WO2022106548A1 - Solid forms of a ror gamma inhibitor - Google Patents
Solid forms of a ror gamma inhibitor Download PDFInfo
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- WO2022106548A1 WO2022106548A1 PCT/EP2021/082159 EP2021082159W WO2022106548A1 WO 2022106548 A1 WO2022106548 A1 WO 2022106548A1 EP 2021082159 W EP2021082159 W EP 2021082159W WO 2022106548 A1 WO2022106548 A1 WO 2022106548A1
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- compound
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- crystalline form
- solid
- adamantane
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- 239000003112 inhibitor Substances 0.000 title description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- the present invention relates to alternative forms of the following compound (I) which is an inhibitor of RORy (retinoic acid receptor related orphan receptor gamma) and which can be used for the treatment of (chronic) inflammatory diseases.
- RORy retinoic acid receptor related orphan receptor gamma
- the presented forms of compound (I) of the present invention show good formulation properties such as high kinetic dissolution.
- 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).
- IL-17 Interleukin 17
- 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.
- thermodynamic solubility of a drug which represents an equilibrium measure
- 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.
- 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).
- a basic drug that may be the thermodynamically most stable form or metastable form
- the duration of the supersaturated state should exceed the rate of transit time in the intestinal lumen for absorption to be optimal.
- 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.
- Torr Unit of pressure 1 torr equals 133.32 Pa
- 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.
- substantially pure 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).
- the spray solution was then delivered into a drying chamber and the spray-dried dispersion was. After spray drying, the material was collected into glass bottle and stored at refrigerated condition.
- the toluene solvate was produced by evaporative crystallization which included suspension of the amorphous form of compound (I) in toluene, incubation at 50 °C for 1 week, separation of the solids from the liquid phases by centrifugation and drying at ambient conditions and under vacuum (around 200 torr) at room temperature.
- the polymorph form V of compound (I) was produced by desolvation of toluene solvate under vacuum (around 200 tor) at room temperature.
- the methyl benzoate solvate of compound (I) was produced by cooling crystallization from a saturated solution of compound in methyl benzoate, followed by drying under vacuum (around 200 tor) at room temperature.
- the polymorph form III of compound (I) was produced by solvent-mediated conversion form the methyl benzoate form of compound (I) in 2-propanol followed by a cooling crystallization in 2-propanol and 1 -butanol, followed by drying under vacuum (around 200 tor) at room temperature. Production of methanol solvate form of compound (I)
- the methanol solvate was produced by solvent-mediated form conversion from the methyl benzoate form of compound (I), followed by a cooling crystallization in methanol followed by drying under vacuum (around 200 tor) at room temperature.
- the ethanol solvate was produced by solvent-mediated form conversion from the methyl benzoate form of compound (I), followed by a cooling crystallization in ethanol followed by drying under vacuum (around 200 tor) at RT.
- Table 2 includes the XRPD characteristic peaks for the crystalline form V of compound (I).
- Table 3 includes the XRPD characteristic peaks for the methanol solvate of compound (I), table 4 those for the ethanol solvate of compound (I), table 5 for the methyl benzoate solvate of compound (I), table 6 for the toluene solvate of compound (I).
- a crystal, obtained from ethanol, 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.
- Form III of compound (I) showed 4 molecules in 1 unit cell in an orthorhombic crystal system of space group P2i2i2i.
- DSC analysis was performed with a differential scanning calorimeter (DSC Q2000 or 2500, TA instruments, New Castle, Delaware, USA). About 5 mg of powder 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 DSC analysis for the Form III of compound (I) shows endothermic events at 159 °C ⁇ 5 °C and 188 °C ⁇ 5 °C, an exemplary trace is depicted in figure 2A.
- the DSC analysis for the Form V of compound (I) shows endothermic events at 126 °C ⁇ 5 °C and 189 ⁇ 5 °C , an exemplary trace is depicted in figure 2B.
- the DSC analysis for the ethanol solvate of compound (I) shows endothermic events at 107 °C ⁇ 5 °C and 190 °C ⁇ 5 °C, an exemplary trace is depicted in figure 2C.
- the DSC analysis for the methanol solvate of compound (I) shows endothermic events at 127 °C ⁇ 5 °C and 189 °C ⁇ 5 °C, an exemplary trace is depicted in figure 2D.
- the DSC analysis for the methyl benzol solvate of compound (I) shows an endothermic event at 94 °C ⁇ 5 °C, an exothermic event at 100 °C ⁇ 5 °C and an endothermic event at 189 °C ⁇ 5 °C, an exemplary trace is depicted in figure 2E.
- the DSC analysis for the toluene solvate of compound (I) shows an endo- /exothermic event at 101 °C ⁇ 5 °C and an endothermic event at 188 °C ⁇ 5 °C, an exemplary trace is depicted in figure 2F.
- TGA data were collected on 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 maximal 300 °C under dry nitrogen.
- An exemplary TGA trace of the crystalline form III of compound (I) is depicted in figure 3 A and shows a mass loss of ⁇ 1.0 % (w/w) up to 180 °C.
- An exemplary TGA trace of the crystalline form V of compound (I) is depicted in figure 3B and shows a mass loss of ⁇ 1.0 % (w/w) up to 150 °C.
- FIG. 3C An exemplary TGA trace of the ethanol solvate of compound (I) is depicted in figure 3C and shows a mass loss of 7.7 % (w/w) up to 175 °C.
- FIG. 3D An exemplary TGA trace of the methanol solvate of compound (I) is depicted in figure 3D and shows a mass loss of 5.5 % (w/w) up to 140 °C.
- FIG. 3E An exemplary TGA trace of the methyl benzoate solvate of compound (I) is depicted in figure 3E and shows a mass loss of 19 % (w/w) up to 200 °C.
- FIG. 3F An exemplary TGA trace of the toluene solvate of compound (I) is depicted in figure 3F and shows a mass loss of 11 % (w/w) up to 180 °C.
- Polymorph form III of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 %.
- An exemplary DVS isotherm can be found in Figure 4A (depicting .
- Polymorph form V of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 %.
- An exemplary DVS isotherm can be found in Figure 4B.
- the ethanol solvate form of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 % and is therefore non-hygroscopic.
- An exemplary DVS isotherm can be found in Figure 4C.
- the methanol solvate form of compound (I) showed more than 1.5 % weight gain up to a relative humidity of 90 % and is therefore hygroscopic.
- An exemplary DVS isotherm can be found in Figure 4D.
- the methyl benzoate solvate form of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 % and is therefore non-hygroscopic.
- An exemplary DVS isotherm can be found in Figure 4E.
- the toluene solvate form of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 % and is therefore non-hygroscopic.
- An exemplary DVS isotherm can be found in Figure 4F.
- 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.
- 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.
- the kinetic solubility measurement yielded a maximum concentration of 168 pg/ml between 0 and 200 min, reaching a supersaturation ration of 3.6, the equilibrium solubility being 47 p/ml.
- An exemplary trace of the kinetic solubility experiment from 0-200 min can be found in Figure 6C.
- the kinetic solubility measurement yielded a maximum concentration of 104 pg/ml between 0 and 200 min, reaching a supersaturation ration of 6.1, the equilibrium solubility being 17 pg/ml.
- An exemplary trace of the kinetic solubility experiment from 0-200 min can be found in Figure 6D.
- 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 79 Br signal from KBr powder at a spinning rate of 5 kHz.
- FIG. 5A An exemplary 13 C SSNMR spectrum of form III of compound I is shown in Figure 5A, of form V of compound I in Figure 5B, of amorphous form of compound (I) in Figure 5C, of spray-dried dispersion in Figure 5D.
- Table 7 includes the chemical shifts shifts obtained from the 13 C SSNMR spectrum acquired for the amorphous form of compound (I), and Table 8 those acquired for the amorphous solid dispersion.
- Table 9 includes the chemical shifts obtained from the 13 C SSNMR spectrum acquired for the form III of compound (I), and Table 10 those acquired for the form V.
- the values reported in Tables 7 and 8 have a margin of error of ⁇ 0.5 ppm, the values reported in Tables 9 and 10 have a margin of error of ⁇ 0.2 ppm.
- the preferred method of determining whether an unknown form of compound (I) is a form described in the present application is to overlay the solid state NMR spectrum of the sample over the solid state NMR spectrum provided for the respective form.
- 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 compound 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.
- 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.
- 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; Pharmazeutician Technologic, 5. Auflage, Gustav Fischer Verlag Stuttgart 1997.
- compositions according to the present invention can be used for the treatment of an inflammatory disease, including but not limited to autoimmune and allergic diseases.
- 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.
- IL-17 Interleukin 17
- the present invention is therefore directed to alternative forms 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, pso- riasis 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
Abstract
The present invention relates to alternative forms of the following compound (I)
Description
SOLID FORMS OF A ROR GAMMA INHIBITOR
BACKGROUND OF THE INVENTION
The present invention relates to alternative forms of the following compound (I)
which is an inhibitor of RORy (retinoic acid receptor related orphan receptor gamma) and which can be used for the treatment of (chronic) inflammatory diseases. The presented forms of compound (I) of the present invention show good formulation properties such as high kinetic dissolution.
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. Inhibitors of RORy are known from, for example, WO2015/160654 or WO2013/169704.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 - XRPD spectra from 5-30 °29
A) Polymorph III of compound (I)
B) Polymorph Form V of compound (I)
C) Ethanol solvate of compound (I)
D) Methanol solvate of compound (I)
E) Methyl benzoate of compound (I)
F) Toluene solvate of compound (I)
Figure 2 - DSC traces
A) Polymorph III of compound (I)
B) Polymorph Form V of compound (I)
C) Ethanol solvate of compound (I)
D) Methanol solvate of compound (I)
E) Methyl benzoate of compound (I)
F) Toluene solvate of compound (I)
G) Amorphous form of compound (I)
Figure 3 - TGA traces
A) Polymorph III of compound (I)
B) Polymorph Form V of compound (I)
C) Ethanol solvate of compound (I)
D) Methanol solvate of compound (I)
E) Methyl benzoate of compound (I)
F) Toluene solvate of compound (I)
G) Amorphous form of compound (I)
Figure 4 - DVS isotherms
A) Polymorph III of compound (I)
B) Polymorph Form V of compound (I)
C) Ethanol solvate of compound (I)
D) Methanol solvate of compound (I)
E) Methyl benzoate of compound (I)
F) Toluene solvate of compound (I) Figure 5 - 13C-SSNMR spectra
A) Polymorph III of compound (I)
B) Polymorph V of compound (I)
C) Amorphous form of compound (I)
D) Spray-dried amorphous solid dispersion of compound (I)
E) KinetiSol®-based amorphous solid dispersion of compound (I) Figure 6 - Traces of kinetic solubility experiments
A) Polymorph III of compound (I)
B) Polymorph V of compound (I)
C) Spray-dried amorphous solid dispersion of compound (I)
D) Amorphous form of compound (I)
E) KinetiSol®-based amorphous solid dispersion 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 alternative forms of compound (I) have the required properties.
ABBREVIATIONS AND DEFINITIONS
API Active pharmaceutical ingredient
DSC Differential scanning calorimetry
DVS Dynamic vapour sorption
FaSSIF fasted state simulated intestinal media 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 spray-dried amorphous form of compound (I)
Compound (I) was dissolved in an acetone/water-mixture (90 % (w/w) acetone) while stirring, the final solid concentration of compound (I) prior to beginning spraying was 3.35 % (w/w). The solution was used for spray drying without filtration.
The spray solution was then delivered into a drying chamber and the spray-dried dispersion was. After spray drying, the material was collected into glass bottle and stored at refrigerated condition.
Production of spray-dried amorphous solid dispersion of compound (I)
Compound (I) was dissolved in an acetone+water mixture (90 % (w/w) acetone) while stirring. Hydroxypropylmethylcelllulose acetate succinate (HPMCAS) was added under agitation in such an amount to result in a 2: 1 ratio (w/w) of HPMCAS: Compound (I). This spray solution was then delivered into a drying chamber and the spray-dried dispersion was collected in glass jars before transfer to steel trays for the final drying step in a tray oven.
Production of KinetiSol®- based amorphous solid dispersion of compound (I)
Production was performed according to Miller D., Keen J. (2014) KinetiSol" -Based Amorphous Solid Dispersions. (In: Shah N., Sandhu H., Choi D., Chokshi H., Malick A. (eds) Amorphous Solid Dispersions. Advances in Delivery Science and Technology. Springer, New York, NY), using HMPCAS as carrier with a ratio of 2: 1 (w/w) of HPM- CAS:Compound (I).
Production of toluene solvate form of compound (I)
The toluene solvate was produced by evaporative crystallization which included suspension of the amorphous form of compound (I) in toluene, incubation at 50 °C for 1 week, separation of the solids from the liquid phases by centrifugation and drying at ambient conditions and under vacuum (around 200 torr) at room temperature.
Production of form V of compound (I)
The polymorph form V of compound (I) was produced by desolvation of toluene solvate under vacuum (around 200 tor) at room temperature.
Production of methyl benzoate solvate form of compound (I)
The methyl benzoate solvate of compound (I) was produced by cooling crystallization from a saturated solution of compound in methyl benzoate, followed by drying under vacuum (around 200 tor) at room temperature.
Production of form III of compound (I)
The polymorph form III of compound (I) was produced by solvent-mediated conversion form the methyl benzoate form of compound (I) in 2-propanol followed by a cooling crystallization in 2-propanol and 1 -butanol, followed by drying under vacuum (around 200 tor) at room temperature.
Production of methanol solvate form of compound (I)
The methanol solvate was produced by solvent-mediated form conversion from the methyl benzoate form of compound (I), followed by a cooling crystallization in methanol followed by drying under vacuum (around 200 tor) at room temperature.
Production of ethanol solvate form of compound (I)
The ethanol solvate was produced by solvent-mediated form conversion from the methyl benzoate form of compound (I), followed by a cooling crystallization in ethanol followed by drying under vacuum (around 200 tor) at RT.
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 Kai 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 includes the X-ray powder diffraction (XRPD) characteristic peaks for the crystalline form III of compound (I).
Table 2 includes the XRPD characteristic peaks for the crystalline form V of compound (I).
Table 3 includes the XRPD characteristic peaks for the methanol solvate of compound (I), table 4 those for the ethanol solvate of compound (I), table 5 for the methyl benzoate solvate of compound (I), table 6 for the toluene solvate of compound (I).
The values in Table 1-6 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 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
A crystal, obtained from ethanol, 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.
The analysis of Form III of compound (I) showed 4 molecules in 1 unit cell in an orthorhombic crystal system of space group P2i2i2i.
The determined unit cell parameters were: a = 7.478(4) A, b = 10.623(6) A, c = 33.420(17) A a =90°, p = 90°, y = 90°, V = 2654.84 A3, Z = 4
The analysis of the methanol solvate of compound (I) showed 4 molecules of compound (I) and 4 molecules of methanol in 1 unit cell in an triclinic crystal system of space group P2i. The determined unit cell parameters were: a = 13.403(6) A, b = 8.550(4) A, c = 23.761(10) A a =90°, p = 90.916(6)°, y = 90°, V = 2722.56 A3, Z = 4
The analysis of the toluene solvate of compound (I) showed 2 molecules of compound (I) and 2 molecules of toluene in 1 unit cell in an monoclinic crystal system of space group P2i.
The determined unit cell parameters were: a = 18.8410(10) A, b = 14.7592(8) A, c = 11.8451(6) A a =90°, p = 96.2151°, y = 90°, V = 3274.5 A3, Z = 4(2)
DSC analysis
DSC analysis was performed with a differential scanning calorimeter (DSC Q2000 or 2500, TA instruments, New Castle, Delaware, USA). About 5 mg of powder 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 DSC analysis for the Form III of compound (I) shows endothermic events at 159 °C ± 5 °C and 188 °C ± 5 °C, an exemplary trace is depicted in figure 2A.
The DSC analysis for the Form V of compound (I) shows endothermic events at 126 °C ± 5 °C and 189 ± 5 °C , an exemplary trace is depicted in figure 2B.
The DSC analysis for the ethanol solvate of compound (I) shows endothermic events at 107 °C ± 5 °C and 190 °C ± 5 °C, an exemplary trace is depicted in figure 2C.
The DSC analysis for the methanol solvate of compound (I) shows endothermic events at 127 °C ± 5 °C and 189 °C ± 5 °C, an exemplary trace is depicted in figure 2D.
The DSC analysis for the methyl benzol solvate of compound (I) shows an endothermic event at 94 °C ± 5 °C, an exothermic event at 100 °C ± 5 °C and an endothermic event at 189 °C ± 5 °C, an exemplary trace is depicted in figure 2E.
The DSC analysis for the toluene solvate of compound (I) shows an endo- /exothermic event at 101 °C ± 5 °C and an endothermic event at 188 °C ± 5 °C, an exemplary trace is depicted in figure 2F.
An exemplary trace of the DSC analysis for the amorphous form of compound (I) shows an is depicted in figure 2G.
Thermogravimetric analysis
TGA data were collected on 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 maximal 300 °C under dry nitrogen.
An exemplary TGA trace of the crystalline form III of compound (I) is depicted in figure 3 A and shows a mass loss of < 1.0 % (w/w) up to 180 °C.
An exemplary TGA trace of the crystalline form V of compound (I) is depicted in figure 3B and shows a mass loss of < 1.0 % (w/w) up to 150 °C.
An exemplary TGA trace of the ethanol solvate of compound (I) is depicted in figure 3C and shows a mass loss of 7.7 % (w/w) up to 175 °C.
An exemplary TGA trace of the methanol solvate of compound (I) is depicted in figure 3D and shows a mass loss of 5.5 % (w/w) up to 140 °C.
An exemplary TGA trace of the methyl benzoate solvate of compound (I) is depicted in figure 3E and shows a mass loss of 19 % (w/w) up to 200 °C.
An exemplary TGA trace of the toluene solvate of compound (I) is depicted in figure 3F and shows a mass loss of 11 % (w/w) up to 180 °C.
An exemplary trace of the TGA analysis for the amorphous form of compound (I) shows an is depicted in figure 3G.
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.
Polymorph form III of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 %. An exemplary DVS isotherm can be found in Figure 4A (depicting .
Polymorph form V of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 %. An exemplary DVS isotherm can be found in Figure 4B.
The ethanol solvate form of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 % and is therefore non-hygroscopic. An exemplary DVS isotherm can be found in Figure 4C.
The methanol solvate form of compound (I) showed more than 1.5 % weight gain up to a relative humidity of 90 % and is therefore hygroscopic. An exemplary DVS isotherm can be found in Figure 4D.
The methyl benzoate solvate form of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 % and is therefore non-hygroscopic. An exemplary DVS isotherm can be found in Figure 4E.
The toluene solvate form of compound (I) showed less than 1 % weight gain up to a relative humidity of 90 % and is therefore non-hygroscopic. An exemplary DVS isotherm can be found in Figure 4F.
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 form III of compound I, the kinetic solubility measurement yielded a maximum concentration of 31 pg/ml between 0 and 200 min, reaching a supersaturation ratio of 1.1, the equilibrium solubility being 29 pg/ml. An exemplary trace of the kinetic solubility experiment from 0-200 min can be found in Figure 6A.
For the form V of compound I, the kinetic solubility measurement yielded a maximum concentration of 176 pg/ml between 0 and 200 min, reaching a supersaturation ratio of 12.6, the equilibrium solubility being 14 pg/ml. An exemplary trace of the kinetic solubility experiment from 0-200 min can be found in Figure 6B.
For the spray-dried amorphous solid dispersion of compound I, the kinetic solubility measurement yielded a maximum concentration of 168 pg/ml between 0 and 200 min, reaching a supersaturation ration of 3.6, the equilibrium solubility being 47 p/ml. An exemplary trace of the kinetic solubility experiment from 0-200 min can be found in Figure 6C.
For the amorphous form of compound I, the kinetic solubility measurement yielded a maximum concentration of 104 pg/ml between 0 and 200 min, reaching a supersaturation ration of 6.1, the equilibrium solubility being 17 pg/ml. An exemplary trace of the kinetic solubility experiment from 0-200 min can be found in Figure 6D.
For the KinetiSol®-based amorphous solid dispersion of compound I the kinetic solubility measurement yielded a maximum concentration of 180 pg/ml between 0 and 200 min, reaching a supersaturation ration of , the equilibrium solubility being 23 pg/ml. An exemplary trace of the kinetic solubility experiment from 0-200 min can be found in Figure 6E.
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 ('H=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.
An exemplary 13C SSNMR spectrum of form III of compound I is shown in Figure 5A, of form V of compound I in Figure 5B, of amorphous form of compound (I) in Figure 5C, of spray-dried dispersion in Figure 5D.
Table 7 includes the chemical shifts shifts obtained from the 13C SSNMR spectrum acquired for the amorphous form of compound (I), and Table 8 those acquired for the amorphous solid dispersion. Table 9 includes the chemical shifts obtained from the 13C SSNMR spectrum acquired for the form III of compound (I), and Table 10 those acquired for the form V.
The values reported in Tables 7 and 8 have a margin of error of ± 0.5 ppm, the values reported in Tables 9 and 10 have a margin of error of ± 0.2 ppm. Since some margin of error is possible due to the 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 solid state NMR spectrum of the sample over the solid state NMR 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 compound 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 diseases.
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 alternative forms 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, pso- riasis 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 spon- dylitis, atherosclerosis, uveitis and non-radiographic spondyloarthropathy, non-alcoholic steatohepatitis.
Claims
WHAT WE CLAIM
1. Polymorphs of the following compound (I)
wherein the polymorph is selected from among the group of polymorph forms III, V and amorphous forms.
2. Crystalline form III of compound (I) according to claim 1, characterized by having an x-ray diffraction pattern comprising peaks at 5.2 ± 0.2, 12. 8 ± 0.2, 13.3 ± 0.2 and 14.6± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu Kai source.
3. Crystalline form III of compound (I) according to claim 2, characterized by having an x-ray diffraction pattern comprising additional peaks at 10.4 ± 0.2, 12.0 ± 0.2, 12.8± 0.2, 14.6 ± 0.2, 16.4 ± 0.2 and 17.8 ± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu Kai source.
4. Crystalline form III of compound (I) according to any one of claims 2-3, characterized by having a 13C-solid-state NMR spectrum comprising chemical shifts at 170.2±0.2, 164.0±0.2, 126.1± 0.2, 58.0± 0.2, 42.6.7± 0.2 ppm, referenced to adamantane with the low frequency resonance being set to 29.5 ppm.
5. Crystalline form III of compound (I) according to claim 4, characterized by having a 13C-solid-state NMR spectrum comprising additional chemical shifts at 132.4±0.2, 45.6±0.2, 17.0± 0.2 ppm, referenced to adamantane with the low frequency resonance being set to 29.5 ppm.
Crystalline form III of compound (I) according to any one of claims 2- 5, characterized in that it has a melting point of 159 °C ± 5 °C. Crystalline form III according to any one of claims 2-6, characterized in that it maintains a supersaturated state for at least 60 min. Crystalline form V of compound (I) according to claim 1, characterized by having an x-ray diffraction pattern comprising peaks at 8.3 ± 0.2, 12.0 ± 0.2, 13.0 ± 0.2 and 16.6 ± 0.2° 29 as measured by x-ray powder diffraction using a Cu Kai source. Crystalline form V of compound (I) according to claim 8, characterized by having an x-ray diffraction pattern comprising additional peaks at 5.7 ± 0.2, 9.6 ± 0.2, 11.3 ± 0.2 and 17.3 ± 0.2 ° 29 as measured by x-ray powder diffraction using a Cu Kai source. Crystalline form V of compound (I) according to any one of claims 1, 8 or 9, characterized by having a 13C-solid-state NMR spectrum comprising chemical shifts at 171.0±0.2, 170.7±0.2, 130.9± 0.2, 130.6± 0.2, 24.7± 0.2 ppm, referenced to adamantane with the low frequency resonance being set to 29.5 ppm. Crystalline form V of compound (I) according to claim 10, characterized by having a 13C-solid-state NMR spectrum comprising additional chemical shifts at 146.9±0.2, 121.4±0.2, 59.0± 0.2, 57.1± 0.2, 25.6± 0.2 and 19.3± 0.2 ppm, referenced to adamantane with the low frequency resonance being set to 29.5 ppm. Crystalline form V of compound (I) according to any one of claims 1, 8-11, characterized in that it has a melting point of 126 °C ± 5 °C. Crystalline form V according to any one of claims 1, 8-12, characterized in that it maintains a supersaturated state for at least 60 min. Amorphous form of compound (I) according to claim 1, characterized by having a 13C-solid-state NMR spectrum comprising chemical shifts at 168.4±0.5, 164.0±0.5,
157.3± 0.5, 136.2± 0.5, 121.9± 0.5 and 22.6± 0.5 ppm, referenced to adamantane with the low frequency resonance being set to 29.5 ppm. Amorphous form of compound (I) according to claim 14, characterized characterized by having a 13C-solid-state NMR spectrum comprising additional chemical shifts at 153.2±0.5, 147.2±0.5, 131.6± 0.5, 126.7± 0.5, 123.8± 0.5, 56.9± 0.5 and 14.3± 0.2 ppm, referenced to adamantane with the low frequency resonance being set to 29.5 ppm. Amorphous form of compound (I) according to any one of claims 14-15, characterized in that it maintains a supersaturated state for at least 60 min. Pharmaceutical composition, characterized in that it comprises a polymorph form of compound (I) according to any one of claims 1 to 16. Pharmaceutical composition according to claim 17, characterized in that it is used in the treatment of an inflammatory disease. Pharmaceutical composition according to claim 18, 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.
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