and porous membrane type or of the solid matrix type. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, Fibers, bandages and microemulsions, liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol and propylene glycol, and penetration enhancers can also be incorporated. Thus, topical formulations of the crystalline form of brepocitinib tosylate of the present disclosure can be administered using such formulations that encompass all conventional methods of administration across the body surface and the lining of body passages, including epithelial and mucosal tissues, including Transdermal, epidermal, oral, pulmonary, ocular, intranasal, vaginal and rectal modes of administration. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol and propylene glycol. Such topical formulations can be prepared in combination with additional pharmaceutically acceptable excipients. Excipients that may be essential for clinical efficacy are one or more penetration enhancers, such as one or more saturated or cis-unsaturated C10-C18 fatty alcohols. Such fatty alcohols include C16-C18 fatty alcohols, and are most preferably C18 fatty alcohols. Examples of cis-unsaturated C16-C18 fatty alcohols include oleyl alcohol, linoleyl alcohol, gamma-linolenic alcohol, and linolenic alcohol. Saturated C10-C18 fatty alcohols useful as penetration enhancers include decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, and stearyl alcohol. Alternatively, other penetration enhancers useful in preparing topical formulations include C10-C18 fatty acids, which when saturated may include capric, lauric, myristic, palmitic, stearic, and arachidic acid. Alternatively, the penetration enhancer may be a cis-unsaturated fatty acid such as palmitoleic acid (cis-9-hexadecenoic acid), oleic acid (cis-9-octadecenoic acid), cis- Formula-Isooleic acid (cis-11-octadecenoic acid), linoleic acid (cis-9,12-octadecadienoic acid), γ-linolenic acid (cis-6,9,12 -Octatrienoic acid), linolenic acid (cis-9,12,15-octadecatrienoic acid) and arachidonic acid (cis-5,8,11,14-eicosatetraene acid). Penetration enhancers, for example, selected from C10-C18 fatty alcohols, at about 0.1 to about 5% (w/v), more preferably 1 to about 4% (w/v), more preferably 1 Amounts in the range to about 3% (w/v) are used.

In yet another aspect, the present disclosure provides the brepocitinib tosylate crystal form 1 or the brepocitinib tosylate crystal form obtained according to the preparation method of the present disclosure or the pharmaceutical composition described in the present disclosure in the preparation of the treatment of TYK2 and/or Use in medicine for JAK1-related diseases.

In certain embodiments, the associated disease is selected from the group consisting of lupus (eg, systemic lupus erythematosus), rheumatoid arthritis (RA), psoriasis (eg, plaque psoriasis), inflammatory bowel disease (IBD) ), ulcerative colitis, Crohn's disease, vitiligo (eg, active non-segmental vitiligo), alopecia (eg, alopecia areata, alopecia areata), hidradenitis suppurativa, and atopic dermatitis.

In another aspect, the present disclosure provides a method of treating a disease associated with TYK2 and/or JAK1, comprising administering to an individual in need of the method a therapeutically effective amount of the brepocitinib tosylate form 1 or a crystalline form according to the present disclosure The brepocitinib tosylate crystal form obtained by the preparation method or the pharmaceutical composition containing the brepocitinib tosylate crystal form 1 of the present disclosure.

In certain embodiments, the individual is a mammal.

In certain embodiments, the mammal is a human.

In certain embodiments, the disease is selected from lupus (eg, systemic lupus erythematosus), rheumatoid arthritis (RA), psoriasis (eg, plaque psoriasis), inflammatory bowel disease (IBD) , ulcerative colitis, Crohn's disease, vitiligo (eg, active non-segmental vitiligo), alopecia (eg, alopecia areata, alopecia areata), hidradenitis suppurativa, and atopic dermatitis.

For oral doses, a typical regimen is one to five oral doses per day, especially one to four oral doses. Using these dosing modes, each dose provides about 0.01-20 mg/kg of the solid form of brepocitinib tosylate form 1 provided by the present disclosure, with preferred doses each providing about 0.1-10 mg/kg, especially about 0.1 -5 mg/kg, depending on the specific condition being treated, the age and weight of the specific patient, and the specific patient's response to drug therapy, the exact dose is to be determined under the guidance of a physician according to standard medical principles. A specific unit dose can be between 5-500 mg, eg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 200 mg, 240 mg, and the like.

The topical formulation contains a therapeutically effective amount of brepocitinib tosylate form 1 or brepocitinib tosylate form obtained according to the preparation methods of the present disclosure, which can be administered to a patient in need thereof in doses ranging from once daily to four times daily. These amounts are in the range of about 0.1% to about 5.0% (w/v), more preferably about 0.1% to about 3.0% (w/v), such as 0.1%, 0.3%, 1%, 3%.

In certain embodiments, the method further comprises administering other drugs.

In certain embodiments, the other drug is selected from antibiotics, anti-inflammatory drugs, and contraceptives.

In certain embodiments, the other drug is selected from the group consisting of Itraconazole, Ethinyl estradiol, and levonorgestrel.

In yet another aspect, the present disclosure provides brepocitinib tosylate crystal form 1 or the brepocitinib tosylate crystal form obtained according to the disclosed preparation method or a pharmaceutical composition containing the brepocitinib tosylate crystal form 1 of the present disclosure and other Combination of drugs.

The present disclosure provides any one of the uses, methods or compositions as defined herein, wherein a crystalline compound herein or a pharmaceutically acceptable solvate of the compound is combined with one or more other therapeutic agents discussed herein used in combination. "Combination" administration of two or more compounds means that all compounds are administered sufficiently close in time that the presence of one compound alters the biological effect of any other compound. Two or more compounds can be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration can be performed by admixing the compounds prior to administration, or by administering the compounds as separate dosage forms at the same time point, but at the same or different administration sites. The phrases "concurrent administration", "co-administration", "concurrent administration" and "concurrent administration" refer to the combined administration of the compounds.

Unless otherwise specified:

"Room temperature" in this disclosure refers to a temperature of 10°C to 30°C.

For "stirring", conventional methods in the art can be used, for example, stirring methods include magnetic stirring and mechanical stirring, and the stirring speed is 50-1800 rpm. In certain embodiments, the stirring speed is 300-900 rpm.

"Isolation" can be performed by conventional methods in the art, such as centrifugation or filtration. Filtration under reduced pressure is preferred, and suction filtration is generally performed at room temperature at a pressure less than atmospheric pressure. In certain embodiments, the pressure is less than 0.09 MPa.

"Drying" can be accomplished by using conventional techniques in the art, such as drying at room temperature, air drying or drying under reduced pressure; it can be under reduced pressure or normal pressure, preferably the pressure is less than 0.09 MPa. The drying apparatus and method are not limited, and can be a fume hood, a forced air oven, a spray dryer, a fluidized bed drying or a vacuum oven; it can be carried out under reduced or no reduced pressure, preferably the pressure is less than 0.09Mpa.

"Toluenesulfonic acid" means p-Toluenesulfonic acid.

"Normal temperature" refers to a temperature of 25°C±5°C.

In the present disclosure, "crystalline form" means as evidenced by the characterization of the X-ray powder diffraction pattern shown. It is well known to those skilled in the art that the experimental errors therein depend upon instrumental conditions, sample preparation and sample purity. Spectra generally vary with instrument conditions. The relative intensities of peaks may vary with experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor; experimental errors in peak angles should also be taken into account, usually allowing an error of ±0.2°; the influence of factors such as sample height can cause The peak angle is shifted as a whole, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present disclosure belongs to the scope of the present disclosure. The "single crystal form" refers to a single crystal form detected by X-ray powder diffraction.

The crystalline form of brepocitinib tosylate of the present disclosure is pure, single, and substantially not mixed with any other crystalline or amorphous forms.

In the present disclosure, "substantially absent" when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms or amorphous states, more particularly less than 10% by weight, especially Less than 5% by weight, especially less than 1% by weight.

Brief Description of Drawings

FIG. 1 is the XRPD pattern of the brepocitinib tosylate crystal form 1 described in Example 1. FIG.

FIG. 2 is a TGA diagram of brepocitinib tosylate crystal form 1 described in Example 1. FIG.

3 is a DSC chart of the brepocitinib tosylate crystal form 1 described in Example 1. FIG.

4 is a DVS graph of brepocitinib tosylate Form 1 described in Example 1. FIG.

5 is a 1H-NMR chart of the brepocitinib tosylate crystal form 1 described in Example 1. FIG.

6 is a PLM image of brepocitinib tosylate Form 1 described in Example 1. FIG.

7 is an FT-IR image of brepocitinib tosylate crystal form 1 described in Example 1. FIG.

FIG. 8 is a graph showing the appearance changes of the free state of brepocitinib in Experiment Example 2 under accelerated conditions into a gel and deliquescence under high humidity conditions.

FIG. 9 is an XRPD diagram of stability of the brepocitinib tosylate crystal form 1 in Experimental Example 3. FIG.

detail

The technical solutions of the present disclosure will be described in detail below with reference to the accompanying drawings and embodiments, but the present disclosure is not limited to the scope of the described embodiments.

X-ray powder diffraction (XRPD) test conditions are: Bruker D8, Cu-Kα radiation, detection range 3°-40°2θ, step size 0.02°2θ, scan rate 0.2s.step ^-1 , current and voltage 40mA, 40KV.

Thermogravimetric analysis (TGA) test conditions are: TA Q500, 10.00°C/min from room temperature to 400°C; for the TGA chart, keep the temperature point and weight loss value.

Differential calorimetry scanning (DSC) test conditions are: equilibrium at 0°C, rising to 350°C at 10°C/min; for the DSC chart, keep the temperature point and enthalpy value.

Dynamic moisture adsorption (DVS) test conditions are: taken from TA Instruments Q5000 TGA, control software Thermal Advantage, analysis software Universal Analysis; usually 1-10 mg of the sample is placed in a platinum crucible, and the TA software records the relative humidity of the sample from Weight change from 0% RH to 80% RH to 0% RH. Depending on the specific conditions of the sample, different adsorption and desorption steps can also be applied to the sample.

Hydrogen nuclear magnetic spectrum data (1H-NMR) were obtained from Bruker Ascend 500M HZ nuclear magnetic resonance spectrometer. Weigh an appropriate amount of sample and dissolve it into a NMR sample tube with about 0.5 mL of deuterated dimethyl sulfoxide reagent for detection.

Polarized light microscope (PLM) spectrum was taken from the hot stage, XP-500, eyepiece 10 times, objective lens 4 times, weigh 20 mg of the ashing sample, evenly disperse it in 50 ml of water, and take the dispersed droplets to a clean carrier. After natural drying, the slides were observed under a polarizing microscope.

Fourier transform infrared spectroscopy (FT-IR) data were obtained from Bruker Tensor 27. The parameters are as follows: detection method: ATR method; collection range: 600cm-1-4000cm ^-1 ; resolution: 4.0cm ^-1 .

High performance liquid chromatography (HPLC) data is collected from Thermo Fisher Dionex U3000, and the detector used is the HPLC method parameters described in the present disclosure of VWD as follows:

Chromatographic column: Eclipse XDB Cl8 250×4.6mm, 5μm;

Mobile phase: A: 0.05% trifluoroacetic acid aqueous solution; B: acetonitrile solution;

The elution gradient is as follows:

Flow rate: l.0mL/min

Injection volume: 5μL

Detection wavelength: 258nm

Column temperature: 35℃

Diluent: acetonitrile

The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description. The reagents and raw materials used in the present disclosure are all commercially available, without special instructions, they are all commercially available.

The free state of Brepocitinib is prepared by the prior art, such as the method mentioned in WO2020165788A1, and can also be purchased commercially.

Example 1

Take 39 g of brepocitinib and dissolve it in 200 mL of acetonitrile by ultrasonic, and take another 17.2 g of toluenesulfonic acid and dissolve it in 25 mL of water by ultrasonic, add the aqueous solution of toluenesulfonic acid dropwise to the acetonitrile solution of brepocitinib (positive addition), stir at room temperature overnight, and precipitate a solid After centrifugation, it was vacuum-dried at room temperature for 24 hours to obtain 46 g of brepocitinib tosylate crystal form 1.

Measured by XRPD (X-ray powder diffractometer), the XRPD pattern of the brepocitinib tosylate crystal form 1 represented by the 2θ angle is shown in FIG. 1 .

The TGA characterization data of Brepocitinib tosylate crystal form 1 is: before 100° C., the weight loss is 0.26%, the decomposition temperature is about 281° C., and it is anhydrous, as shown in FIG. 2 .

The DSC characterization data of Brepocitinib tosylate crystal form 1 are: the Onset value is 281±2°C, and the peak value is 282±2°C, as shown in FIG. 3 .

The DVS characterization data of Brepocitinib tosylate crystal form 1 is: at 25°C, the weight gain is 0.14% between 0-80% RH, as shown in FIG. 4 .

The 1H-NMR characterization data of Brepocitinib tosylate crystal form 1, the molar ratio of brepocitinib and tosylate is 1:1, as shown in Figure 5.

The PLM characterization data of Brepocitinib tosylate form 1 are shown in FIG. 6 .

The FT-IR characterization data of Brepocitinib tosylate form 1 are shown in FIG. 7 .

Example 2

Take 15mg of brepocitinib in 1mL of isopropanol and dissolve it in 1mL of isopropanol by ultrasonic filtration, and take another 66.35mg of toluenesulfonic acid in 5mL of isopropanol to dissolve it in 5mL of isopropanol. (positive addition), stirred at room temperature, and immediately after the solid was precipitated, centrifuged and vacuum-dried at room temperature for 24 hours to obtain brepocitinib tosylate crystal form 1.

Example 3

Take 60 mg of brepocitinib and dissolve it in 0.2 mL of acetone by ultrasonic, and take another 26.54 mg of toluenesulfonic acid and dissolve it in 1.29 mL of acetone by ultrasonic. Add the acetone solution of toluenesulfonic acid dropwise to the acetone solution of brepocitinib (positive addition), and stir at room temperature. Immediately after precipitation of solid, centrifugation, and vacuum drying at room temperature for 24 hours to obtain brepocitinib tosylate crystal form 1.

Experimental Example 1: Equilibrium Solubility Experiment

Take 3 mL of water and form brepocitinib tosylate crystal form 1 prepared in Example 1 to form a saturated suspension solution. The solid-liquid mixture is stirred at room temperature for 24 hours, and the filtrate is taken for HPLC detection. The equilibrium solubility in 24 hours is 0.44 mg/mL.

Experimental Example 2: Accelerated and High Humidity Experiments

The free state of brepocitinib and the crystal form 1 of brepocitinib tosylate prepared in Example 1 were taken for 0-day purity testing, and then placed openly under accelerated (40°C, 75%RH) and high humidity (normal temperature, 92%RH) conditions 20 days, take samples for observation.

Results: In the free state of brepocitinib, the sample powder became gel-like and foamed and adhered to the bottom of the bottle under accelerated conditions; the sample powder deliquesced in the bottle under high-humidity conditions, as shown in Figure 8. However, the appearance of brepocitinib tosylate crystal form 1 did not change, and its purity was further determined to remain unchanged; and its crystal form remained unchanged, as shown in Figure 9, showing good crystal form stability.

Experimental Example 3: Stability Experiment

Take the free state of brepocitinib and the brepocitinib tosylate crystal form 1 prepared in Example 1, respectively, and place them in long-term (normal temperature, 60% RH), accelerated (40 ℃, 75% RH), high temperature (50 ℃), high humidity (normal temperature) , 92% RH) and oxidative conditions for 20 days, the samples were weighed for HPLC detection, and the respective 0-day samples were used as controls.

The results are shown in Table 1:

Table 1. Results of stability experiments

Under long-term, accelerated, high temperature, high humidity and oxidative conditions, the free content of brepocitinib was significantly reduced, that is, the active ingredients of the drug were reduced; the content of brepocitinib tosylate crystal form 1 did not change significantly.

Experimental Example 4: Tablet Compression Experiment and Detection

The active ingredient and each auxiliary material were mixed according to the prescription in Table 2, and then pressed into tablets under the pressure of 20 MPa on an infrared tablet machine for 2 minutes, and the blank auxiliary materials were mixed at the same time for tableting.

Tablet formulations are shown in Table 2:

Table 2. Unit Tablet Formulation

RESULTS: The tablet containing brepocitinib free state had sticking phenomenon in some of the tablets during the compression process, and there was residue on the punch surface; while the tablet containing brepocitinib tosylate crystal form 1 had no sticking phenomenon.

Experimental Example 5: Tablet hygroscopicity test

The whole tablet compressed in Experimental Example 4 was placed under accelerated conditions (40°C, 75% RH) and high humidity conditions (normal temperature, 92% RH), and its weight and appearance were checked regularly.

RESULTS: Under accelerated conditions, the hygroscopic weight changes of brepocitinib free form and brepocitinib tosylate form 1 were not significant, but brepocitinib free form became yellow and viscous in appearance under accelerated conditions, while brepocitinib tosylate There was no change in the appearance of Salt Form 1.

Under high humidity conditions, the hygroscopic weight change of the tablets containing brepocitinib tosylate form 1 was small at 1 and 7 days, but the hygroscopic weight change of the tablets containing brepocitinib free state was very large, and brepocitinib free state Tablets of brepocitinib tosylate form 1 showed no change in appearance under high humidity conditions.

Table 3. Tablet hygroscopicity results under high humidity conditions

Experimental Example 6: Dissolution Test Experiment

Carry out dissolution test by pressing the complete tablet of Table 2 tablet prescription of Experimental Example 4, and the conditions are as follows:

Dissolution Apparatus: RC12AD Tianda Tianfa Dissolution Apparatus

Dissolution medium: pH 6.8 phosphate buffer

Medium volume: 900mL

Dissolution method: basket method

Medium temperature: 37℃

Speed: 100rpm

The results are shown in Table 4: the tablets containing brepocitinib tosylate crystal form 1 reached 91.5% dissolution in 30 minutes, while the tablets containing brepocitinib free state reached 85% dissolution in 45 minutes, reflecting the brepocitinib tosylate Tablets of salt form 1 had better dissolution than brepocitinib free form tablets.

Table 4. Dissolution Assay Results

Formulation Example 1: Preparation of Cream

The components of the cream are as follows in Table 5:

table 5

The preparation steps are as follows:

1) Dissolving brepocitinib tosylate crystal form 1 in a propylene glycol solvent at room temperature;

2) The other components are first emulsified at 70°C, and then cooled to 30°C;

3) The propylene glycol solution of brepocitinib tosylate crystal form 1 is added to the emulsification system, and the cream is obtained after homogenization.

Formulation Example 2: Preparation of Tablets 1

The components of the chip are shown in Table 6:

Table 6

The components of the coating are as follows in Table 7:

Table 7

The preparation method is as follows: weigh brepocitinib tosylate crystal form 1 and various excipients according to the prescription amount and mix and press the tablet, after preparing the tablet core, then coating the aqueous solution/suspension of the coating on the tablet core to obtain 4 different specifications film-coated tablets.

Formulation Example 3: Preparation of Tablets 2

The components of the chip are shown in Table 8:

Table 8

The preparation process is as follows: brepocitinib tosylate crystal form 1 is mixed with lactose and microcrystalline cellulose, and then an aqueous solution of hypromellose is added. Vidone K30, silicon dioxide mixed, plus magnesium stearate mixed to lubricate tableting.

The above-mentioned embodiments are preferred embodiments of the present disclosure, but the embodiments of the present disclosure are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, Simplification, all should be equivalent substitutions, and are all included in the protection scope of the present disclosure.

Claims (21)

1. Brepocitinib tosylate crystal form 1, wherein, the X-ray powder diffraction pattern of the crystal form 1 at 2θ angle has the following characteristic diffraction peaks: 6.3°±0.2°, 9.4°±0.2°, 18.7°±0.2° , 19.2±0.2° and 22.6°±0.2° have characteristic diffraction peaks.
2. The brepocitinib tosylate crystal form 1 according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form 1 at 2θ angle further has at least one of the following characteristic diffraction peaks: 14.7°±0.2°, 16.8°±0.2°, 19.4°±0.2°, 19.9°±0.2° and 21.6°±0.2°; preferably at least 3 characteristic diffraction peaks.
3. The brepocitinib tosylate crystal form 1 according to claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal form 1 at 2θ angle further has at least one of the following characteristic diffraction peaks: 13.5°±0.2 °, 14.2°±0.2°, 21.2°±0.2°, 24.9°±0.2°, 27.1°±0.2°; preferably at least 3 characteristic diffraction peaks.
4. The brepocitinib tosylate crystal form 1 according to any one of claims 1 to 3, wherein the Fourier transform infrared spectrum (FT-IR) of the crystal form 1 is at 654±2 cm ⁻¹ , 682± 2cm ^-1 , 774±2cm ^-1 , 820±2cm ^-1 , 876±2cm ^-1 , 960±2cm ^-1 , 980±2cm ^-1 , 1009±2cm ^-1 , 1032±2cm ^{-1 ,} 1086±2cm -1 ¹ , 1121±2cm ^-1 , 1156±2cm ^-1 , 1216±2cm ^-1 , 1234±2cm ^-1 , 1254±2cm ^-1 , 1273±2cm ^-1 , 1333±2cm ^-1 , 1364±2cm ^-1 , At least one of 1398±2 cm ⁻¹ , 1423±2 cm ⁻¹ , 1445±2 cm ⁻¹ , 1523±2 cm ⁻¹ and 1635±2 cm ⁻¹ has a characteristic peak.
5. The brepocitinib tosylate crystal form 1 according to any one of claims 1 to 4, wherein the Fourier transform infrared spectrum characterization of the brepocitinib tosylate salt form 1 is substantially as shown in FIG. 7 .
6. The brepocitinib tosylate form 1 according to any one of claims 1 to 5, wherein the brepocitinib tosylate form 1 is anhydrous.
7. The brepocitinib tosylate crystal form 1 according to any one of claims 1 to 6, whose TGA characterization is basically shown in Figure 2, before 100 °C, the weight loss is 0.26%, and the decomposition temperature is about 281 °C.
8. The brepocitinib tosylate form 1 according to any one of claims 1 to 7, wherein the DSC characterization of the brepocitinib tosylate form 1 is basically as shown in FIG. 3 , and the Onset value is 281± 2℃, the peak value is 282±2℃.
9. The method for preparing the crystal form 1 of any one of claims 1 to 8, comprising:

   The toluenesulfonic acid aqueous solution and the brepocitinib solution are mixed, stirred, and a solid is precipitated to obtain the brepocitinib tosylate crystal form;
10. The method of claim 9, wherein the mixing method is to drop the toluenesulfonic acid aqueous solution into the brepocitinib solution.
11. The method of claim 9 or 10, wherein the brepocitinib solution is sonicated in acetonitrile or acetone or isopropanol.
12. The method according to any one of claims 9 to 11, wherein the aqueous solution of toluenesulfonic acid is ultrasonically dissolved in water.
13. The method according to any one of claims 9 to 12, wherein the stirring mode is overnight stirring at room temperature.
14. The method according to any one of claims 9 to 13, wherein after the solid is precipitated, separation and drying are performed, and the drying method is vacuum drying for 10 to 24 hours; preferably, the drying is performed at room temperature conduct.
15. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form of any one of claims 1 to 8, the brepocitinib tosylate crystal form 1 or the method of any one of claims 9 to 14. brepocitinib tosylate form 1, and at least one pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15, wherein the composition is selected from the group consisting of tablets, capsules, creams, transdermal patches, ointments, eye drops, lotions and gels.
17. A method of treating a disease associated with TYK2 and/or JAK1, comprising administering to an individual in need of the method a therapeutically effective amount of the brepocitinib tosylate form 1 of any one of claims 1 to 8, comprising The brepocitinib tosylate crystal form prepared by the method according to any one of claims 9 to 14, and the pharmaceutical composition according to claim 15 or 16.
18. The method of claim 17, wherein the disease is selected from the group consisting of lupus, rheumatoid arthritis, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, vitiligo, alopecia, purulent sweat glands inflammation and atopic dermatitis.
19. 18. The method of claim 17, further comprising administering other drugs.
20. The method of claim 19, wherein the other drug is selected from antibiotics, anti-inflammatory drugs and contraceptives, preferably Itraconazole, Ethinyl estradiol and levonorgestrel.
21. The method of any one of claims 17 to 20, wherein the individual is a mammal, preferably a human.

Images