FIELD OF THE DISCLOSURE

The present invention is directed to co-crystal forms of baricitinib; particularly with fumaric acid as the co-crystal former (coformer) in solvated and anhydrous forms. Further, the present disclosure is also related to processes for the preparation of the solvated and anhydrous forms of baricitinib co-crystals with fumaric acid. Further, the present disclosure also relates to pharmaceutical compositions comprising the forms of baricitinib co-crystals with fumaric acid, and methods for treating disease using the forms.

BACKGROUND OF THE DISCLOSURE

Baricitinib, having the chemical designation { 1 -(ethyl sulfonyl)-3- [4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl- ]azetidin-3-yl}acetonitrile, is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. Baricitinib has the following structure:

Baricitinib is commercially marketed in Europe and in the U.S. under the name Olumiant. In the U.S., it is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have responded inadequately to one or more TNF antagonist therapies. Olumiant may be used as monotherapy or in combination with methotrexate or other DMARDs.

Baricitinib is described in U.S. Patent No. 8158616. Solid forms of baricitinib are described in U.S. Patent Nos. 9827230 (amorphous hybrid nanoparticles), 9938283 (crystalline form comprising 3% water) and 10377757 (crystalline forms I and II, and crystalline phosphate salt forms A, B and C), and U.S. Publication No. 20170129895 (amorphous). Methods of treating rheumatoid arthritis and psoriasis using baricitinib are described in U.S. Patent No. 8420629. Processes for preparing baricitinib and intermediates are described in U.S. Patent Nos. 8410265, 9873706, and 9908888, U.S. Patent Publication Nos. 20190100538, 20180134713, and 20190062337, International Publication No. WO2017109524 and European Patent No. EP3253760. None of the references describe any co-crystal of baricitinib. Specifically, none of the references describe a baricitinib co-crystal comprising baricitinib and fumaric acid as the coformer.

SUMMARY OF THE DISCLOSURE

The present invention is directed to a baricitinib co-crystal with fumaric acid/DCM solvate and to an anhydrous baricitinib co-crystal with fumaric acid. The present disclosure is also related to processes for the preparation of these forms of baricitinib co-crystal with fumaric acid. Further, the present invention also relates to pharmaceutical compositions comprising a form of baricitinib co-crystal with fumaric acid and to methods for treating disease using a form of baricitinib co-crystal with fumaric acid.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents the experimental and calculated XRPD patterns of Form I baricitinib co-crystal with fumaric acid/DCM solvate.

Figure 2 is a TGA plot of Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 3 is a DSC plot of Form I baricitinib co-crystal with fumaric acid/DCM solvate.

Figure 4 is a ^X H NMR spectra of Form I baricitinib co-crystal with fumaric acid/DCM solvate.

Figure 5 is directed to FT-IR spectra comparison of Form I baricitinib co-crystal with fumaric acid/DCM solvate versus that of baricitinib and fumaric acid.

Figure 6 is directed to FT-IR spectra comparison of Form I baricitinib co-crystal with fumaric acid/DCM solvate versus a physical mixture of baricitinib and fumaric acid.

Figures 7 A and 7B together represent the asymmetric unit of Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 7 A depicts the interaction between baricitinib and fumaric acid in Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 7B depicts the relationship between baricitinib and DCM in Form I baricitinib co-crystal with fumaric acid/DCM solvate (only one molecule of DCM shown).

Figures 8A and 8B together show the inter-molecular hydrogen bonding between baricitinib molecules and between baricitinib molecules and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 8A shows the inter- molecular hydrogen bonding between baricitinib molecules in Form I baricitinib co- crystal with fumaric acid/DCM solvate (fumaric acid not shown). Figure 8B shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate (DCM not shown).

Figure 9 represents the comparison of XRPD patterns of Form I baricitinib co crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid.

Figure 10 represents a comparison of XRPDs for wet cake and dried precipitate of Form II baricitinib co-crystal with fumaric acid (prepared according to Example 7), and the calculated XRPD for Form II baricitinib co-crystal with fumaric acid.

Figure 11 contains TGA and DSC plots of Form II baricitinib co-crystal with fumaric acid. Figure 12 is a ^X H NMR spectra of Form II baricitinib co-crystal with fumaric acid.

Figure 13 represents crystals of Form II baricitinib co-crystal with fumaric acid examined by PLM.

Figure 14 shows the asymmetric unit of Form II baricitinib co-crystal with fumaric acid.

Figure 15 shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form II baricitinib co-crystal with fumaric acid.

Figure 16 represents a comparison of XRPDs for wet cake and dried precipitate of Form II baricitinib co-crystal with fumaric acid (prepared according to Example 8), and the calculated XRPD for Form II baricitinib co-crystal with fumaric acid.

DETAILED DESCRIPTION OF THE DISCLOSURE

The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be clear to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are not intended to be limited to the examples described herein and shown but are to be accorded the scope consistent with the claims.

As used herein and unless otherwise specified, the terms“about” and

“approximately,” when used in connection with a numeric value or a range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, e.g., that describing a DSC or TGA thermal event, including, e.g., melting, dehydration, desolvation or glass transition events; a mass change, such as, e.g., a mass change as a function of temperature or humidity; a solvent or water content, in terms of, e.g., mass or a percentage; or a peak position, such as, e.g., in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form. As used herein and unless otherwise specified,“co-crystal” and“co-crystal systems” refer to solid materials composed of two or more different components that are solid at room temperature and in particular stoichiometric ratios which interact through non-covalent interactions which can be designed utilizing supramolecular synthon approach. The co-crystal, in which at least one of the components is baricitinib and the coformer is a second pharmaceutically acceptable compound, is called a pharmaceutical baricitinib co-crystal with the coformer.

As used herein and unless otherwise specified, the term“pharmaceutical composition” is intended to encompass a pharmaceutically effective amount of the baricitinib in the co-crystal of the invention and a pharmaceutically acceptable excipient. As used herein, the term“pharmaceutical compositions” includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

As used herein and unless otherwise specified, the term“crystalline” and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, mean that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 2lst edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).

As used herein and unless otherwise specified, the term“excipient” refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients may be natural or synthetic substances formulated alongside the active ingredient of a medication, included for bulking-up formulations that contain potent active ingredients (thus often referred to as“bulking agents,”“fillers,” or“diluents”), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Excipients can also be useful in the

manufacturing process, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life. As used herein and unless otherwise specified, the term“patient” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. Further, a patient may not have exhibited any symptoms of the disorder, disease or condition to be treated and/or prevented, but has been deemed by a physician, clinician or other medical professional to be at risk for developing said disorder, disease or condition.

As used herein and unless otherwise specified, the terms“treat,”“treating” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more therapeutic agents to a patient with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agents, after the onset of symptoms of a disease.

Particular embodiments of the invention are directed to solvated and anhydrous forms of a baricitinib co-crystal with fumaric acid; more particularly to Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid. The forms are considered to have an isostructural relationship which lends to them looking identical. Form I baricitinib co-crystal with fumaric acid/DCM solvate is a site disordered baricitinib co-cry stal/solvate, where the fumaric acid molecule that links two molecules of baricitinib is replaced by two dichloromethane molecules in approximately 15% of the unit cells. Form II baricitinib co-crystal with fumaric acid has no solvent associated therewith, i.e., it is anhydrous. The present disclosure is also related to processes for the preparation of Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid.

Another embodiment according to the invention is a method of making a baricitinib co-crystal with fumaric acid, comprising dissolving baricitinib and fumaric acid in a solvent to form a clear solution, allowing the solution to evaporate to yield the baricitinib co-crystal with fumaric acid. A further embodiment according to the invention is a method of making a baricitinib co-crystal with fumaric acid, comprising dissolving baricitinib and fumaric acid in a solvent to form a clear solution, adding an antisolvent thereto, and allowing the baricitinib co-crystal with fumaric acid to precipitate from the solvent-anti solvent mixture. The aforesaid method uses as the solvent, for example dimethylsulfoxide (DMSO) and uses as the antisolvent, for example methanol or water. Where the antisolvent is methanol the mole ratio of the baricitinib to fumaric acid is 1 : 1.5-3.5.

Where the antisolvent is water the mole ratio of the baricitinib to fumaric acid is 1 : 1-1.5.

A further embodiment according to the invention is a method for the preparation of a baricitinib co-crystal with fumaric acid/DCM solvate comprising:

(a) dissolving baricitinib (BCT) and fumaric acid (FUM) in a solvent mixture of methanol (MeOH) and dichloromethane (DCM) by heating, wherein the ratios of BCTmmokFUMmmol is about 1 : 1 and

BCTmmol:MeOHmL:DCMmL is about 1 :22:28 to about 1 :25:40;

(b) evaporation of the solvent mixture to yield the baricitinib co-crystal with fumaric acid/DCM solvate.

The aforesaid method of preparation embodiment wherein the heating is affected at about 50°C. The aforesaid method wherein the baricitinib co-crystal with fumaric acid prepared is Form I. The aforesaid method wherein Form I is a baricitinib co-crystal with fumaric acid/DCM solvate. The aforesaid method wherein Form I baricitinib co-crystal with fumaric acid/DCM solvate consists of one molecule of baricitinib, half a molecule of fumaric acid that is disordered in the cocrystal, and 0.14 molecules of disordered DCM.

A further embodiment according to the invention is a method for the preparation of a baricitinib co-crystal with fumaric acid comprising:

(a) combining fumaric acid (FUM) dissolved in methanol (MeOH) and

baricitinib (BCT) dissolved in dimethylsulfoxide (DMSO) wherein the ratios of BCTmmokFUMmmol is about 1 :3.6 and BCTmmol: DMSOmL and FUMmmokMeOHmL are respectively about 1 : 1.9 and 1 :2.1

(b) stirring the combined solutions of step (a) overnight (8-10 hr) at room temperature (RT) to yield the baricitinib co-crystal with fumaric acid;

(c) isolating the baricitinib co-crystal with fumaric acid formed in step (b). The aforesaid method of preparation embodiment wherein in the combining the fumaric acid in MeOH is added to the baricitinib in DMSO. The aforesaid method wherein the combining is at about 50 °C. The aforesaid method wherein the isolating of the baricitinib co-crystal with fumaric acid is by filtering. The aforesaid method wherein the isolated baricitinib co-crystal with fumaric acid prepared is Form II. The aforesaid method wherein Form II baricitinib co-crystal with fumaric acid consists of one molecule of baricitinib and half a molecule of fumaric acid that is disordered in the cocrystal.

Furthermore, the present invention also relates to pharmaceutical compositions comprising Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid, and methods for treating disease using these forms. Pharmaceutical compositions comprising Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid may be prepared according to U.S. Patent No. 8420629, which is incorporated herein by reference in its entirety. The dosage of the pharmaceutical compositions may be varied over a wide range. Optimal dosages and dosage regimens to be administered may be readily determined by those skilled in the art, and will vary with the mode of

administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the patient being treated, including patient’s sex, age, weight, diet, physical activity, time of administration and concomitant diseases, will result in the need to adjust dosages and/or regimens. For example, a dosage of the pharmaceutical composition of the invention is available as 2 mg tablets. The recommended dose of baricitinib is 2 mg once daily and may be used as monotherapy or in combination with methotrexate or other DMARDs.

The present disclosure provides for a method of treating a disease comprising administering to a patient, in need thereof, a pharmaceutical composition comprising Form I baricitinib co-crystal with fumaric acid/DCM solvate or Form II baricitinib co- crystal with fumaric acid. Baricitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more TNF antagonist therapies. EXAMPLES

Examples, which follow herein, are directed to embodiments of the invention. The examples are presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various

embodiments are illustrative of the present disclosure and the disclosure is not intended to be limited to the examples described herein and shown.

Analytical Techniques

XRPD patterns are obtained using a Bruker D8 Advance equipped with a Cu Ka radiation source (l=1.54 A), a 9-position sample holder and a LYNXEYE super speed detector. Samples are placed on air sensitive silicon plate holders with zero-background with domes, for analysis. One skilled in the art would recognize that the °2Q values and the relative intensity values are generated by performing a peak search on the measured data and the r -spacing values are calculated by the instrument from the °2Q values using Bragg’s equation. One skilled in the art would further recognize that the relative intensity for the measured peaks may vary because of sample preparation, orientation and instrument used, for example.

DSC data are collected using a TA Instruments Q10 DSC. Approximately, samples (2-8 mg) are placed in unsealed but covered hermetic alodined aluminum sample pans and scanned from about 30 to about 300 °C at a rate of about 10 °C/min under a nitrogen purge of about 50 mL/min. Some of the DSC runs are generated on a TA Instruments Q2000 equipped with an auto-sampler and RSC40. The sampling is conducted at a ramp rate of about 10 °C/min from 20 °C to 320 °C using Tzero hermetic sealed aluminum sample pans in T4P (or T3) mode.

TGA measurements are recorded using TA Q500 instrument. Approximately, 2-5 mg samples are placed in a pin holed sealed hermetic alodined aluminum DSC pan, pre- tared with an aluminum pan. TGA investigations are performed at a heating rate of 10.0 °C/min over a temperature range of from about 30 to about 300 °C, with purging with nitrogen at a flow rate of 60 mL/min.

'H-NMR data is collected using a Bruker Avance 300 MHz NMR equipped with TopSpin software. Samples are prepared by dissolving the compound in deuterated dimethylsulfoxide with 0.05% (v/v) tetramethylsilane (TMS). The number of scans is 16 for 'H-NMR.

IR analysis is done by employing solid samples for FTIR using KBr pellet. The pellet is prepared by mixing KBr and the sample in 1 : 150 ratio (approximately 2-5 mg of the sample with 350 mg of KBr). Omnic software is used for the analysis and the samples are collected with 32 scans.

Crystalline morphology of samples is analyzed using an Olympus BX53 polarized light microscope (PLM) equipped with a PAXcam 3 digital microscope camera.

Experimental

Examples below provide embodiments of the preparation of co-crystal forms of baricitinib with fumaric acid.

Example 1

Preparation of Form I baricitinib co-crystal with fumaric acid/DCM solvate

About 74 mg of baricitinib and about 24 mg of fumaric acid are placed in about 7- 10 mL of 20% methanol in dichloromethane (DCM), and then about 3 mL methanol is added to facilitate the dissolution. The dissolution is carried out at about 45-50 °C to obtain a clear solution. The clear solution is left to evaporate. The crystals are identified as Form I baricitinib co-crystal with fumaric acid/DCM solvate.

Figure 1 represents the experimental and calculated XRPD patterns of Form I baricitinib co-crystal with fumaric acid/DCM solvate obtained by the instant method. Form I baricitinib co-crystal with fumaric acid/DCM solvate is characterized by its XRPD pattern peaks and their corresponding intensities that are listed in Table I below. Table I

The angle measurements are ± 0.2° 2Q. Key defining peaks or solid-state Form I baricitinib co-crystal with fumaric acid/DCM solvate include 7.8, 10.2, 15.9, 19.2, 19.9,

21.5, 25.9, and 27.7° 2Q degrees.

The TGA plot (Figure 2) shows a weight loss of about 2.5% from about 100 °C through about 175 °C for Form I baricitinib co-crystal with fumaric acid/DCM solvate. The DSC plot (Figure 3) shows a small thermal event at about 151 °C and another thermal event at about 207 °C for Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 4 is an 'H NMR spectra for Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 5 is directed to FT-IR spectra comparison of Form I baricitinib co-crystal with fumaric acid/DCM solvate versus that of baricitinib and fumaric acid. Figure 6 is directed to FT-IR spectra comparison of Form I baricitinib co crystal with fumaric acid/DCM solvate versus a physical mixture of baricitinib and fumaric acid.

The single crystal parameters for Form I baricitinib co-crystal with fumaric acid/DCM solvate as determined by SCXRD are:

Space Group: Monoclinic, P2i/C

a = 6.7Ά ± 1.5%

b = 12.9A ± 1.5%

c = 23.5A ±1.5% a = g = 90° ± 3°, b = 97° ± 3°

Volume: 2013 A ³ ± 3%

Z=4, Z’=l.

Figures 7A and 7B together represent the asymmetric unit of Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 7 A depicts the interaction between baricitinib and fumaric acid in Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 7B depicts the relationship between baricitinib and DCM in Form I baricitinib co-crystal with fumaric acid/DCM solvate.

Figures 8A and 8B together show the inter-molecular hydrogen bonding between baricitinib molecules and between baricitinib molecules and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate. Figure 8A shows the inter- molecular hydrogen bonding between baricitinib molecules in Form I baricitinib co crystal with fumaric acid/DCM solvate (fumaric acid not shown). Figure 8B shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form I baricitinib co-crystal with fumaric acid/DCM solvate (DCM not shown).

Example 2

Preparation of Form II baricitinib co-crystal with fumaric acid 100 mg of BCT in 0.5 mL of DMSO is dissolved at 60°C. 113 mg FUM in 2 mL of MeOH at 60°C is added slowly to the BCT solution. The mixture is then held at 5 °C.

After 18 h the precipitate is filtered, rinsed with MeOH and analyzed by XRPD. Form II baricitinib co-crystal with fumaric acid is isolated by filtration. Figure 9 represents the comparison of XRPD patterns of Form I baricitinib co-crystal with fumaric acid/DCM solvate and Form II baricitinib co-crystal with fumaric acid.

Example 3

Preparation of Form II baricitinib co-crystal with fumaric acid 1 g of BCT + 0.625 g of FEIM are dissolved in 2.5 mL of DMSO at 60 °C. A clear solution is obtained within 15 min. The temperature is reduced to 45 °C and 3 mL MeOH is added slowly (drop by drop). After 2 min, nucleation is observed. Then an additional 4 mL of MeOH is added and the mixture is then held at 5 °C and stirred for 18 h

(overnight). Form II baricitinib co-crystal with fumaric acid is isolated by filtration. Example 4

Preparation of Form II baricitinib co-crystal with fumaric acid 1 g of BCT + 0.625 g of FUM are dissolved in 2.5 mL of DMSO at 60 °C. A clear solution is obtained within 15 min. The temperature is reduced to 45 °C and 2.5 mL MeOH was added slowly (drop by drop). After 2.5 min, nucleation is observed. Then an additional 4.5 mL of MeOH is added and the mixture is then held at 25 °C and stirred for 18 h (overnight). Form II baricitinib co-crystal with fumaric acid is isolated by filtration. Example 5

Preparation of Form II baricitinib co-crystal with fumaric acid 1 g of BCT + 0.625 g of FUM are dissolved in 2.5 mL of DMSO at 60 °C. A clear solution is obtained within 15 min. The temperature is reduced to 45 °C and 1.5 mL H2O is added slowly (drop by drop). Within 1 min, nucleation is observed. 11.5 mL of H2O is added, and the mixture is then held at 25 °C and stirred for 18 h (overnight). Form II baricitinib co-crystal with fumaric acid is isolated by filtration.

Example 6

Preparation of Form II baricitinib co-crystal with fumaric acid 1 g of BCT + 0.625 g of FUM are dissolved in 2.5 mL of DMSO at 60 °C. A clear solution is obtained within 15 min. The temperature is reduced to 45 °C and 1.5 mL H2O is added slowly (drop by drop). Within 1 min, nucleation is observed. 11.5 mL of H2O is added, and the mixture is moved to 5 °C and stirred for 18 h (overnight). Form II baricitinib co-crystal with fumaric acid is isolated by filtration.

Example 7

Preparation of Form II baricitinib co-crystal with fumaric acid 8 g of BCT and 2.75 g of FUM are dissolved in 20 mL of DMSO in a EasyMax reactor at 60 °C with continuous stirring (500 rpm). The mixture is stirred for about 15- 20 min until a clear solution is obtained. (BCT:FUM ratio is 1 : 1.1). To the clear solution, 100 mL of water is charged at 1 mL/min. Once the addition of water is completed, the temperature of the reaction mixture is reduced to 5 °C at a rate of about 1 °C/min. After 9-10 min, nucleation is observed and within the next 20-30 minutes more solids appear in the reactor. The reaction mixture is stirred overnight (18- 20 h). The solids are filtered and the wet cake is rinsed with 10 mL of water and the final rinse with 15 mL of TBME. The sample is double bagged and dried in the oven at 45 °C over the weekend. A small portion of the wet cake is analyzed by XRPD. Yield = 86%. The wet cake and dried precipitate are analyzed by XRPD, and those XRPDs are compared to the calculated XRPD for Form II baricitinib co-crystal with fumaric acid. See Figure 10.

Form II baricitinib co-crystal with fumaric acid is characterized by its XRPD pattern peaks and their corresponding intensities that are listed in Table II below.

Table II

The angle measurements are ± 0.2° 2Q. Key defining peaks or solid-state Form II baricitinib co-crystal with fumaric acid include 7.8, 10.2, 13.8, 22.1 and 27.8 ° 2Q degrees.

Figure 11 shows the TGA plot that shows <1 % weight loss when heated to 200 °C for Form II baricitinib co-crystal with fumaric acid, and the DSC plot that shows a thermal event at about 212 °C. Figure 12 is directed to the 'H NMR for Form II baricitinib co-crystal with fumaric acid. Crystals of Form II baricitinib co-crystal with fumaric acid are examined by PLM (Figure 13).

Single crystals of Form II baricitinib co-crystal with fumaric acid are obtained by the instant method, and the single crystal parameters for Form II baricitinib co-crystal with fumaric acid as determined by SCXRD are:

Space Group: Monoclinic, P2i/C

a = 6.7Ά ± 1.5%

b = 12.8A ± 1.5%

C = 23.5A ± 1.5%

a = g = 90° ± 3°, b = 97° ± 3°

Volume: 2008A ³ ± 3%

Z=4, Z’ =1.

Figure 14 shows the asymmetric unit of Form II baricitinib co-crystal with fumaric acid. Figure 15 shows the inter-molecular hydrogen bonding between baricitinib and fumaric acid molecules in Form II baricitinib co-crystal with fumaric acid.

Example 8

Preparation of Form II baricitinib co-crystal with fumaric acid 8 g of BCT and 2.75 g of fumaric acid are dissolved in 20 mL of DMSO in a EasyMax reactor at 60 °C with continuous stirring (500 rpm). Within 5-10 min, a clear solution is obtained. (BCT :FETM ratio is 1 : 1.1)

To the clear solution, 100 mL of water is charged at 1 mL/min. Once the addition of water is completed, the temperature of the reaction mixture is reduced to 5 °C at the rate of 1 °C/min. After 10-15 min, nucleation is observed and within the next 20-30 minutes more solid appears in the reactor. After the addition of water is completed the reaction is left to stir for 5-6 h.

The precipitate is filtered and the wet cake is rinsed with 10-15 mL of water. The sample is double bagged and dried in the oven at 45 °C over the weekend. A small portion of the wet cake is analyzed by XRPD. Yield = 98%.

A small portion of the wet cake and dried precipitate are analyzed by XRPD, and those XRPDs are compared to the calculated XRPD for Form II baricitinib co-crystal with fumaric acid. See Figure 16. The above examples are presented to aid in the understanding of the disclosure and enable a person of ordinary skill in the art to make and use the various embodiments, and are not intended and should not be construed to limit in any way the disclosure set forth in the claims which follow hereafter.