Solid forms of 3-((1r, 3r)-1-(2, 6-difluoro-4-((1-(3-fluoropropyl) azetidin-3-yl) amino) phenyl)-3-methyl-1, 3, 4, 9-tetrahydro-2h-pyrido [3, 4-b] indol-2-yl)-2, 2-difluoropropan-1-ol tartrate

Abstract

The present invention relates to crystalline forms of gemresterin tartrate with improved particle size distribution, as well as processes for their preparation, pharmaceutical compositions comprising them and their use as medicaments.

Description

Technical Field

[0001] The present invention relates to a crystalline form of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol tartrate, a pharmaceutical composition containing the crystalline form, a method for preparing the crystalline form and the use of the crystalline form as a drug for treating cancer. Background Art

[0002] Estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of a variety of biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β (beta) -estradiol and estrone. It has been found that ER has two isoforms, i.e. ER-α (alpha) and ER-β (beta). Estrogen and estrogen receptors are associated with many diseases or conditions, such as breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, endometrial cancer, uterine cancer and other diseases or conditions. ER-α targeting agents have specific activity in the context of metastatic disease and acquired resistance. International patent applications WO2016097072 and WO2019245974, the entire contents of which are incorporated herein by reference, disclose a number of ER-α targeting agents, including the compound 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, which has a recommended INN giredestrant (WHO Drug Information, Vol. 33, No. 4, 2019, Proposed INN: List 122), which is being studied in clinical trials for the treatment of breast cancer.

[0003]

[0004] Among other salt forms, WO2019245974 discloses tartrate salts of giressatrant having formula (I) and certain crystalline forms thereof.

[0005]

[0006] One of the crystalline forms of the tartrate of formula (I) described in WO2019245974 is Form B (hereinafter referred to as "Form B"). It has been found that Form B exhibits unique mechanical properties, which makes it very difficult to process it by mechanical compression. Therefore, the mechanical compression applied during the tableting of conventional pharmaceutical compositions usually leads to partial decomposition of the API (see Examples 7 and 8), color change and agglomeration formation. One way to avoid harmful compression forces applied during tableting is to fill the API or a pharmaceutical composition containing it directly into a capsule ("direct encapsulation"). However, it has been found that Form B is not very suitable for capsule formulations because it exhibits an uneven particle size distribution that varies between batches (such as Figure 8 a) to c)) and low bulk density and poor flowability (see Example 9), which hinders processing on an industrial scale.

[0007] In summary, Form B is not well suited for providing tablet and capsule formulations on an industrial scale.

[0008] Therefore, there is a high unmet need for new forms of girenstra that can be formulated on an industrial scale as a drug product for administration to patients. Summary of the invention

[0009] The inventors of the present invention have developed a novel process for preparing crystalline Form B of Girestatin tartrate (see Examples 1 and 2) which reliably and reproducibly provides said Form B ( Figure 1 ). Surprisingly, compared to the crystalline form B prepared according to the procedure described in WO2019245974, the crystalline form B with the new particle size distribution has improved flow characteristics and bulk density (see Example 9), and is very suitable for providing capsule formulations, thereby overcoming the problems outlined above. Capsule formulations containing improved bulk drugs can be conveniently prepared without the need for a granulation step, and without the need to use a binder as an excipient. In addition, compared with preparations containing previously known forms of giressastatin, the capsule formulations of the present invention have lower variability in their dissolution profiles while showing similar release profiles.

[0010] In a first aspect, the present invention provides crystalline 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol tartrate of formula (I)

[0011]

[0012] It has:

[0013] (i) an X-ray powder diffraction pattern comprising a peak at 11.49, 12.54, 19.16, 19.42 or 24.67 [° 2θ ± 0.1° 2θ, Cu Kα radiation]; and

[0014] (ii) A unimodal particle size distribution with particle sizes of D[v,10] = 20-54 μm and D[v,90] = 38-120 μm.

[0015] In yet another aspect, the present invention provides processes for preparing the crystalline forms of the invention, formulations comprising the crystalline forms and methods of using them in medical therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Particle size distribution (PSD) of the crystalline compound of formula (I) according to the invention is depicted.

[0017] Figure 2 Flowchart depicting a process for preparing a pharmaceutical composition according to the present invention.

[0018] Figure 3 Depicted is the API content in the sieved fractions of a final blend containing as API the crystalline compound of formula (I) according to the invention ("GPV0137") or containing as API the compound of formula (I) of the quality disclosed in WO2019245974 ("GMP0492").

[0019] Figure 4 Plotted are impurities observed in API stability samples (uncompressed and compressed) stored at 60°C / 11%RH for 4 weeks with RRT = 0.58.

[0020] Figure 5 Plotted are impurities observed in stability samples stored for 6 months at 30°C / 65%RH with RRT = 0.60 (left) and RRT = 0.73 (right).

[0021] Figure 6 Plotted are impurities observed in stability samples stored for 6 months at 40°C / 75%RH with RRT = 0.60 (left) and RRT = 0.73 (right).

[0022] Figure 7 Plotted are impurities observed in stability samples stored for 6 months at 60°C / 11%RH with RRT = 0.60 (left) and RRT = 0.73 (right).

[0023] Figure 8a) Depicts the particle size distribution of API batch "A" obtained by the method described in WO2019245974 (compared to Figure 9C of WO2019245974).

[0024] Figure 8 b) depicts the particle size distribution of API batch "B" obtained by recrystallization of API batch "A".

[0025] Figure 8 c) depicts the particle size distribution of API batch "C" obtained by recrystallization of API batch "A". DETAILED DESCRIPTION

[0026] definition

[0027] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for combinations in which at least some of these features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0028] As used herein, the term "Form B" relates to a crystalline Form B of giressatin tartrate (Formula (I)) as described in WO2019245974, i.e. having an X-ray powder diffraction pattern comprising peaks at 11.49, 12.54, 19.16, 19.42 or 24.67 [°2θ±0.1°2θ, Cu Kα radiation]. In a preferred embodiment, the crystalline Form B has an X-ray powder diffraction pattern comprising the peaks outlined in Table 1:

[0029] Table 1: Representative XRPD peaks of Form B of Girestatin Tartrate

[0030]

[0031]

[0032] The particle size distribution of the crystalline 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol tartrate of the present invention is analyzed by laser diffraction, as described in USP <429> Laser diffraction measurements of particle size are described in Ph. Eur. 2.9.31 Laser diffraction particle size analysis. Details of the equipment used and the measurements are given in Example 3.

[0033] As used herein, the terms "hydroxypropyl methylcellulose," "HPMC," and "hydroxypropyl methylcellulose" refer to 2-hydroxypropylcellulose methyl ether (CAS 9004-65-3) and are used interchangeably.

[0034] As used herein, the term "HDPE" refers to high density polyethylene.

[0035] As used herein, the term "filler" refers to a substance added to a pharmaceutical composition to increase the weight and / or size of the pharmaceutical composition. Pharmaceutically acceptable fillers are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of fillers are starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose) and lactose (e.g., lactose monohydrate). Preferred but non-limiting examples of fillers are cellulose and lactose.

[0036] As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to help break down (disintegrate) (e.g., after administration) and release the active ingredient (such as Form B described herein). Pharmaceutically acceptable disintegrants are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of disintegrants are low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose. A preferred but non-limiting example of a disintegrant is cross-linked sodium carboxymethyl cellulose.

[0037] As used herein, the term "lubricant" refers to a substance added to a pharmaceutical composition to help reduce the adhesion of particles of the powder to the surface of the equipment. Pharmaceutically acceptable lubricants are described in Remington's Pharmaceutical Sciences and listed in Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of lubricants are sodium stearyl fumarate and magnesium stearate. A preferred but non-limiting example of a lubricant is magnesium stearate.

[0038] As used herein, the term "treat" means all or part of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition; or the slowing down or stopping of further progression or worsening of these symptoms; or the alleviation or elimination of the cause of the disorder, disease or condition itself. In one embodiment, the disorder is cancer.

[0039] As used herein, the term "effective amount" refers to an amount of a compound described herein that is capable of treating a disorder, disease or condition disclosed herein, or a symptom thereof.

[0040] As used herein, the term "patient" refers to an animal, such as a mammal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, monkey, chicken, turkey, quail or guinea pig, etc., in one embodiment a mammal, in another embodiment a human. In one embodiment, the individual is a human suffering from cancer or at risk of cancer.

[0041] Crystalline Form B of Girestatin tartrate with improved particle size distribution

[0042] In a first aspect, the present invention provides crystalline 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol tartrate of formula (I)

[0043]

[0044] It has:

[0045] (i) an X-ray powder diffraction pattern comprising a peak at 11.49, 12.54, 19.16, 19.42 or 24.67 [°2θ±0.1°2[°2θ±0.2°2θ, Cu Kα radiation]; and

[0046] (ii) A unimodal particle size distribution with particle sizes of D[v,10] = 20-54 μm and D[v,90] = 38-120 μm.

[0047] In one embodiment, the crystalline form has a monomodal particle size distribution, wherein the particle size is D[v,10]=24-50 μm and D[v,90]=45-100 μm.

[0048] In one embodiment, the crystalline form has a monomodal particle size distribution, wherein the particle size is D[v,10]=28-46 μm and D[v,90]=50-90 μm.

[0049] In a particularly preferred embodiment, the crystalline form has a monomodal particle size distribution, wherein the particle sizes are D[v,10]=30-42 μm and D[v,90]=56-84 μm.

[0050] In particularly preferred embodiments, the crystalline form has a monomodal particle size distribution, wherein the particle sizes are D[v,10]=30-42 μm, D[v,50]=40-60 μm and D[v,90]=56-84 μm.

[0051] Methods for preparing novel forms

[0052] As described above, when the crystalline form is prepared by a specific method, a crystalline form B of giressatran tartrate having a favorable particle size distribution is formed.

[0053] Therefore, in yet another aspect, the present invention provides a method for preparing the crystalline form of girefelostat tartrate as described herein, the method comprising the following steps:

[0054] a) providing a solution of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoro-propan-1-ol ("free base") in an organic solvent;

[0055] b1) adding the solution of step a) to a solution of tartaric acid in an organic solvent at 15°C to 30°C; or

[0056] b2) Adding a solution of tartaric acid in an organic solvent to the solution of step a) at 15°C to 30°C.

[0057] In one embodiment, the organic solvent used in the method of the present invention is ethanol.

[0058] In one embodiment, the method of the present invention further comprises:

[0059] c) The suspension obtained from b1) or b2) is stirred at 15°C to 30°C for at least 8 hours.

[0060] In one embodiment, the temperature in steps b1), b2) and c) of the method of the present invention is maintained at 20°C to 25°C.

[0061] In a preferred embodiment, the temperature in steps b1), b2) and c) of the method of the present invention is maintained at 20°C.

[0062] In one embodiment, the concentration of free base in the solution provided in step a) of the process of the present invention is about 13%-w / w to 19%-w / w.

[0063] In one embodiment, the concentration of tartaric acid in the solution used in step b1) or b2) of the process of the present invention is about 8%-w / w to 12%-w / w.

[0064] In one embodiment of the method of the present invention, step b1) comprises:

[0065] b1a) adding a first portion of the solution of step a) to a solution of tartaric acid in an organic solvent;

[0066] b1b) seeding the solution of step b1a) with the crystalline compound of formula (I) according to claim 1; and

[0067] b1c) adding the remaining portion of the solution of step a) to the mixture of step b1b); and

[0068] and

[0069] Step b2) comprises:

[0070] b2a) adding a first portion of a solution of tartaric acid in an organic solvent to the solution of step a);

[0071] b2b) seeding the solution of step b2a) with the crystalline compound of formula (I) according to claim 1; and

[0072] b2c) adding a second portion of the solution of tartaric acid in the organic solvent to the mixture of step b2b).

[0073] In one embodiment of the method of the present invention:

[0074] (i) said first portion of the solution of step a) in step b1a) corresponds to about 10% to 30% of the total amount of the solution of step a); and

[0075] (ii) said first portion of the solution of tartaric acid in an organic solvent in step b2a) corresponds to about 20% of the total amount of the solution of tartaric acid in an organic solvent used in step b2)

[0076] to 30%.

[0077] In one aspect, the present invention provides a crystalline compound of formula (I) as described herein when obtained by a process described herein.

[0078] Pharmaceutical composition

[0079] In one aspect, the present invention provides a pharmaceutical composition for oral administration comprising a crystalline compound of formula (I) as described herein and one or more pharmaceutically acceptable excipients selected from a filler, a disintegrant and a lubricant.

[0080] In one embodiment, a pharmaceutical composition according to the present invention comprises a crystalline compound of formula (I) as described herein and one or more fillers, disintegrants and lubricants.

[0081] In one embodiment, a pharmaceutical composition according to the present invention comprises a crystalline compound of formula (I) as described herein and:

[0082] (i) a first filler;

[0083] (ii) a second filler;

[0084] (iii) a disintegrant; and

[0085] (iv) Lubricants.

[0086] In a preferred embodiment:

[0087] (i) the first filler is microcrystalline cellulose;

[0088] (ii) the second filler is lactose monohydrate;

[0089] (iii) the disintegrant is croscarmellose sodium; and

[0090] (iv) The lubricant is magnesium stearate.

[0091] In one embodiment:

[0092] (i) the weight of the first filler accounts for 33±1% of the total weight of the composition;

[0093] (ii) the weight of the second filler accounts for 10±1% of the total weight of the composition;

[0094] (iii) the weight of the disintegrant accounts for 5±1% of the total weight of the composition;

[0095] (iv) the weight of the lubricant accounts for 0.5±1% of the total weight of the composition; and

[0096] (v) the weight of the crystalline compound of formula (I) accounts for 51.5±1% of the total weight of the composition.

[0097] In a preferred embodiment, the pharmaceutical composition according to the present invention comprises 38.62 mg (equivalent to 30 mg of "free base") of the compound of formula (I).

[0098] In one aspect, the present invention provides a capsule for oral administration comprising a pharmaceutical composition described herein.

[0099] In one embodiment, the capsule is made of hydroxypropyl methylcellulose.

[0100] In a particularly preferred embodiment, the pharmaceutical composition according to the present invention is:

[0101]

[0102] Preparation method of pharmaceutical composition

[0103] The present invention further provides a method for preparing a pharmaceutical composition as described herein. In particular, the present invention provides a method for preparing a pharmaceutical composition according to Figure 2 Method of pharmaceutical composition.

[0104] In one aspect, the present invention provides a method for preparing a pharmaceutical composition as described herein, the method comprising:

[0105] a) combining and blending a crystalline compound of formula (I) described herein with a first filler;

[0106] b) sieving the blend obtained in step a);

[0107] c) adding a second filler and a disintegrant to the blend obtained in step b);

[0108] d) sieving the blend obtained in step c);

[0109] e) Screening lubricant;

[0110] f) adding the screened lubricant from step e) to the blend obtained in step d); and

[0111] g) blending the mixture obtained in step f).

[0112] In one embodiment, the sieving in steps b) and d) is performed using a cone mill.

[0113] In one embodiment, the sieving in step e) is performed using a sieve having a mesh size of 0.5-1.0 mm.

[0114] In one embodiment, the method for preparing the pharmaceutical composition of the present invention further comprises:

[0115] (h) transferring the final blend obtained in step g) into capsules.

[0116] use

[0117] A particular aspect of the invention relates to crystalline Form B as defined above for use as a medicament.

[0118] A further aspect of the present invention relates to the crystalline form B as defined herein and to a pharmaceutical composition comprising the crystalline form for use in the treatment of cancer.

[0119] In yet another aspect, the present invention provides a method for treating cancer in a patient suffering from cancer, the method comprising administering to the cancer patient an effective amount of the crystalline Form B described herein or the pharmaceutical composition described herein.

[0120] In a further aspect, the present invention provides the use of crystalline Form B as defined herein and the pharmaceutical composition described herein in a method for treating cancer in a patient suffering from said cancer.

[0121] In a further aspect, the present invention provides the use of crystalline Form B as defined herein in the preparation of a medicament for treating cancer in a patient suffering from said cancer.

[0122] In one embodiment, the cancer is selected from lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer.

[0123] In a preferred embodiment, the cancer is breast cancer.

[0124] In one embodiment, the cancer is breast cancer selected from hormone receptor positive breast cancer, HER2 positive breast cancer, and triple negative breast cancer.

[0125] In one embodiment, the cancer is breast cancer selected from HER2-negative, HER2-positive breast cancer, and triple-negative breast cancer.

[0126] In one embodiment, the cancer is metastatic breast cancer.

[0127] In one embodiment, the compounds or pharmaceutical compositions of the present invention are administered as a component of adjunctive therapy.

[0128] In one embodiment, the compounds or pharmaceutical compositions of the invention are administered as a component of neoadjuvant therapy.

[0129] In one embodiment, the cancer is stage 0, stage I, stage II, stage III, or stage IV breast cancer.

[0130] In one embodiment, the patient has been previously treated with one or more anti-cancer agents or radiation therapy.

[0131] In one embodiment, the patient has undergone surgery prior to treatment with Form B of the invention.

[0132] In one embodiment, Form B of the invention is administered in combination with one or more of radiation therapy, hormone therapy, or an anti-cancer agent.

[0133] In one embodiment, Form B of the invention is administered in combination with one or more anticancer agents.

[0134] In one embodiment, the anticancer agent is selected from doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, albumin-bound paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone, eribulin, olaparib, methotrexate, anastrozole, ixemestane, toremifene, rituximab, 1,2-dimethoate ... etrozole, tamoxifen, 4-hydroxytamoxifen, raloxifene, droloxifene, trioxifene, keoxifene, flutamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, or venetoclax,

[0135] In one embodiment, the anticancer agent is selected from an AKT inhibitor, a CDK4 / 6 inhibitor, a PARP inhibitor, and an aromatase inhibitor.

[0136] In one embodiment, the anticancer agent is abemaciclib, ribociclib, or palbociclib.

[0137] In one embodiment, the anticancer agent is abemaciclib.

[0138] In one embodiment, the anticancer agent is ribociclib.

[0139] In one embodiment, the anticancer agent is palbociclib.

[0140] In one embodiment, the anticancer agent is ipatasertib.

[0141] In one embodiment, the anticancer agent is everolimus or fulvestrant.

[0142] In one embodiment, the anticancer agent is ado-trastuzumab emtansine, trastuzumab, pertuzumab, or atezolizumab.

[0143] In one embodiment, the anticancer agent is alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or a combination thereof.

[0144] Examples

[0145] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the present invention, but are merely representative.

[0146] Example 1 - Preparation of crystalline girefactant tartrate

[0147] 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoro-propan-1-ol tartrate (9.0 kg crude, as obtained from the method described in WO2019245974, Example 8,

[0550] , 13.4 mol, 1.0 equiv, hereinafter referred to as "tartrate") was suspended in methyl tertiary butyl ether (TBME) at ambient temperature. 5%-w / w aqueous sodium hydroxide solution (22.4 kg, 28 mol NaOH, 2.1 equiv) was added at ambient temperature to provide a solution of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoro-propan-1-ol tartrate (hereinafter referred to as "free base"). The aqueous phase was separated; the organic phase was washed with water to remove salts and filtered through charcoal. Subsequently, a solvent exchange from TBME to EtOH was performed by vacuum distillation. At the end of the solvent exchange, the final concentration of the free base in EtOH was adjusted to 18%-w / w. 20% of this solution was added to a solution of tartaric acid (2.1 kg, 14.0 mol, 1.1 equivalents) in ethanol (17.9 kg) at 20 to 25 ° C. The resulting solution was seeded with tartrate, and then the final amount of ethanol free base solution was added at 20 to 25 ° C. The resulting suspension was stirred for about 10 hours at 20 to 25 ° C. The suspension was filtered, the filter cake was washed twice with ethanol (9 kg each time), and dried overnight at 50 ° C in vacuum (10 mbar). Tartrate (8.5 kg, 94% yield) was obtained as a pale yellow solid.

[0148] Example 2 - Preparation of crystalline girefexant tartrate

[0149] 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoro-propan-1-ol tartrate (5.5 kg crude, as obtained from the method described in WO2019245974, Example 8,

[0550] , 8.2 mol, 1.0 equiv., hereinafter referred to as "tartrate") was suspended in methyl tertiary butyl ether (TBME) at ambient temperature. 5%-w / w aqueous sodium hydroxide solution (2.1 eq., 13.8 kg, 17.2 mol NaOH) was added at ambient temperature to provide a solution of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoro-propan-1-ol tartrate (hereinafter referred to as "free base"). The aqueous phase was separated; the organic phase was washed twice with water and filtered through charcoal. Subsequently, a solvent exchange from TBME to EtOH was performed by vacuum distillation. At the end of the solvent exchange, the final concentration of the free base in EtOH was adjusted to 16%-w / w.

[0150] In parallel, an ethanolic solution of tartaric acid (1.3kg, 8.7mol, 1.1 equivalents) in ethanol (12.0kg) was prepared at ambient temperature. 25% of this solution was added to the above-mentioned free alkali solution at 20°C to 25°C. The resulting solution was inoculated with tartrate, and then the final amount of ethanolic tartaric acid solution was added at 20°C to 25°C. The resulting suspension was stirred at 20°C to 25°C for at least 8 hours. Then, the final suspension was optionally wet-milled to control the quantity of oversized agglomerates (if any). The suspension was filtered, the filter cake was washed twice with ethanol (2kg each time), and dried overnight at 50°C in a vacuum (10mbar). Tartrate (5.0kg, 91% yield) was obtained as a pale yellow solid.

[0151] Example 3 - General Procedure for Particle Size Distribution (PSD) Measurement

[0152] For the measurements, a Malvern MasterSizer 3000 from Malvern, UK was used, which was coupled to a liquid dispersion unit Hydro Coupling. Crystalline girestatin tartrate obtained from Example 1 or 2 is dispersed in a dispersion medium consisting of technical grade n-heptane and unsaturated 0.2% w / w.-% Span 85 (sorbitan trioleate, e.g. Fluka / Sigma catalogue number 85549 or equivalent).

[0153] program : Crystalline girestrant tartrate was added directly to the Hydro MV dispersing unit and stirred at 2500 rpm to reach a suitable optical concentration (between 5% and 25% optical concentration).

[0154] Measurement : According to the manual, the above laser diffractometer was used to measure the test dispersion and determine the cumulative volume dispersion. The measurement was performed after stirring for 2 minutes. The particle diameter was calculated using the Fraunhofer approximation, the particle type was opaque particles and the analysis model was general purpose. The background and measurement duration were set to 30 seconds.

[0155] Three independent samples were measured at a time.The volume average particle size distribution at the 10%, 50% and 90% (x10, x50 and x90) percentiles of overfineness was evaluated from the cumulative distribution.

[0156] The obtained particle size distribution is Figure 1 as shown in .

[0157] Example 4 - General Procedure for Preparing Capsule Formulations

[0158] Capsule formulations comprising the crystalline compound of formula (I) according to the present invention such as Figure 2 The detailed procedures were described in the flowchart and followed.

[0159] Step 1a: Combine and blend Girestatin tartrate and microcrystalline cellulose in one container.

[0160] Step 1b: Sieve Blend 1a using a cone mill.

[0161] Step 1c: Add lactose monohydrate and croscarmellose sodium to Blend 1b and blend.

[0162] Step 1d: Sieve Blend 1c using a cone mill.

[0163] Step 2: Sieve magnesium stearate through a sieve with a mesh size of 0.5 mm (0.5-1.0 mm), add to the blend from step 1d and blend.

[0164] Step 3: Transfer the final blend into empty size 3 HPMC capsules.

[0165] Step 4: Pack the capsules in HDPE bottles with desiccant.

[0166] Example 5 - 30 mg capsule formulation

[0167]

[0168]

[0169] All excipients used in the formulations were of pharmacopoeial (Ph. Eur. and / or USP / NF) grade.

[0170] Reference Example 6 – Alternative Capsule Formulation

[0171] A capsule formulation for oral administration is also provided, which is composed of the same ingredients as the capsule formulation of Example 5, except for hydroxypropyl methylcellulose. All excipients used in the formulation are of pharmacopoeia (Ph.Eur. and / or USP / NF) grade. The dosage strength of the capsule formulation is preferably 30 mg (free base equivalent).

[0172] Reference Example 6 - Immediate Release Tablet Formulation

[0173] Also provided is an oral immediate-release tablet formulation consisting of girefestrant tartrate, microcrystalline cellulose, lactose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. All excipients used in the formulation are of pharmacopoeia (Ph. Eur. and / or USP / NF) grade. The dosage strength of the capsule formulation is preferably 50 mg or 10 mg (free base equivalent).

[0174] Example 7 - Stability Data of API

[0175] The effect of compression on API degradation was studied. Uncompressed API (pure API powder as is) and compressed API (compact) samples were aged at 60°C / 11%RH with the container open for 1 month. The samples were analyzed by HPLC. (See Example 10). Figure 4 The levels of impurities observed at RRT = 0.58 in samples stored at 60°C / 11% RH for 4 weeks are shown. At RRT = 0.58, growth of impurities was observed in both uncompressed and compressed API samples, with a faster growth rate observed in compressed samples. The results show that the levels of degradation products increased more significantly in the compressed samples compared to the uncompressed samples, indicating that the API is sensitive to compression forces.

[0176] Example 8 - Stability Data for 100 mg Capsule and Tablet Formulations

[0177] abbreviation:

[0178] RRT: relative retention time

[0179] RH: Relative humidity

[0180] FBG Fluidized Bed Granulation

[0181] RC Rollover

[0182] DP Pharmaceuticals

[0183] The chemical stability of the capsule and tablet formulations was monitored by HPLC (see Example 10) at the initial point, 1 month, 3 months and 6 months. The stability data are listed in Tables 2 to 4. The impurity profiles of the capsule and tablet formulations at RRT = 0.60 and RRT = 0.73 observed in the stability samples stored for 6 months at 30°C / 65%RH, 40°C / 75%RH and 60°C / 11%RH are as follows: Figure 5 , 6 and 7. At 30°C / 65%RH and 40°C / 75%RH, a linear growth of impurities at RRT=0.60 was observed for all samples, but the growth rate was the slowest for the FBG capsules. Under the same storage conditions, the growth rate of impurities at RRT=0.73 was not as fast as that at RRT=0.60. The growth rate of the capsules seemed to be slower than that of the tablets. Under the conditions of 60°C / 11%RH, the growth of impurities at RRT=0.60 stabilized after 3 months, except for the RC tablets. The impurities at RRT=0.73 continued to grow under this condition, while for the FBG capsules it began to stabilize.

[0184] The stability results indicate that the capsules appear to be chemically more stable than the tablets, with the FBG capsules performing best, followed by the RC capsules. Comparable growth rates of impurities at RRT=0.60 were observed from the FBG and RC tablets, and were significantly faster than those observed from the capsules. Thus, the effect of compression force on DP degradation is consistent with previous findings on APIs (see Example 7). In summary, the higher the compression force applied during DP preparation, the faster DP degradation occurs.

[0185] Table 2 - 1 month purity results for 100 mg capsules and tablets (FBG and RC)

[0186]

[0187] Table 3 - 3-month purity results for 100 mg capsules and tablets (FBG and RC)

[0188]

[0189] Table 4 - 6-month purity results for 100 mg capsules and tablets (FBG and RC)

[0190]

[0191] Example 9 - Improved Manufacturability

[0192] The following table illustrates the improved manufacturability properties of a crystalline API (batch "BS2008SA02") prepared according to the process of the present invention. Batch E1 was prepared according to the process described in WO2019245974.

[0193]

[0194] Example 10 - HPLC Method

[0195] The RRC described herein was determined using the following HPLC method:

[0196]

Claims

1. A crystalline 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol tartrate of formula (I) It has: (i) an X-ray powder diffraction pattern comprising a peak at 11.49, 12.54, 19.16, 19.42 or 24.67 [° 2θ ± 0.1° 2θ, CuKα radiation]; and (ii) A unimodal particle size distribution with particle sizes of D[v,10] = 20-54 μm and D[v,90] = 38-120 μm.

2. A method for preparing a crystalline compound of formula (I) according to claim 1, comprising the following steps: a) providing a solution of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoro-propan-1-ol ("free base") in an organic solvent; b1) adding the solution of step a) to a solution of tartaric acid in an organic solvent at 15°C to 30°C; or b2) adding a solution of tartaric acid in an organic solvent to said solution of step a) at 15°C to 30°C.

3. The preparation method according to claim 2, wherein the organic solvent is ethanol.

4. The preparation method according to any one of claims 2 or 3, further comprising: c) The suspension obtained from b1) or b2) is stirred at 15°C to 30°C for at least 8 hours.

5. The preparation method according to any one of claims 2 to 4, wherein the temperature in steps b1), b2) and c) is maintained at 20°C to 25°C.

6. The preparation method according to claim 5, wherein the temperature in steps b1), b2) and c) is maintained at 20°C.

7. The preparation method according to any one of claims 2 to 6, wherein the concentration of the free base in the solution provided in step a) is about 13%-w / w to 19%-w / w.

8. The preparation method according to any one of claims 2 to 7, wherein the concentration of tartaric acid in the solution used in step b1) or b2) is about 8%-w / w to 12%-w / w.

9. The preparation method according to any one of claims 2 to 8, wherein: Step b1) comprises: b1a) adding a first portion of the solution of step a) to a solution of tartaric acid in an organic solvent; b1b) seeding the solution of step b1a) with the crystalline compound of formula (I) according to claim 1; and b1c) adding the remaining part of the solution of step a) to the mixture of step b1b); and Step b2) comprises: b2a) adding a first portion of a solution of tartaric acid in an organic solvent to said solution of step a); b2b) seeding the solution of step b2a) with the crystalline compound of formula (I) according to claim 1; and b2c) adding a second portion of the solution of tartaric acid in the organic solvent to the mixture of step b2b).

10. The preparation method according to claim 9, wherein: (i) the first portion of the solution of step a) in step b1a) corresponds to about 10% to 30% of the total amount of the solution of step a); and (ii) said first portion of the solution of tartaric acid in an organic solvent in step b2a) corresponds to about 20% to 30% of the total amount of the solution of tartaric acid in an organic solvent used in step b2).

11. The crystalline compound of formula (I) according to claim 1, obtained by the process according to any one of claims 2 to 10.

12. A pharmaceutical composition for oral administration, comprising a crystalline compound of formula (I) according to claim 1 or 11 and one or more pharmaceutically acceptable excipients selected from fillers, disintegrants and lubricants.

13. A pharmaceutical composition according to claim 12, comprising a crystalline compound of formula (I) according to claim 1 or 11 and one or more fillers, disintegrants and lubricants.

14. The pharmaceutical composition according to claim 12, wherein the pharmaceutically acceptable excipient comprises: (i) a first filler; (ii) a second filler; (iii) a disintegrant; and (iv) Lubricants.

15. The pharmaceutical composition according to claim 14, wherein: (i) the first filler is microcrystalline cellulose; (ii) the second filler is lactose monohydrate; (iii) the disintegrant is cross-linked carboxymethyl cellulose sodium; and (iv) The lubricant is magnesium stearate.

16. The pharmaceutical composition according to any one of claims 14 or 15, wherein: (i) the weight of the first filler accounts for 33±1% of the total weight of the composition; (ii) the weight of the second filler accounts for 10±1% of the total weight of the composition; (iii) the weight of the disintegrant accounts for 5±1% of the total weight of the composition; (iv) the weight of the lubricant accounts for 0.5±1% of the total weight of the composition; and (v) the weight of the crystalline compound of formula (I) accounts for 51.5±1% of the total weight of the composition.

17. A pharmaceutical composition according to any one of claims 12 to 16, wherein the compound of formula (I) is present in an amount of 38.62 mg (equivalent to 30 mg of the "free base").

18. A capsule for oral administration containing the pharmaceutical composition according to any one of claims 12 to 17.

19. The capsule according to claim 18, wherein the capsule is made of hydroxypropyl methylcellulose.

20. The pharmaceutical composition according to any one of claims 12 to 17, which is:

21. A method for preparing a pharmaceutical composition according to any one of claims 12 to 20, comprising: a) combining and blending a crystalline compound of formula (I) according to claim 1 or 11 with a first filler; b) sieving the blend obtained in step a); c) adding a second filler and a disintegrant to said blend obtained in step b); d) sieving the blend obtained in step c); e) Screening lubricant; f) adding the screened lubricant from step e) to said blend obtained in step d); and g) blending the mixture obtained in step f).

22. The method according to claim 21, wherein the sieving in steps b) and d) is performed using a cone mill.

23. The method according to any one of claims 21 or 22, wherein the sieving in step e) is performed using a sieve having a mesh size of 0.5 mm to 1.0 mm.

24. The method according to any one of claims 21 to 23, further comprising: (h) transferring the final blend obtained in step g) into capsules.

25. A compound according to claim 1 or 11 for use as a medicament.

26. A method for treating cancer in a patient suffering from cancer, the method comprising administering to the cancer patient an effective amount of a compound according to claim 1 or 11 or a pharmaceutical composition according to any one of claims 12 to 20.

27. A compound according to claim 1 or 11 or a pharmaceutical composition according to any one of claims 12 to 20 for use in a method according to claim 26.

28. Use of a compound according to claim 1 or 11 or a pharmaceutical composition according to any one of claims 12 to 20 in a method according to claim 26.

29. Use of a compound according to claim 1 or 11 in the preparation of a medicament for treating cancer in a patient suffering from said cancer.

30. The invention as herein described.

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