WO2022106551A1

WO2022106551A1 - Co-crystals of a ror gamma inhibitor

Info

Publication number: WO2022106551A1
Application number: PCT/EP2021/082162
Authority: WO
Inventors: Joe Ju GAO; Corinne B. JANKOVSKY
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2020-11-19
Filing date: 2021-11-18
Publication date: 2022-05-27
Anticipated expiration: 2023-05-19

Abstract

The present invention relates to co-crystal forms of the following compound (I).

Description

CO-CRYSTALS OF A ROR GAMMA INHIBITOR

BACKGROUND OF THE INVENTION

The present invention relates to co-crystal forms of the following compound (I)

which is an inhibitor of RORy (retinoic acid receptor related orphan receptor gamma) that can be used for the treatment of (chronic) inflammatory diseases. The co-crystal forms of compound (I) of the present invention show good formulation properties such as high kinetic dissolution and high crystallinity.

RORy is a transcription factor belonging to the steroid hormone receptor superfamily (review in Jetten 2006, Adv. Dev. Boil. 16: 313-355). RORy has been identified as a transcriptional factor that is required for the differentiation of T cells and secretion of Interleukin 17 (IL-17) from a subset of T cells termed Thn cells (Ivanov 2006, Cell, 126, 1121-1133).

The rationale for the use of a RORy targeted therapy for the treatment of chronic inflammatory disesases is based on the emerging evidence that Thn cells and the cytokine IL-17 contribute to the initiation and progression of the pathogenesis of several diseases. Inhibitors of RORy are known from, for example, WO2015/160654 or WO2013/169704.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : A) XRPD-Spectrum from 5-30 °29 of fumarate co-crystal of compound (I)

B) XRPD-Spectrum from 5-30 °29 of gentisic acid co-crystal of compound (I)

C) XRPD-Spectrum from 5-30 °29 of hydroxybenzamide monohydrate cocrystal of compound (I)

Figure 2: A) DSC trace of crystalline of fumarate co-crystal of compound (I)

B) DSC trace of crystalline of gentisic acid co-crystal of compound (I)

C) DSC trace of crystalline of hydroxybenzamide monohydrate co-crystal of compound (I)

Figure 3: A) TGA trace of crystalline of fumarate co-crystal of compound (I) B) TGA trace of crystalline of gentisic acid co-crystal of compound (I)

C) TGA trace of crystalline of hydroxybenzamide monohydrate co-crystal of compound (I)

Figure 4: A) 13C-ss-NMR-Spectrum of fumarate co-crystal of compound (I)

B) 13C-ss-NMR-Spectrum of gentisic acid co-crystal of compound (I)

C) 13C-ss-NMR-Spectrum of of hydroxybenzamide monohydrate co-crystal of compound (I)

Figure 5: A) Trace of kinetic solubility measurement of fumarate co-crystal of compound (I)

B) Trace of kinetic solubility measurement of gentisic acid co-crystal of compound (I)

C) Trace of kinetic solubility measurement of hydroxybenzamide monohydrate co-crystal of compound (I)

Figure 6: A) DVS isotherm of fumarate co-crystal of compound (I)

B) DVS isotherm of gentisic acid co-crystal of compound (I)

C) DVS isotherm of hydroxybenzamide monohydrate co-crystal of compound (I)

DETAILED DESCRIPTION OF THE INVENTION

The development of medicaments containing a given active pharmaceutical ingredient for different patient groups requires the adaption of the pharmaceutical compositions to the need of the specific patient populations. Small children, for example, will often not be able to swallow tablets sized for adults, or there might be patient populations that require a dissoluble formulation.

During the development process of a new active pharmaceutical ingredient for oral delivery, solubility data are used to make key decisions on the developability throughout the process.

Thermodynamic solubility of a compound is the concentration of the compound in solution when excess solid is present at constant temperature and pressure. Thermodynamic solubility, also termed equilibrium solubility, represents the saturation and therefore the maximal, time-independent concentration of a compound in equilibrium with an excess of undissolved solid phase and is an intrinsic property that affects the potential for drug absorption after oral administration.

In addition to thermodynamic solubility of a drug, which represents an equilibrium measure, the rate at which solid drug passes into solution, also termed dissolution rate or kinetic solubility, is important in drug absorption and therefore in pharmaceutical development. Kinetic solubility is therefore an important factor when evaluating the impact of specific physical forms of a certain compound on its absorption in the intestine. Forms of higher energy than the thermodynamically most stable form (which are also called “metastable forms”) can exist as specific polymorphs, hydrates, solvates, co-crystals, salt or amorphous forms of a certain compound. The so-called supersaturated state where upon dissolution the amount of drug dissolved exceeds the equilibrium solubility in a medium can be more pronounced in these forms of higher energy. This effect of supersaturation can be applied in a formulation strategy to achieve increased drug concentrations in the intestinal lumen. The intestinal supersaturation can also occur when a basic drug (that may be the thermodynamically most stable form or metastable form) is dissolved in the acidic gastric fluids, and is then transferred into the intestinal lumen, which has a higher pH (Strindberg et al., European Journal of Pharmaceutics and Biopharmaceutics 151 (2020) 108-115).

However, supersaturation is not predictable, neither with regard to the amount of dissolved drug nor with regard to the duration of supersaturation.

The duration of the supersaturated state should exceed the rate of transit time in the intestinal lumen for absorption to be optimal. By increasing the concentration of a drug at the absorption site, enhancing the intestinal absorption may be possible and the increase in intestinal drug concentration has the potential to increase drug bioavailability.

As the transit time of substances through the small intestine is usually between 0-6 h (Hua, Frontiers in Pharmacology 2020 (524)) depending on the dietary state of the person, once supersaturation is achieved, it should be maintained for another at least 60 min, preferably at least 70 min, most preferably at least 90 min.

Surprisingly is has been found that the co-crystals of compound (I) of the present invention have the required properties.

ABBREVIATIONS AND DEFINITIONS

API Active pharmaceutical ingredient

DHBA 2,5-Dihydroxybenzoic acid, also known as gentisic acid

DSC Differential scanning calorimetry

DVS Dynamic vapour sorption

FaSSIF fasted state simulated intestinal media

HBA Hydroxybenzamide ppm Parts per million

RT Room temperature

RORy Retinoic acid receptor related orphan receptor gamma

SS-NMR Solid state nuclear magnetic resonance

TGA Thermogravimetric analysis

Torr Unit of pressure; 1 torr equals 133.32 Pa

WL Wave Length

XRPD X-Ray Powder Diffraction Supersaturation ratio: The supersaturation ratio is the ratio of the concentration of solute in solution, at a given time, in the kinetic solubility experiment to the solute's equilibrium solubility in the same media.

The term “substantially pure” as used herein means at least 95% (w/w) pure, preferably 99% (w/w) pure, where 95% (w/w) pure means not more than 5% (w/w), and 99% (w/w) pure means not more than 1% (w/w), of any other form of the Compound (I) being present (other crystalline form, amorphous form, co-crystal, salt forms or similar).

EXPERIMENTAL DETAILS

Production of compound (I)

The synthesis of the compound of formula (I) is known from WO2015/160654.

Production of fumarate co-crystal of compound (I)

The fumarate-compound I co-crystal was obtained by dissolution of compound (I) and fumaric acid in hot 2-butanone (around 70 °C). Cool to room temperature. The fumarate cocrystal of compound (I) is then isolated by filtration and dried under vacuum (around 200 tor) at 50 °C for 18 h.

Alternatively, the fumarate-compound I co-crystal can be obtained by adding heptane to the hot 2-butanone as antisolvent before cooling to room temperature, then following the steps outlined above.

Production of gentisic acid co-crystal of compound (I)

The gentisic acid (2,5-Dihydroxybenzoic acid) co-crystal of compound (I) was produced by dissolution of the crystalline form of compound (I) and gentisic acid (1 equivalent compound (I) and 1.1 equivalent gentisic acid) in ethyl acetate, followed by a cooling crystallization. The filtrated solid was dried under vacuum (approx 200 tor) at 50 °C for 18h.

Production of hydroxybenzamide monohydrate co-crystal of compound (I)

The hydroxybenzamide monohydrate co-crystal of compound (I) was produced by dissolution of the crystalline form of compound (I) and 4-Hydroxybenzamide (4 equivalents compound (I) and 1 equivalent 4-hydroxybenzamid) in 10 equivalents ACN-H2O (9: 1 vol/vol) at 70 °C, followed by cooling the solution to room temperature and isolation of the solid by filtration. The filtrated solid was dried under vacuum (approx 200 tor) at 50 °C for 18h.

Kinetic solubility measurements

The kinetic solubility of each solid form was measured using the small scale pDiss Profiler dissolution apparatus (Pion Inc., Billerica, MA) with in situ fiber optic UV probes for real time detection. Approximately 4 mg of active drug substance were added to 20 mL of fasted simulated intestinal media (using commercially available FaSSIF powder from Biorelevant, Inc.) preheated at 37 °C and stirred at a speed of 150 RPM (rotations per minute) throughout the experiment.

The UV spectra (200-720 nm) was recorded at specified time intervals throughout the experiment and the concentration of the dissolved drug was calculated using the AUC (area under curve) of the second derivative spectra between 328-335 nm. This second derivative of the UV spectra was used to normalize the effects of turbidity during the experiment. Equilibrium solubility values for calculation of the supersaturation ratio were taken after 24 h from the Pion System.

For the fumarate-compound I-co-crystal, the kinetic solubility measurement yielded a maximum concentration of 114 pg/ml, reaching a supersaturation ratio of 9, the equilibrium solubility being 13 pg/ml. An exemplary trace from 0 - 200 min can be seen in Figure 5 A, showing that supersaturation is maintained for at least 60 min.

For the gentisic acid-compound I-co-crystal, the kinetic solubility measurement yielded a maximum concentration of 195 pg/ml, reaching in a supersaturation ratio of 19, the equilibrium solubility being 10 pg/ml. An exemplary trace of kinetic solubility experiment from 0 - 200 min can be seen in Figure 5B, showing that supersaturation is maintained for at least 60 min.

For the hydroxybenzamide monohydrate co-crystal of compound I, the kinetic solubility measurement yielded a maximum concentration of 162 pg/ml, reaching in a supersaturation ratio of 12, the equilibrium solubility being 13 pg/ml. An exemplary trace of kinetic solubility experiment from 0 - 200 min can be seen in Figure 5C, showing that supersaturation is maintained for at least 60 min.

X-Ray Powder Diffraction (XRPD) Diagram

The data underlying the diagrams in figure 1 was obtained on a Bruker AXS X-Ray Powder Diffractometer Model D8 Advance, using Cu K_ai radiation (1.54A) in parafocusing mode with a graphite monochromator and a scintillation detector. The pattern was obtained by scanning over a range of 2°- 35° 20, step size of 0.05° 20, with a step time of 4 sec per step. Table 1 displays the X-ray powder diffraction (XRPD) characteristic peaks for the fumarate co-crystal form of compound (I).

Table 2 lists the X-ray powder diffraction (XRPD) characteristic peaks for the gentisic acid co-crystal form of compound (I).

The data to determine the crystal system of the gentisic acid-compound (I) co-crystal were collected on a Bruker D8 Advance diffractometer using Cu K_ai radiation (1.54A) with germanium monochromator at RT. Diffraction data were collected in the 20 range 2-41 ° 20. Detector sea on solid state LynxEye detector was performed using 0.016 ° per step with 2sec/step scan speed. The crystal system has a monoclinic space group P2i. The determined unit cell parameters were: a =19.5272(8) A, b = 7.3828(4) A, c = 24.1229(9) A p = 90.688(3)°, V = 3477.4(3 )A³, Z = 4

Table 3 displays the X-ray powder diffraction (XRPD) characteristic peaks for the hydroxybenzamide co-crystal form of compound (I).

The values in Table 1-3 are reported with a margin of error of ± 0.2° 20. Since some margin of error is possible either due to the sample preparation or the assignment of peaks, the preferred method of determining whether an unknown form of compound (I) is a form described in the present application is to overlay the XRPD spectrum of the sample over the XRPD spectrum provided for the respective form.

Single crystal X-Ray Diffraction analysis

The crystal structures of the crystals mentioned below in detail were solved by single crystal X-Ray diffraction analysis. For this, a crystal, with approximate dimensions of 0.1 x 0.1 x 0.05 mm was selected, mounted on a MicroMount and centered on a Bruker X8 Prospector diffractometer equipped with a CuKal Ips microsource and an APEXII CCD detector. Three batches of 30 frames separated in reciprocal space were obtained to provide an orientation matrix and initial cell parameters. Final cell parameters were obtained and refined based on the full data set. A diffraction data set of reciprocal space was obtained to a resolution of 0.84 A using 1.0° 2 0 steps with 30 s exposure for each frame. Data were collected at 100 K. Integration of intensities and refinement of cell parameters was accomplished using APEX2 software. Observation of the crystal after data collection showed no signs of decomposition.

The fumaric acid-compound (I) co-crystal has a triclinic crystal system of space group P 1.

The determined unit cell parameters were: a = 10.564(6) A, b = 13.516(7) A, c = 21.417(11) A a = 86.174(12)°, p = 77.65(2)°, y = 88.716(11) °, V = 2981(3) A³, Z = 2

There are four molecules of compound (I) and two molecules of fumaric acid in the unit cell of the co-crystal.

The hydroxybenzamid-compound (I) co-crystal monohydrate has a triclinic crystal system of space group P 1. The determined unit cell parameters were: a = 10.6326(4) A, b = 12.9512(4) A, c = 13.7855(4) A a = 70.3004(14)°, p = 71.5259(16)°, y = 83.0683(15)°, V = 1694.92A³, Z = 2

There are two molecules of compound (I), two molecules of 4-Hydroxybenzamide and two molecules of water in the unit cell of the co-crystal.

DSC analysis

DSC analysis was performed with a calibrated differential scanning calorimeter (DSC Q2000 or 2500, TA instruments, New Castle, Delaware, USA). About 5 mg of powder of substantially pure test substance was weighted in a crimped aluminum pan with a pin hole. The sample was heated at 10K per minute from 22°C to 250°C. The melting point for the fumaric acid-compound (I) co-crystal as determined by DSC is 185 °C ± 5 °C, for a product with higher puritiy, e.g. substantially pure co-crystals, the margin of error is ± 3°C. An exemplary DSC trace can be seen in Figure 2A.

The DSC analysis of the hydroxybenzamid monohydrate-compound (I) co-crystal shows broad endothermic events with an extrapolated onset temperature of 109.9°C due to melting and removal of water. The melting point can be stated as 125 °C ± 5 °C, for a product with higher puritiy, e.g. substantially pure co-crystals, the margin of error is ± 3°C. An exemplary DSC trace can be seen in Figure 2B.

The melting point for the gentisic acid-compound (I) co-crystal as determined by DSC is 169 °C ± 5 °C, for a product with higher puritiy, e.g. substantially pure co-crystals, the margin of error is ± 3°C. An exemplary DSC trace can be seen in Figure 2C.

Thermogravimetric analysis

TGA data were collected on a a thermogravimetric analyzer (TGA Q500 or 550, TA instruments, New Castle, Delaware, USA). 1-5 mg of sample are loaded onto the tared TGA pan and heated at a heating rate of 10 K per minute from 22 °C to 300 °C under dry nitrogen. Exemplary traces of the co-crystals of compound (I) are depicted in figure 3 (3 A: Fumaric acid co-crystal, 3B: gentisic acid co-crystal, 3C: hydroxybenzamid monohydrate co-crystal). The analysis of the fumaric acid-compound (I) co-crystal showed a mass loss of < 1.0 % (w/w) in the range 40-160°C. Thermal decomposition occurred above 180°C.

The analysis of the hydroxybenzamid-compound (I) co-crystal detected a weight loss of 2.67% (w/w) up to 150°C, indicating a monohydrate (2.62 % for one water molecule). Decomposition starting around 150 °C.

The analysis of the gentisic acid co-crystal revealed a weight loss of < 1.0 % (w/w) up to 175°C. The sample decomposed above 160 °C.

Dynamical vapor sorption (DVS)

Water sorption isotherms are determined using a dynamic vapor sorption system (Advantage, DVS, London, UK). The samples are subjected to relative humidity (RH) values between 0% RH - 90% RH in a stepwise manner with a step size of 10% at 25°C. Each sample is equilibrated at each RH step for at least 60 min, and equilibrium is assumed if weight increase is less than 0.1% within one minute, and the maximum duration on each RH is 6 hours.

The fumaric acid-compound (I) co-crystal takes up < 1 % water at 90 % RH, see figure 6A (where a water uptake less than 0.2% is depicted).

The gentisic acid-compound (I) co-crystal takes up < 1.2 % water at 90 % RH, see figure 6B (where a water uptake less than 1% is depicted).

The HBA-monohydrate-compound (I) co-crystal takes up < 1 % water at 90 % RH, see figure 6C (where a water uptake less than 0.4% is depicted).

Solid-state NMR (SSNMR)

¹³C Solid-state NMR (SSNMR) data for samples of Form I, is acquired on a Bruker Avance III HD NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) at 11.7 T (¹H=500.28 MHz, ¹³C=125.81 MHz). Samples are packed in 4 mm O.D. zirconia rotors with Kel-F(R) drive tips. A Bruker model BL4 VTN probe is used for data acquisition and sample spinning about the magic-angle (54.74 degrees). Sample spectrum acquisition uses a spinning rate of 12 kHz. A standard cross-polarization pulse sequence is used with a ramped Hartman- Hahn match pulse on the proton channel at ambient temperature and pressure. The pulse sequence uses an 8 millisecond contact pulse and a 6 second recycle delay. SPINAL64 decoupling and TOSS sideband suppression are also employed in the pulse sequence. No exponential line broadening is used prior to Fourier transformation of the free induction decay. Chemical shifts are referenced using the secondary standard of adamantane, with the low frequency resonance being set to 29.5 ppm. The magic-angle is set using the ⁷⁹Br signal from KBr powder at a spinning rate of 5 kHz. Exemplary ¹³C SSNMR spectrum of the different Co-Crystal forms are found in Figure 4. Table 4 includes the chemical shifts obtained from the ¹³C SSNMR spectrum acquired for the fumaric acid co-crystal of compound I, table 5 for the gentisic acid co-crystal of compound I, table 6 for the hydroxybenzamide monohydrate co-crystal of compound I.

The values reported in Tables 4-6 have a margin of error of ± 0.2 ppm. Since some margin of error is possible due to sample preparation and in the assignment of chemical shifts, the preferred method of determining whether an unknown form of compound (I) is a form described in the present application is to overlay the ¹³C SSNMR spectrum of the sample over the ¹³C SSNMR spectrum provided for the respective form.

GENERAL ADMINISTRATION AND PHARMACEUTICAL COMPOSITIONS

When used as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and generally comprise at least one com- pound of the invention and at least one pharmaceutically acceptable carrier. The compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased antagonist activity, provide adjunct therapy, and the like.

The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. In general, the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes.

Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, orally, buc- cally (e.g., sublingually), nasally, parenterally, topically, transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), American Pharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish, Pharmaceutical.

Suitable tablets may be obtained, for example, by mixing one or more compounds of the invention with known excipients, for example inert diluents, carriers, disintegrates, adjuvants, surfactants, binders and/or lubricants. Examples for suitable tablets are

A standard hypromellose film-coat can be applied on tablet cores e.g. as found in Kurt H. Bauer, Karl-Heinz Frbmming, Claus Fiihrer; Pharmazeutische Technologic, 5. Auflage, Gustav Fischer Verlag Stuttgart 1997.

Pharmaceutical compositions according to the present invention can be used for the treatment of an inflammatory disease, including but not limited to autoimmune and allergic dis- eases.

THERAPEUTIC USE

RORy is a transcription factor belonging to the steroid hormone receptor superfamily (review in Jetten 2006, Adv. Dev. Biol. 16: 313-355). RORy has been identified as a transcriptional factor that is required for the differentiation of T cells and secretion of Interleukin 17 (IL-17) from a subset of T cells termed Thn cells (Ivanov 2006, Cell, 126, 1121-1133). The rationale for the use of a RORy targeted therapy for the treatment of chronic inflammatory disesases is based on the emerging evidence that Thn cells and the cytokine IL-17 contribute to the initiation and progression of the pathogenesis of several diseases.

The present invention is therefore directed to co-crystals of compound (I) which are useful in the treatment of a disease and/or condition wherein the activity of RORy modulators is of therapeutic benefit, including but not limited to the treatment of autoimmune or allergic disorders. Such disorders include for example: rheumatoid arthritis, psoriasis, psoriasis vulgaris, generalized pustular psoriasis (GPP), erythrodermic psoriasis (EP), systemic lupus erythromatosis, lupus nephritis, systemic sclerosis, vasculitis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, type I diabetes, Crohn’s disease, ulcerative colitis, graft versus host disease, axial spondyloarthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, atherosclerosis, uveitis and non-radiographic spondyloarthropathy, non-alcoholic steato- hepatitis.

Claims

WHAT WE CLAIM

1. Co-crystal forms of the following compound (I),

in which the co-crystal is formed between compound (I) and a selection from the group consisting of fumaric acid, gentisic acid and hydroxybenzamid monohydrate.

2. Co-crystal according to claim 1, in which the co-crystal is a fumaric acid - compound (I) co-crystal, characterized by having an x-ray diffraction pattern comprising peaks at 10.7 ± 0.2, 13.3 ± 0.2, 16.1± 0.2 and 17.0 ± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu K_ai source.

3. Co-crystal according to claim 2, characterized by having an x-ray diffraction pattern comprising additional peaks at 8.0± 0.2, 12.4 ± 0.2, 15.6± 0.2 and 18.4± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu K_ai source.

4. Co-Crystal according to any one of claims 2 or 3, characterized by having a desolid state NMR spectrum comprising chemical shifts at 170.5 ± 0.2, 169.8 ± 0.2, 136.6 ± 0.2, 58.7± 0.2, 56.7± 0.2, 56.2 ± 0.2 ppm, referenced to adamantine with the low frequency resonance being set to 29.5 ppm.

5. Co-Crystal according to claim 4, characterized by having a ¹³C-solid state NMR spectrum comprising additional chemical shifts at 156.6 ± 0.2, 156.1 ± 0.2, 155.7 ± 0.2, 127.5 ± 0.2, 126.1 ± 0.2, 125.7 ± 0.2, 22.9 ± 0.2, 22.2 ± 0.2, 21.5 ± 0.2, 21.0 ± 0.2 ppm, referenced to adamantine with the low frequency resonance being set to 29.5 ppm.

6. Co-crystal according to any one of claims 2-5 characterized by having a melting point of 180 °C ± 5 °C.

7. Co-crystal according to any one of claims 2-6 characterized in that it maintains a supersaturated state for at least 60 min.

8. Co-crystal according to claim 1, in which the co-crystal is a gentisic acidcompound (I) co-crystal, characterized by having an x-ray diffraction pattern comprising peaks at 5.8 ± 0.2,

9.3 ± 0.2, 11.8 ± 0.2 and 16.7± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu K_ai source. Co-crystal according to claim 8, characterized by having an x-ray diffraction pattern comprising additional peaks at 13.8 ± 0.2, 14.7± 0.2, 18.0 and 19.9 ± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu K_ai source. Co-Crystal according to any one of claims 8 or 9, characterized by having a desolid state NMR spectrum comprising chemical shifts at 172.2 ± 0.2, 171.4 ± 0.2, 164.8 ± 0.2, 164.0 ± 0.2, 137.0 ± 0.2, ± 0.2 ppm, 117.7 ± 0.2, 116.7 ± 0.2, 53.1 ± 0.2 ppm referenced to adamantine with the low frequency resonance being set to 29.5 ppm. Co-Crystal according to claim 10, characterized by having a ¹³C-solid state NMR spectrum comprising additional chemical shifts at 147.6 ± 0.2, 146.4 ± 0.2, 112.2 ± 0.2, 110.9 ± 0.2, 23.1 ± 0.2 ppm, referenced to adamantine with the low frequency resonance being set to 29.5 ppm. Co-crystal according to any one of claims 8-11, characterized by having a melting point of 165 °C ± 5 °C. Co-crystal according to any one of claims 8-12, characterized in that it maintains a supersaturated state for at least 60 min. Co-crystal according to claim 1, in which the co-crystal is a hydroxybenzamide- compound (I) co-crystal, characterized by having an x-ray diffraction pattern comprising peaks at 13.4 ± 0.2, 16.8 ± 0.2, 15.8± 0.2 and 18.0 ± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu K_ai source. Co-crystal according to claim 14, characterized by having an x-ray diffraction pattern comprising additional peaks at 7.1 ± 0.2, at 8.8 ± 0.2, 11.7± 0.2 and 13.8± 0.2 °29 as measured by x-ray powder diffraction using a Cu K_ai source. Co-Crystal according to any one of claims 14 or 15, characterized by having a desolid state NMR spectrum comprising chemical shifts at 169.8 ± 0.2, 165.6 ± 0.2, 162.4 ± 0.2, 127.9 ± 0.2, 47.7, 45.9 ± 0.2 ppm referenced to adamantine with the low frequency resonance being set to 29.5 ppm. Co-Crystal according to claim 16, characterized by having a ¹³C-solid state NMR spectrum comprising additional chemical shifts at 160.6 ± 0.2, 117.2 ± 0.2, 116.0 ± ± 0.2 ppm, referenced to adamantine with the low frequency resonance being set to 29.5 ppm. Co-crystal according to any one of claims 14-17, characterized by having a melting 16 point of 125 °C ± 5 °C. Co-crystal according to any one of claims 14-18, characterized in that it maintains a supersaturated state for at least 60 min. Pharmaceutical composition, characterized in that it comprises a co-crystal according to any one of claims 1 to 19. Pharmaceutical composition according to claim 20, characterized in that is used in the treatment of an inflammatory disease. Pharmaceutical composition according to claim 21, characterized in that is selected from among the group consisting of: rheumatoid arthritis, psoriasis, psoriasis vulgaris, generalized pustular psoriasis (GPP), erythrodermic psoriasis (EP), systemic lupus erythromatosis, lupus nephritis, systemic sclerosis, vasculitis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, type I diabetes, Crohn’s disease, ulcerative colitis, graft versus host disease, axial spondyloarthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, atherosclerosis, uveitis and nonradiographic spondyloarthropathy, non-alcoholic steatohepatitis.