Solid 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

Abstract

The present invention relates to a crystalline form of gildedestrant tartrate having an improved particle size distribution, as well as processes for its preparation, pharmaceutical compositions containing it and its use as a medicament.

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 it, as well as a process for its preparation and its use as a medicament for the treatment of cancer. [Background technology]

[0002] Estrogen receptors ("ER") are ligand-activated transcriptional regulatory proteins that mediate the induction of various biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17β (beta)-estradiol and estrone. ER has been found to have two isoforms, ER-α (alpha) and ER-β (beta). Estrogens and estrogen receptors have been implicated in 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 targeted agents have unique activity in metastatic disease and acquired resistance settings. International patent applications WO 2016097072 and WO 2019245974, the entire contents of which are incorporated herein by reference, disclose several 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, along with the recommended INN giledestrant (WHO Drug Information, Vol. 33, No. 4, 2019, Proposed INN: List 122), which is being investigated in clinical trials for the treatment of breast cancer. [ka]

[0003] Among other salt forms, WO2019245974 discloses the tartrate salt of gildedestrant having formula (I), as well as certain crystalline forms thereof. [ka]

[0004] One of the crystalline forms of the tartrate salt of formula (I) described in WO2019245974 is form B (hereinafter "form B"). It has been found that said form B exhibits a unique mechanical behavior that makes its processing by mechanical compression very difficult. Thus, mechanical compression, as applied during the tableting of conventional pharmaceutical compositions, regularly leads to partial degradation of the API (see Examples 7 and 8), discoloration and the formation of lumps. One way to avoid the 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 less suitable for capsule formulations, since it exhibits a non-uniform particle size distribution that varies from batch to batch, as shown in Figures 8a)-c), a low bulk density, and poor flowability (see Example 9), which hinders processing on an industrial scale.

[0005] In summary, Form B is less suitable for providing tablet and capsule formulations on an industrial scale.

[0006] Thus, there is a high unmet need for new forms of giledestrant that can be formulated into pharmaceuticals on an industrial scale for administration to patients. Summary of the Invention

[0007] The inventors of the present invention have developed a new method for preparing crystalline form B of giledestrant tartrate (see Examples 1 and 2), which reliably and reproducibly obtains said form B with a well-defined unimodal particle size distribution (Figure 1). Surprisingly, crystalline form B with the new particle size distribution has improved flow properties and bulk density compared to crystalline form B prepared according to the procedure described in WO2019245974 (see Example 9), and is very well suited to provide a capsule formulation, overcoming the problems outlined above. Capsule formulations containing the improved drug substance can be conveniently prepared without a granulation step and without using binders as excipients. Moreover, the capsule formulations of the present invention have lower variability in their dissolution profile than formulations containing previously known forms of giledestrant, while exhibiting similar release profiles.

[0008] In a first aspect, the present invention provides a compound of formula (I) [ka] 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 salt of (i) an X-ray powder diffraction pattern containing peaks at 11.49, 12.54, 19.16, 19.42, or 24.67 [° 2 theta ± 0.1° 2 theta, CuKα radiation]; and (ii) providing 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 having a unimodal particle size distribution with particle sizes of D[v,10]=20-54 μm and D[v,90]=38-120 μm;

[0009] In further aspects, the present invention provides methods for making the crystalline forms of the invention, formulations containing same, and methods of using same in medical therapy. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the particle size distribution (PSD) of the crystalline compound of formula (I) according to the present invention. [Diagram 2] FIG. 2 shows a flow chart of a method for producing a pharmaceutical composition according to the present invention. [Diagram 3] FIG. 3 illustrates the API content in sieve fractions of final blends containing a crystalline compound of formula (I) according to the present invention as an API ("GPV0137") or containing a compound of formula (I) of the quality disclosed in WO2019245974 ("GMP0492") as an API. [Figure 4] FIG. 4 shows a plot of the impurity with RRT=0.58 observed in API stability samples (uncompressed vs. compressed) stored at 60° C. / 11% RH for up to 4 weeks. [Diagram 5] FIG. 5 shows plots of impurities with RRT=0.60 (left) and RRT=0.73 (right) observed in stability samples stored at 30° C. / 65% RH for up to 6 months. [Figure 6] FIG. 6 shows plots of impurities with RRT=0.60 (left) and RRT=0.73 (right) observed in stability samples stored at 40° C. / 75% RH for up to 6 months. [Figure 7] FIG. 7 shows plots of impurities with RRT=0.60 (left) and RRT=0.73 (right) observed in stability samples stored at 60° C. / 11% RH for up to 6 months. [Figure 8a)] Figure 8a) shows the particle size distribution of API lot "A" obtained by the method described in WO2019245974 (compare Figure 9C of WO2019245974). [Figure 8b)] FIG. 8b) shows the particle size distribution of API lot "B" obtained by recrystallization of API lot "A". [Figure 8c)] FIG. 8c) shows the particle size distribution of API lot "C" obtained by recrystallization of API lot "A". DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] definition It should be understood that features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed herein (including any accompanying claims, abstracts and drawings), and / or all of the methods or method steps so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed herein (including any accompanying claims, abstracts and drawings), or any novel one or any novel combination of methods or method steps so disclosed.

[0012] As used herein, the term "Form B" refers to crystalline Form B of giledestrant 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 [° 2 theta ± 0.1° 2 theta, CuKα radiation]. In a preferred embodiment, the crystalline Form B has an X-ray powder diffraction pattern comprising peaks as outlined in Table 1. [Table 1]

[0013] 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 described in U.S. Pat. <429> The particles were analyzed by laser diffraction as described in Laser Diffraction Measurement of Particle Size and European Pharmacopoeia 2.9.31 Particle size analysis by Laser Diffraction. Details of the equipment and measurements used are given in Example 3.

[0014] As used herein, the terms "hypromellose," "HPMC," and "hydroxypropyl methylcellulose" refer to cellulose, 2-hydroxypropyl methyl ether (CAS 9004-65-3) and are used interchangeably.

[0015] As used herein, the term "HDPE" refers to high density polyethylene.

[0016] 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.

[0017] As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to help break down (disintegrate) and release an active ingredient, such as, for example, Form B described herein, after administration. 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 hydroxypropylcellulose and croscarmellose sodium. A preferred but non-limiting example of a disintegrant is croscarmellose sodium.

[0018] As used herein, the term "lubricant" refers to a substance added to a pharmaceutical composition to help reduce the adhesion of powder granules to equipment surfaces. Pharmaceutically acceptable lubricants are described in Remington's Pharmaceutical Sciences and listed in the 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.

[0019] As used herein, the term "treating" means the total or partial alleviation of a disorder, disease or condition, or of one or more symptoms associated with a disorder, disease or condition, or the slowing or halting of further progression or worsening of those symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease or condition itself. In one embodiment, the disorder is cancer.

[0020] 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.

[0021] As used herein, the term "patient" is defined to include animals such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quails, or guinea pigs, and in one embodiment is a mammal, and in another embodiment is a human. In one embodiment, the subject is a human having or at risk for cancer.

[0022] Crystalline Form B of Gildestran Tartrate with Improved Particle Size Distribution In a first aspect, the present invention provides a compound of formula (I) [ka] 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 salt of (i) an X-ray powder diffraction pattern containing peaks at 11.49, 12.54, 19.16, 19.42, or 24.67[°2theta ± 0.1° 2[°2theta ± 0.2° 2theta, Cu Kα radiation]; and (ii) providing 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 having a unimodal particle size distribution with particle sizes of D[v,10]=20-54 μm and D[v,90]=38-120 μm;

[0023] In one embodiment, the crystalline form has a unimodal particle size distribution with particle sizes D[v,10]=24-50 μm and D[v,90]=45-100 μm.

[0024] In one embodiment, the crystalline form has a unimodal particle size distribution with particle sizes D[v,10]=28-46 μm and D[v,90]=50-90 μm.

[0025] In a particularly preferred embodiment, the crystalline form has a monomodal particle size distribution with particle sizes of D[v,10]=30-42 μm and D[v,90]=56-84 μm.

[0026] In a particularly preferred embodiment, the crystalline form has a monomodal particle size distribution with particle sizes D[v,10]=30-42 μm, D[v,50]=40-60 μm and D[v,90]=56-84 μm.

[0027] Methods for producing new forms As outlined above, crystalline form B of giledestrant tartrate having a preferred particle size distribution is formed when the crystalline form is prepared by certain methods.

[0028] Thus, in a further aspect, the present invention provides a method for preparing the crystalline form of giledestrant tartrate described herein, the method comprising: 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 15-30° C.; or b2) adding a solution of tartaric acid in an organic solvent at 15-30° C. to the solution of step a).

[0029] In one embodiment, the organic solvent used in the process of the present invention is ethanol.

[0030] In one embodiment, the method of the invention comprises the steps of: c) further comprising stirring the suspension obtained from b1) or b2) at 15-30° C. for at least 8 hours.

[0031] In one embodiment, the temperature of steps b1), b2) and c) of the method of the present invention is maintained at 20-25°C.

[0032] In a preferred embodiment, the temperature of steps b1), b2) and c) of the method of the present invention is maintained at 20°C.

[0033] In one embodiment, the concentration of the free base in the solution provided in step a) of the method of the invention is about 13-19% (w / w).

[0034] In one embodiment, the concentration of tartaric acid in the solution used in step b1) or b2) of the method of the invention is about 8-12% (w / w).

[0035] In one embodiment of the process of the present invention, 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 a crystalline compound of formula (I) according to claim 1; b1c) adding the remainder of the solution of step a) to the mixture of step b1b), Step b2) is b2a) adding a first portion of a solution of tartaric acid in an organic solvent to the solution of step a); b2b) seeding the solution of step b2a) with a crystalline compound of formula (I) according to claim 1; b2c) adding a second portion of the solution of tartaric acid in an organic solvent to the mixture of step b2b).

[0036] In one embodiment of the method of the present invention, (i) the first portion of the solution of step a) in step b1a) is about 10-30% of the total volume of the solution of step a); (ii) said first portion of the solution of tartaric acid in an organic solvent in step b2a) represents about 20-30% of the total amount of the solution of tartaric acid in an organic solvent used in step b2).

[0037] In one aspect, the present invention provides a crystalline compound of formula (I) as described herein when obtained by a process as described herein.

[0038] Pharmaceutical Compositions 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 pharma- ceutically acceptable excipients selected from fillers, disintegrants and lubricants.

[0039] 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.

[0040] In one embodiment, the pharmaceutical composition according to the invention comprises a crystalline compound of formula (I) as described herein, (i) a first filler; (ii) a second filler; (iii) a disintegrant, and (iv) a lubricant.

[0041] In a preferred embodiment, (i) the first filler is microcrystalline cellulose; (ii) the second filler is lactose monohydrate; (iii) the disintegrant is croscarmellose sodium; (iv) The lubricant is magnesium stearate.

[0042] In one embodiment, (i) the weight of said first filler represents 33±1% of the total weight of the composition; (ii) the weight of said second filler represents 10±1% of the total weight of the composition; (iii) the weight of said disintegrant represents 5±1% of the total weight of the composition; (iv) the weight of the lubricant represents 0.5 ± 1% of the total weight of the composition; (v) the weight of said crystalline compound of formula (I) represents 51.5±1% of the total weight of the composition.

[0043] In a preferred embodiment, the pharmaceutical composition according to the invention comprises the compound of formula (I) in an amount of 38.62 mg (corresponding to 30 mg of the "free base").

[0044] In one aspect, the present invention provides a capsule for oral administration containing a pharmaceutical composition described herein.

[0045] In one embodiment, the capsule is made from hypromellose.

[0046] In a particularly preferred embodiment, the pharmaceutical composition according to the invention is as follows: [Table 2]

[0047] Method for producing pharmaceutical composition The present invention further provides a method for the preparation of a pharmaceutical composition as described herein. In particular, the present invention provides a method for the preparation of a pharmaceutical composition according to FIG.

[0048] In one aspect, the invention provides a method for making a pharmaceutical composition described herein, comprising the steps of: a) combining and blending a crystalline compound of formula (I) as described herein with a first filler; b) screening the blend obtained in step a); c) adding a second filler and a disintegrant to the blend obtained in step b); d) sieving the blend obtained in step c); e) screening the lubricant; and f) adding the screened lubricant from step e) to the blend obtained in step d); g) blending the mixture obtained in step f).

[0049] In one embodiment, said sieving of steps b) and d) is carried out using a cone mill.

[0050] In one embodiment, said sieving in step e) is carried out using a sieve having a mesh size of 0.5-1.0 mm.

[0051] In one embodiment, a method for making a pharmaceutical composition of the invention comprises: (h) further comprising transferring the final blend obtained in step g) into a capsule.

[0052] use A particular embodiment of the present invention relates to crystalline form B as defined above for use as a medicament.

[0053] A further aspect of the invention relates to crystalline form B as defined herein, and pharmaceutical compositions comprising same, for use in the treatment of cancer.

[0054] In a further aspect, the present invention provides a method for treating cancer in a patient having cancer, comprising administering to the cancer patient an effective amount of crystalline form B as described herein or a pharmaceutical composition as described herein.

[0055] In a further aspect, the present invention provides the use of crystalline form B as defined herein, as well as the pharmaceutical compositions described herein, in a method for treating cancer in a patient suffering from said cancer.

[0056] In a further aspect, the present invention provides the use of crystalline form B as defined herein in the manufacture of a medicament for the treatment of a patient with cancer.

[0057] In one embodiment, the cancer is selected from lung cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, or breast cancer.

[0058] In a preferred embodiment, the cancer is breast cancer.

[0059] In one embodiment, the cancer is a breast cancer selected from hormone receptor positive breast cancer, HER2 positive breast cancer, and triple negative breast cancer.

[0060] In one embodiment, the cancer is a breast cancer selected from HER2-negative, HER2-positive breast cancer, and triple-negative breast cancer.

[0061] In one embodiment, the cancer is metastatic breast cancer.

[0062] In one embodiment, a compound or pharmaceutical composition of the invention is administered as a component of an adjuvant therapy.

[0063] In one embodiment, a compound or pharmaceutical composition of the invention is administered as a component of neoadjuvant therapy.

[0064] In one embodiment, the cancer is breast cancer that is stage 0, I, II, III or IV.

[0065] In one embodiment, the patient has undergone previous treatment with one or more anti-cancer agents or radiation therapy.

[0066] In one embodiment, the patient has undergone surgery prior to treatment with form B of the present invention.

[0067] In one embodiment, form B of the present invention is administered in combination with one or more radiation therapy, hormonal therapy, or anti-cancer agents.

[0068] In one embodiment, form B of the present invention is administered in combination with one or more anti-cancer agents.

[0069] 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, exemestane, toremifene, letrozole, tamoxifen, 4-hydroxytamoxifen, raloxifene, droxifene, trioxyfene, keoxifene, futhamide, nilutamide, bicalutamide, lapatinib, vinblastine, goserelin, leuprolide, pegfilgrastim, filgrastim, and venetoclax.

[0070] In one embodiment, the anti-cancer agent is selected from an AKT inhibitor, a CDK4 / 6 inhibitor, a PARP inhibitor, and an aromatase inhibitor.

[0071] In one embodiment, the anticancer drug is abemaciclib, ribociclib, or palbociclib.

[0072] In one embodiment, the anticancer drug is abemaciclib.

[0073] In one embodiment, the anticancer drug is ribociclib.

[0074] In one embodiment, the anticancer drug is palbociclib.

[0075] In one embodiment, the anticancer drug is ipatasertib.

[0076] In one embodiment, the anticancer drug is everolimus or fulvestrant.

[0077] In one embodiment, the anticancer agent is trastuzumab emtansine, trastuzumab, pertuzumab, or atezolizumab.

[0078] In one embodiment, the anti-cancer agent is alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, tositumomab, or a combination thereof. EXAMPLES

[0079] The following examples are given by way of illustration of the present invention, and should not be construed as limiting the scope of the invention, but should be understood as merely representative thereof.

[0080] Example 1 - Preparation of Crystalline Gilredestrant Tartrate 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 obtained from the method described in WO2019245974, Example 8,

[0550] , 13.4 mol, 1.0 equiv., hereafter "tartrate") was suspended in tert-butyl methyl ether (TBME) at ambient temperature. Aqueous 5% w / w sodium hydroxide solution (22.4 kg, 28 mol NaOH, 2.1 eq.) was added at ambient temperature to give 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 (hereafter "free base"). The aqueous phase was discarded and the organic phase was washed with water to remove salts and filtered through charcoal. A solvent exchange from TBME to EtOH was then performed by vacuum distillation. The final concentration of the free base in EtOH at the end of the solvent exchange 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 equiv.) in ethanol (17.9 kg) at 20-25 °C. The resulting solution was seeded with the tartrate salt and then the final amount of the ethanolic free base solution was added at 20-25 °C. The resulting suspension was stirred at 20-25 °C for about 10 h. The suspension was filtered and the filter cake was washed twice with ethanol (9 kg each) and dried in vacuum at 50 °C (10 mbar) overnight. The tartrate salt was obtained as a yellowish solid (8.5 kg, 94% yield).

[0081] Example 2 - Preparation of Crystalline Gilredestrant Tartrate 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 obtained from the method described in WO2019245974, Example 8,

[0550] , 8.2 mol, 1.0 equiv., hereafter "tartrate") was suspended in tert-butyl methyl ether (TBME) at ambient temperature. A 5% w / w aqueous solution of sodium hydroxide (2.1 equivalents, 13.8 kg, 17.2 mol NaOH,) was added at ambient temperature to give 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 (hereafter "free base"). The aqueous phase was discarded. The organic phase was washed twice with water and filtered through charcoal. A solvent exchange from TBME to EtOH was then performed by vacuum distillation. The final concentration of the free base in EtOH at the end of the solvent exchange was adjusted to 16% (w / w).

[0082] In parallel, an ethanolic solution of tartaric acid (1.3 kg, 8.7 mol, 1.1 equiv.) in ethanol (12.0 kg) at ambient temperature was prepared. 25% of this solution was added to the above free base solution at 20-25 °C. The resulting solution is seeded with the tartrate salt, after which the final amount of ethanolic tartaric acid solution is added at 20-25 °C. The resulting suspension is stirred at 20-25 °C for at least 8 h. The final suspension is then optionally wet-milled to control the number of excessively large aggregates, if any. The suspension is filtered, the filter cake is washed twice with ethanol (2 kg each) and dried overnight in vacuum at 50 °C (10 mbar). The tartrate salt is obtained as a yellowish solid (5.0 kg, 91% yield).

[0083] Example 3 - General procedure for particle size distribution (PSD) measurements For the measurements, a Malvern MasterSizer 3000 device (Malvern, UK) coupled with a liquid dispersion unit Hydro MV® (Malvern, UK) was used. Crystalline giledestrant tartrate obtained from Example 1 or 2 was dispersed in a dispersion medium consisting of technical grade n-heptane containing 0.2% w / w-% Span 85 (sorbitan trioleate, e.g. Fluka / Sigma catalogue no. 85549 or equivalent) non-saturated.

[0084] Procedure: Add crystalline gyredestrant tartrate directly to a Hydro MV dispersion unit and stir at 2500 rpm to achieve an appropriate optical density (5%-25% optical density).

[0085] Measurement: The test dispersion was measured using the laser diffraction device described above according to the instruction manual to determine the cumulative volume dispersion. The measurement was performed after a mixing time of 2 minutes. The Fraunhofer approximation was used to calculate the particle size, opaque particles were used as the particle type, and general-purpose was used as the analytical model. The background and measurement period were set to 30 seconds.

[0086] Three independent samples were measured once. The volume mean particle size distributions at the 10%, 50% and 90% (×10, ×50 and ×90) percentile undersize values ​​were estimated from the cumulative distribution.

[0087] The particle size distribution obtained is shown in FIG.

[0088] Example 4 - General procedure for preparation of capsule formulation A capsule formulation containing the crystalline compound of formula (I) according to the present invention was prepared according to the flow diagram in Figure 2 and detailed procedure below.

[0089] Step 1a: Giledestran tartrate and microcrystalline cellulose were combined in a container and blended. Step 1b: Blend 1a was sieved using a cone mill. Step 1c: Lactose monohydrate and croscarmellose sodium were added to blend 1b and blended. Step 1d: Blend 1c was sieved using a cone mill. Step 2: Magnesium stearate was sieved through a sieve having a mesh size of 0.5 mm (0.5-1.0 mm) and added to the blend from step 1d and blended. Step 3: The final blend was transferred into empty size 3 HPMC capsules. Step 4: The capsules were packaged in HDPE bottles with desiccant.

[0090] Example 5 - 30 mg Capsule Formulation [Table 3]

[0091] All excipients used in the formulations are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade.

[0092] Reference Example 6 - Alternative capsule formulation 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 hypromellose. All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade. The dosage strength of the capsule formulation is preferably 30 mg (free base equivalent).

[0093] Reference Example 6 - Immediate Release Tablet Formulation Also provided is an immediate release tablet formulation for oral administration consisting of giledestrant tartrate, microcrystalline cellulose, lactose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. All excipients used in the formulation are of compendial (European Pharmacopoeia and / or United States Pharmacopoeia / National Formulary (USP / NF)) grade. The dosage strength of the capsule formulation is preferably 50 mg or 10 mg (free base equivalent).

[0094] Example 7 - Stability Data of API The effect of compression on API degradation was investigated. Samples of uncompressed API (neat API powder) and compressed API (compact) were aged at 60°C / 11% RH for up to 1 month with the container open. Samples were assayed by HPLC (see Example 10). Figure 4 shows the level of impurities at RRT=0.58 observed in samples stored at 60°C / 11% RH for up to 4 weeks. Growth of impurities at RRT=0.58 was observed in both uncompressed and compressed API samples, with a faster growth rate observed in the compressed samples. The results show that the level of degradation products increased more significantly in the compressed samples than in the uncompressed samples, indicating that the API is responsible for the compression force.

[0095] Example 8 - Stability Data for 100mg Capsule and Tablet Formulations Abbreviation: RRT: Relative retention time RH: Relative humidity FBG fluidized bed granulation RC Roller Compaction DP formulation

[0096] The chemical stability of the capsule and tablet formulations was monitored by HPLC (see Example 10) at initial, 1, 3, and 6 months. The stability data are listed in Tables 2-4. The impurity profiles of capsule and tablet formulations at RRT=0.60 and RRT=0.73 observed in stability samples stored at 30°C / 65%RH, 40°C / 75%RH, and 60°C / 11%RH for up to 6 months are shown in Figures 5, 6, and 7, respectively. At 30°C / 65%RH and 40°C / 75%RH, linear growth of the impurity RRT=0.60 was observed in all samples, but the growth rate was slowest in the FBG capsules. The impurity at RRT=0.73 did not grow as fast as the impurity at RRT=0.60 under the same storage conditions. The growth rate appeared to be slower in the capsules than in the tablets. At 60°C / 11%RH, the growth of the impurity at RRT=0.60 reached a plateau after 3 months, except for the RC tablets. The impurity with RRT=0.73 continued to grow under these conditions, but began to reach a plateau for the FBG capsule.

[0097] The stability results show that capsules appear to be more chemically stable than tablets, with FBG capsules performing best, followed by RC capsules. Comparable growth rates of impurities at RRT=0.60 were observed from FBG and RC tablets, which were significantly faster than those observed from capsules. Thus, the effect of compression force on DP degradation was consistent with previous findings for API (see Example 7). In summary, the higher the compression force applied during DP production, the faster DP degradation occurs. [Table 4] [Table 5] [Table 6]

[0098] Example 9 - Improved manufacturability The following table shows the improved manufacturability characteristics of the crystalline API (Lot "BS2008SA02") prepared according to the methods of the present invention. Lot E1 was prepared according to the methods described in WO2019245974. [Table 7]

[0099] Example 10 - HPLC Method The following HPLC method was used to measure the RRC described herein. [Table 8]

Claims

1. Equation (I) 【Transformation 5】 The crystalline 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2,2-difluoropropan-1-ol tartrate, (i) X-ray powder diffraction pattern containing peaks at 11.49, 12.54, 19.16, 19.42, or 24.67 [°² theta ± 0.1°² theta, CuKα line], (ii) Unimodal particle size distribution having particle sizes D[v,10] = 20–54 μm and D[v,90] = 38–120 μm A crystalline 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2,2-difluoropropane-1-ol tartrate having the above characteristics.

2. A method for producing a crystalline compound of formula (I) as described in claim 1, wherein the method is: a) A step of providing a solution of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl)-2,2-difluoro-propan-1-ol ("free base") in an organic solvent, b1) Adding the solution from step a) to a solution of tartaric acid in an organic solvent at 15 to 30°C, or b2) Adding a tartaric acid solution in an organic solvent to the solution from step a) at 15-30°C. Methods that include...

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

4. c) The method for production according to claim 2 or 3, further comprising stirring the suspension obtained from b1) or b2) at 15 to 30°C for at least 8 hours.

5. The method for manufacturing according to claim 2 or 3, wherein the temperature of steps b1), b2), and c) is maintained at 20 to 25°C.

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

7. The method for manufacturing according to claim 2 or 3, wherein the concentration of the free base in the solution provided in step a) is about 13 to 19% (w / w).

8. The method for production according to claim 2 or 3, wherein the concentration of tartaric acid in the solution used in step b1) or b2) is about 8 to 12% (w / w).

9. Step b1) is, b1a) Adding the first portion of the solution from step a) to a solution of tartaric acid in an organic solvent, b1b) Adding the crystalline compound of formula (I) described in claim 1 as a seed crystal to the solution of step b1a), b1c) Adding the remainder of the solution from step a) to the mixture from step b1b), Step b2) is, b2a) Adding a first portion of the tartaric acid solution in the organic solvent to the solution in step a), b2b) Adding the crystalline compound of formula (I) described in claim 1 as a seed crystal to the solution of step b2a), The method for production according to claim 2 or 3, comprising b2c) adding a second portion of a solution of tartaric acid in an organic solvent to the mixture of step b2b).

10. (i) In step b1a), the first portion of the solution in step a) is approximately 10 to 30% of the total amount of the solution in step a). (ii) The first portion of the tartaric acid solution in the organic solvent in step b2a) is approximately 20-30% of the total amount of the tartaric acid solution in the organic solvent used in step b2). A method for manufacturing according to claim 9.

11. A pharmaceutical composition for oral administration comprising a crystalline compound of formula (I) as described in claim 1, and one or more pharmaceutically acceptable additives selected from fillers, disintegrants, and lubricants.

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

13. The aforementioned pharmaceutically acceptable additives are (i) First filler, (ii) Second filler, (iii) Disintegrant, and (iv) Lubricant A pharmaceutical composition according to claim 11, comprising:

14. (i) The first filler is microcrystalline cellulose, (ii) The second filler is lactose monohydrate, (iii) The disintegrant is croscarmellose sodium, (iv) The lubricant is magnesium stearate. The pharmaceutical composition according to claim 13.

15. (i) The weight of the first filler corresponds to 33 ± 1% of the total weight of the composition, (ii) The weight of the second filler corresponds to 10 ± 1% of the total weight of the composition, (iii) The weight of the disintegrant corresponds to 5 ± 1% of the total weight of the composition, (iv) The weight of the lubricant corresponds to 0.5 ± 1% of the total weight of the composition, (v) The weight of the crystalline compound of formula (I) corresponds to 51.5 ± 1% of the total weight of the composition. The pharmaceutical composition according to claim 13.

16. The pharmaceutical composition according to claim 11, wherein the compound of formula (I) is present in an amount of 38.62 mg (corresponding to 30 mg of "free base").

17. An oral capsule containing the pharmaceutical composition described in claim 11.

18. The capsule according to claim 17, wherein the capsule is made of hypromellose.

19. below, Table 1 The pharmaceutical composition according to claim 11, as described above.

20. a) Blending a crystalline compound of formula (I) described in claim 1 with a first filler, b) Sifting the blend obtained in step a), c) Adding a second filler and disintegrant to the blend obtained in step b), d) Sifting the blend obtained in step c), e) Sieving the lubricant, f) Adding the sieved lubricant from step e) to the blend obtained in step d), g) Blend the mixture obtained in step f) A method for preparing the pharmaceutical composition according to claim 11, comprising the above.

21. The method according to claim 20, wherein the sieving in steps b) and d) is performed using a conical mill.

22. The method according to claim 20, wherein the sieving in step e) is performed using a sieve having a mesh size of 0.5 to 1.0 mm.

23. The method according to claim 20, further comprising transferring the final blend obtained in step g) to a capsule.

24. A pharmaceutical product comprising the compound described in Claim 1.

25. A pharmaceutical for treating cancer in a patient having cancer, comprising the compound described in Claim 1 or the pharmaceutical composition described in Claim 11.

26. Use of the compound according to claim 1 in the manufacture of a pharmaceutical product for treating cancer in a patient having cancer.

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