Novel crystalline form of succinate of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dimethylamide

Abstract

In this specification, novel crystalline forms of succinate(s) of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (also known as ribociclib), pharmaceutical compositions comprising the same, therapeutic methods using the same, and methods for preparing the same are provided.

Description

Technology Field

[0001] Related applications

[0002] This application claims priority and benefit to U.S. provisional application No. 62 / 795,799 filed January 23, 2019, the contents of which are incorporated herein by reference in their entirety.

[0003] Technology field

[0004] The present application relates to a novel crystalline form of succinate(s) of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, a pharmaceutical composition comprising the same, a therapeutic method using the same, and a method for obtaining the form. Background Technology

[0005] Compound of the following chemical formula I 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide:

[0006] [Chemical Formula I]

[0007]

[0008] The synthesis thereof is specifically described in WO 2010 / 020675 A1, Example 74. WO 2010 / 020675 discloses that the compound of Formula I has valuable pharmaceutical properties and can be used, for example, as an inhibitor of (1) cyclin-dependent kinases (particularly, cyclin-dependent kinases selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9); and (2) as a modulator and / or inhibitor of glycogen synthase kinase-3 (GSK-3). The compound of Formula I is also known as ribociclib.

[0009] WO2012 / 064805 (PCT patent application PCT / US2011 / 059890) discloses a succinate of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide described by the following chemical formula II:

[0010] [Chemical Formula II]

[0011] .

[0012] In one aspect, the present invention relates to a novel crystalline form of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide succinate, namely, a novel crystalline form(s) of ribociclib succinate.

[0013] In one embodiment, the novel crystalline form is Modification E, also referred to as Mod. E or Form E. Modification E is an anhydrous crystalline form of ribociclib succinate.

[0014] In another embodiment, the novel crystalline form is a variant F, also referred to as Mod. F or form F. The variant F is anhydrous ribociclib hemisuccinate.

[0015] In another embodiment, the novel crystalline form is deformation H B , or Mod. H B , or form H B It is called. Variant H B is ribociclib succinate dihydrate.

[0016] In an additional embodiment, the novel crystalline form is deformation H A , or Mod. H A or form H A It is called. Variant H Ais a hydrated form of ribociclib hemisuccinate (e.g., a hemihydrate, monohydrate, or hydrate in a ribociclib:water ratio in the range of 2:1 to 1:1 or 3:1 to 2:1 or 3:2 to 2:1).

[0017] As used herein, the term "hemisuccinate" refers to a salt having a stoichiometric ratio of two molecules of the compound of Formula I to one molecule of the succinate counterion or succinic acid. The hemisuccinate of the compound of Formula I may be represented as shown below:

[0018]

[0019] As used herein and unless otherwise specified, the terms “succinate” or “succinate” refer to a salt having a viable stoichiometric ratio (e.g., 1:1, 1:2, 2:1, etc.) of the compound of Formula I (i.e., ribociclib) to the succinate counterion or succinic acid. In other words, the terms “succinate” or “succinate” include, but are not limited to, the hemisuccinate and succinate (or monosuccinate) described by Formula II of this specification. Similarly, the terms “hydrate” or “hydrated form” refer to a hydrate having a viable stoichiometric ratio (e.g., 1:1, 1:2, 2:1, etc.) of the compound of Formula I (i.e., ribociclib) to water molecules, which include, but are not limited to, hemihydrates, monohydrates, or dihydrates.

[0020] Designations used in this specification to characterize specific forms, e.g., "E, F, H A or H B"etc. should not be considered restrictive to any other substance having similar or identical physical and chemical characteristics; rather, such names should be understood as merely identifiers to be interpreted in accordance with the characteristic identification information presented in this specification.

[0021] In another aspect, the present invention also relates to novel crystalline forms(s) of ribociclib succinate (variation E, variation F, variation H B or deformation H A This relates to a pharmaceutical composition containing ).

[0022] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 3% w / w of the total amount of ribociclib or its salt.

[0023] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 5% w / w or more of the total amount of ribociclib or a salt thereof.

[0024] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 10% w / w or more of the total amount of ribociclib or its salt.

[0025] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 20% w / w of the total amount of ribociclib or its salt.

[0026] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 30% w / w of the total amount of ribociclib or its salt.

[0027] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 40% w / w of the total amount of ribociclib or its salt.

[0028] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 50% w / w of the total amount of ribociclib or its salt.

[0029] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 60% w / w of the total amount of ribociclib or its salt.

[0030] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 70% w / w of the total amount of ribociclib or its salt.

[0031] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is at least about 80% w / w of the total amount of ribociclib or its salt.

[0032] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 90% w / w or more of the total amount of ribociclib or a salt thereof.

[0033] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein ribociclib or a salt thereof is substantially a pure variant E.

[0034] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 90% w / w of the total amount of ribociclib or a salt thereof.

[0035] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 80% w / w of the total amount of ribociclib or a salt thereof.

[0036] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 70% w / w of the total amount of ribociclib or a salt thereof.

[0037] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 60% w / w of the total amount of ribociclib or a salt thereof.

[0038] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 50% w / w of the total amount of ribociclib or a salt thereof.

[0039] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 40% w / w of the total amount of ribociclib or a salt thereof.

[0040] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 30% w / w of the total amount of ribociclib or a salt thereof.

[0041] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 20% to about 30% w / w of the total amount of ribociclib or a salt thereof.

[0042] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 30% to about 40% w / w of the total amount of ribociclib or a salt thereof.

[0043] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification E is about 3% to about 20% w / w of the total amount of ribociclib or a salt thereof.

[0044] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein variant E is up to 10% (e.g., less than about 10%, about 0% to about 10%, about 0.5% to 10%, or up to about 5%, up to about 3%, or about 3 to 5%) of the total amount of ribociclib or its salt thereof w / w.

[0045] The present invention also relates to a treatment method utilizing a novel anhydrous crystalline form modification E of ribociclib succinate.

[0046] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is at least about 3% w / w of the total amount of ribociclib or its salt.

[0047] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is at least about 5% w / w of the total amount of ribociclib or its salt.

[0048] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is at least about 10% w / w of the total amount of ribociclib or its salt.

[0049] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is at least about 20% w / w of the total amount of ribociclib or its salt.

[0050] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 30% w / w or more of the total amount of ribociclib or its salt.

[0051] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is at least about 40% w / w of the total amount of ribociclib or its salt.

[0052] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 50% w / w or more of the total amount of ribociclib or its salt.

[0053] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 60% w / w or more of the total amount of ribociclib or its salt.

[0054] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 70% w / w or more of the total amount of ribociclib or its salt.

[0055] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is at least about 80% w / w of the total amount of ribociclib or its salt.

[0056] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 90% w / w or more of the total amount of ribociclib or its salt.

[0057] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein ribociclib or a salt thereof is substantially a pure variant F.

[0058] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 90% w / w of the total amount of ribociclib or a salt thereof.

[0059] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 80% w / w of the total amount of ribociclib or a salt thereof.

[0060] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 70% w / w of the total amount of ribociclib or a salt thereof.

[0061] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 60% w / w of the total amount of ribociclib or a salt thereof.

[0062] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 50% w / w of the total amount of ribociclib or a salt thereof.

[0063] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 40% w / w of the total amount of ribociclib or a salt thereof.

[0064] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 30% w / w of the total amount of ribociclib or a salt thereof.

[0065] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 20% to about 30% w / w of the total amount of ribociclib or a salt thereof.

[0066] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 30% to about 40% w / w of the total amount of ribociclib or a salt thereof.

[0067] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modification F is about 3% to about 20% w / w of the total amount of ribociclib or a salt thereof.

[0068] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the modified F is up to 10% (e.g., less than about 10%, about 0% to about 10%, about 0.5% to 10%, or up to about 5%, up to about 3%, or about 3 to 5%) of the total amount of ribociclib or its salt thereof w / w.

[0069] In an embodiment, the present invention also relates to a treatment method utilizing a novel anhydrous crystalline form modification F of ribociclib hemisuccinate.

[0070] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 3% w / w or more of the total amount of ribociclib or its salt.

[0071] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 5% w / w or more of the total amount of ribociclib or its salt.

[0072] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 10% w / w or more of the total amount of ribociclib or its salt.

[0073] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 20% w / w or more of the total amount of ribociclib or its salt.

[0074] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 30% w / w or more of the total amount of ribociclib or its salt.

[0075] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 40% w / w or more of the total amount of ribociclib or its salt.

[0076] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 50% w / w or more of the total amount of ribociclib or its salt.

[0077] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 60% w / w or more of the total amount of ribociclib or its salt.

[0078] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 70% w / w or more of the total amount of ribociclib, or its salt.

[0079] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 80% w / w or more of the total amount of ribociclib or its salt.

[0080] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 90% w / w or more of the total amount of ribociclib, or its salt.

[0081] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein the ribociclib or the salt thereof is substantially pure modified H B am.

[0082] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 10% to about 90% w / w of the total amount of ribociclib, or its salt.

[0083] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 10% to about 80% w / w of the total amount of ribociclib, or its salt.

[0084] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 10% to about 70% w / w of the total amount of ribociclib or its salt.

[0085] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 10% to about 60% w / w of the total amount of ribociclib or its salt.

[0086] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 10% to about 50% w / w of the total amount of ribociclib or its salt.

[0087] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 10% to about 40% w / w of the total amount of ribociclib or its salt.

[0088] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 10% to about 30% w / w of the total amount of ribociclib or its salt.

[0089] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 20% to about 30% w / w of the total amount of ribociclib or its salt.

[0090] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B It is about 30% to about 40% w / w of the total amount of ribociclib or its salt.

[0091] In one embodiment, the present invention relates to a pharmaceutical composition comprising ribociclib or a salt thereof, wherein modified H B is about 10% to about 20% w / w of the total amount of ribociclib or its salt.

[0092] Each specific form disclosed herein in the pharmaceutical composition (i.e., variations E, F, H) A or H B The concentration of (e.g., weight percentage or mole percentage) can be measured and determined by conventional methods, such as XRPD (X-ray powder diffraction) data analysis.

[0093] The present invention also relates to a novel crystalline form modification H of ribociclib succinate. B This concerns a treatment method using [it].

[0094] The present invention also relates to a pharmaceutical composition comprising a combination of variants A and E of ribociclib succinate.

[0095] The present invention also relates to variations A and H of ribociclib succinate. B This relates to a pharmaceutical composition comprising a combination of

[0096] The present invention also relates to variations E and H of ribociclib succinate. A This relates to a pharmaceutical composition comprising a combination of Brief explanation of the drawing

[0097] Figure 1 shows the XRPD diffraction pattern of variant A of ribociclib succinate reported by reflection method. Figure 2 shows the XRPD diffraction pattern of the anhydrous strain E of ribociclib succinate reported by reflection method. Figure 3 shows the XRPD diffraction pattern of the anhydrous strain F of ribociclib succinate reported by reflection method. Figure 4 shows the modified H of ribociclib succinate B It shows the XRPD diffraction pattern. Figure 5 shows the modified H of ribociclib succinate reported by the reflection method. A It shows the XRPD diffraction pattern. Figure 6 shows the DSC (differential scanning calorimetry) trace of ribociclib succinate variant A. Figure 7 shows the DSC trace of anhydrous ribociclib succinate variant E. Figure 8 shows the DSC trace of anhydrous ribociclib succinate variant F. Fig. 9 shows the modified H of ribociclib succinate dihydrate at a heating rate of 10°C / min in a closed gold crucible. B Shows the DSC plot. Figure 10 shows the thermogravimetric curve of ribociclib succinate variant A. Figure 11 shows the thermogravimetric curve of anhydrous ribociclib succinate variant E. Figure 12 shows the thermogravimetric curve of anhydrous ribociclib succinate modified F. Fig. 13 shows deformation H at a heating rate of 10°C per minute. B It shows the thermogravimetric curve. Figure 14 shows the DVS (Dynamic Vapor Adsorption) isotherm of ribociclib succinate variant A at 25°C. Figure 15 shows the DVS isotherm of anhydrous ribociclib succinate variant E at 25°C. Figure 16 shows ribociclib succinate dihydrate H at 25°C. B Plot the DVS isotherm. Specific details for implementing the invention

[0098] The present invention relates to several novel crystalline forms(s) of the succinate(s) of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide. 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide is known by its INN ribociclib.

[0099] In one embodiment, the novel crystalline form is a variant E, also referred to as Mod. E or form E. The variant E is anhydrous ribociclib succinate and is described by the following chemical formula II:

[0100] [Chemical Formula II]

[0101] .

[0102] In another embodiment, the novel crystalline form is a variant F, also referred to as Mod. F or form F. The variant F is anhydrous ribociclib hemisuccinate.

[0103] In another embodiment, the novel crystalline form is deformation H B , or Mod. H B , or form H B It is called. Variant HB is ribociclib succinate dihydrate.

[0104] In an additional embodiment, the novel crystalline form is deformation H A , or Mod. H A or form H A It is called. Variant H A is a hydrated form of ribociclib hemisuccinate.

[0105] The present invention further relates to a pharmaceutical composition comprising a modified E and at least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient.

[0106] The present invention further modifies H B The invention relates to a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient.

[0107] The present invention further modifies H A The invention relates to a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient.

[0108] The present invention also relates to a method for treating a disease responsive to inhibition of a cyclin-dependent kinase (particularly, a cyclin-dependent kinase selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, and CDK9), comprising the step of administering a therapeutically effective amount of modified E to a subject requiring such treatment.

[0109] The present invention also relates to a therapeutically effective amount of modified H B The present invention relates to a method for treating a disease that responds to the inhibition of a cyclin-dependent kinase (particularly, a cyclin-dependent kinase selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, and CDK9), comprising the step of administering the substance to a subject requiring such treatment.

[0110] The present invention also relates to a therapeutically effective amount of modified H AThe present invention relates to a method for treating a disease that responds to the inhibition of a cyclin-dependent kinase (particularly, a cyclin-dependent kinase selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, and CDK9), comprising the step of administering the substance to a subject requiring such treatment.

[0111] These diseases responding to the inhibition of cyclin-dependent kinases include breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermal carcinoma, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, head and neck cancer, or bladder cancer, or in a broad sense, renal cell carcinoma, brain, or gastric cancer; leukemia, hyperplasia, gastric cancer, colon cancer, laryngeal cancer, lymphoma, genitourinary cancer, bone cancer, prostate cancer, small cell lung cancer, glioma, colorectal cancer, kidney cancer, epidermal carcinoma, liver cancer, esophageal cancer, hematopoietic cancer, lymphoma, multiple myeloma, thyroid follicular carcinoma; tumors of mesenchymal origin, e.g., fibrosarcoma or rhabdomyosarcoma; tumors of the central or peripheral nervous system, e.g., astrocytoma, neuroblastoma, glioma, or schwannoma; melanoma; seminoma; teratoma; osteosarcoma; xeroderma pigmentosa; acanthoma; thyroid follicular carcinoma; Includes, but is not limited to, Kaposi's sarcoma, chronic lymphocytic leukemia, mantle cell lymphoma, and large B-cell lymphoma.

[0112] In one specific embodiment, the disease is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal women.

[0113] "Substantially pure" as used herein means, when used in relation to form, that the compound has a purity of greater than 90 wt% based on the weight of the compound (including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 wt%, and also including about 100 wt%). The remaining material comprises other form(s) of the compound and / or reaction impurities and / or processing impurities resulting from its manufacture. For example, the crystalline form of ribociclib succinate may be considered substantially pure in that it has a purity of greater than 90 wt% when measured by methods known and generally accepted in the art (e.g., the European Pharmacopoeia or USP), and the remaining material of less than 10 wt% comprises other form(s) of ribociclib succinate and / or reaction impurities and / or processing impurities.

[0114] "Therapeutic effective dose" is intended to mean an amount of compound sufficient to achieve treatment for a disease state alleviated by the inhibition of cyclin-dependent kinase activity when administered to a subject requiring treatment. The therapeutically effective amount of a given compound of the present invention will vary depending on factors such as the disease state and its severity, and the identity of the subject requiring such treatment, and this amount can be routinely determined by a person skilled in the art.

[0115] "At least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient" may be readily selected by a person skilled in the art and will be determined by the intended mode of administration. Exemplary examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal. The pharmaceutical composition of the present invention may take any pharmaceutical form that is recognized as suitable by a person skilled in the art. Suitable pharmaceutical forms include solid, semi-solid, liquid, or lyophilized formulations, e.g., tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.

[0116] With respect to X-ray diffraction peak positions, the terms "substantially identical" or "substantially according to" mean that typical peak position and intensity variability are taken into account. For example, those skilled in the art will acknowledge that the peak position (2θ) will typically exhibit some degree of inter-device variability of 0.2°. Additionally, those skilled in the art will acknowledge that relative peak intensity will exhibit variability due to crystallinity, preferred orientation, surface of the prepared sample, and other factors known to those skilled in the art, as well as inter-device variability, and should be considered only as a qualitative measure.

[0117] In both the detailed description and the claims of the invention, the use of the singular form shall be interpreted as encompassing both the singular and plural forms unless otherwise indicated in this specification or clearly contradictory in the context. Terms such as “having,” “comprising,” and “containing,” as in “comprising,” “having a chemical formula,” shall be considered open terms (i.e., meaning “comprising, but not limited thereto”) unless otherwise indicated. Furthermore, it should be understood that whenever “comprising” or other open terms are used in an embodiment, the same embodiment may be claimed more narrowly by using the intermediate term “essentially comprising” or the closed term “comprising.”

[0118] When used in relation to numerical values, the terms “about,” “approximately,” or “approximate” mean that a collection or range of values ​​is included. For example, “about X” includes a range of values ​​that are ±20%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of X, where X is a numerical value. In one embodiment, the term “about” refers to a range of values ​​that are 10% more or less than a specified value. In another embodiment, the term “about” refers to a range of values ​​that are 5% more or less than a specified value. In yet another embodiment, the term “about” refers to a range of values ​​that are 1% more or less than a specified value.

[0119] Unless otherwise stated, the enumeration of ranges of values ​​is intended merely to serve as a method of individually referring to each individual value within the range, and each individual value is incorporated into the specification as if individually cited in the specification. Unless otherwise stated, the ranges used in the specification include two limits of the range. For example, the terms “between X and Y” and “range between X and Y” include X and Y and the integers between them. Meanwhile, when a series of individual values ​​is mentioned in the specification (excluding 2-θ values ​​in XRPD patterns), any range including any two individual values ​​as two endpoints is also included in the specification. For example, the expression “purity of 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 wt%” may also mean “purity of the range of 90 wt% to 95 wt%”, “purity of the range of 93 wt% to 97 wt%”, or “purity of the range of 90 wt% to 99 wt%”.

[0120] Modification E is anhydrous. The crystalline form disclosed in WO2012 / 064805 is hereinafter referred to herein as Modification A or Mod. A.

[0121] Deformation E, Deformation F, Deformation H A , deformation H Band / or control variant A is characterized by various methods including single X-ray data, X-ray powder diffraction (XRPD), DSC, Karl Fischer titration, etc.

[0122] In one embodiment, the strain E exhibits an X-ray powder diffraction pattern having characteristic peaks represented by °2-θ at angles of 11.0° + / - 0.2°, 13.0° + / - 0.2°, and 17.2° + / - 0.2°. In another embodiment, the strain E exhibits an X-ray powder diffraction pattern having at least four characteristic peaks represented by °2-θ selected from 11.0° + / - 0.2°, 13.0° + / - 0.2°, 17.2° + / - 0.2°, 20.0° + / - 0.2°, and 23.0° + / - 0.2°. In another embodiment, the strain E exhibits an X-ray powder diffraction pattern having at least five characteristic peaks represented by °2-θ selected from 8.8° + / - 0.2°, 11.0° + / - 0.2°, 13.0° + / - 0.2°, 13.7° + / - 0.2°, 15.7° + / - 0.2°, 17.2° + / - 0.2°, 18.7° + / - 0.2°, 20.0° + / - 0.2°, 21.1° + / - 0.2°, 23.0° + / - 0.2°, and 24.9° + / - 0.2°. In another embodiment, the strain E exhibits an X-ray powder diffraction pattern having at least seven characteristic peaks represented by °2-θ selected from 7.9° + / - 0.2°, 8.8° + / - 0.2°, 11.0° + / - 0.2°, 12.4° + / - 0.2°, 13.0° + / - 0.2°, 13.7° + / - 0.2°, 15.7° + / - 0.2°, 17.2° + / - 0.2°, 18.7° + / - 0.2°, 20.0° + / - 0.2°, 21.1° + / - 0.2°, 23.0° + / - 0.2°, and 24.9° + / - 0.2°. In an additional embodiment, deformation E substantially represents an X-ray powder diffraction pattern according to FIG. 2 or Table 4.

[0123] In one embodiment, strain F exhibits an X-ray powder diffraction pattern having characteristic peaks represented by °2-θ at angles of 4.9° + / - 0.2°, 11.9° + / - 0.2°, and 12.6° + / - 0.2° (CuKα λ= 1.5406 Å). In another embodiment, strain F exhibits an X-ray powder diffraction pattern having at least three characteristic peaks represented by °2-θ selected from 4.9° + / - 0.2°, 11.9° + / - 0.2°, 12.6° + / - 0.2°, and 22.8° + / - 0.2°. In another embodiment, the strain F exhibits an X-ray powder diffraction pattern having at least four characteristic peaks represented by °2-θ selected from 4.9° + / - 0.2°, 11.9° + / - 0.2°, 12.6° + / - 0.2°, 22.8° + / - 0.2°, and 26.6° + / - 0.2°. In another embodiment, the strain F exhibits an X-ray powder diffraction pattern having at least five characteristic peaks represented by °2-θ selected from 4.9° + / - 0.2°, 11.9° + / - 0.2°, 12.6° + / - 0.2°, 22.8° + / - 0.2°, 26.6° + / - 0.2°, and 29.4° + / - 0.2°. In an additional embodiment, the deformation F substantially exhibits an X-ray powder diffraction pattern according to FIG. 3 or Table 5.

[0124] In one embodiment, deformation H B represents an X-ray powder diffraction pattern having characteristic peaks expressed as °2-θ at angles of 6.4° + / - 0.2° and 20.6° + / - 0.2°. In another embodiment, strain H B represents an X-ray powder diffraction pattern having at least three characteristic peaks represented by °2-θ selected from 6.4° + / - 0.2°, 20.1° + / - 0.2°, 20.6° + / - 0.2°, 22.7° + / - 0.2°, and 26.5° + / - 0.2°. In another embodiment, deformation H Brepresents an X-ray powder diffraction pattern having at least five characteristic peaks represented by °2-θ selected from 6.4° + / - 0.2°, 7.4° + / - 0.2°, 10.1° + / - 0.2°, 10.7° + / - 0.2°, 11.9° + / - 0.2°, 20.1° + / - 0.2°, 20.6° + / - 0.2°, 22.7° + / - 0.2°, 26.5° + / - 0.2°, and 33.9° + / - 0.2°. In a further embodiment, the modified H B It substantially represents the X-ray powder diffraction pattern according to Fig. 4 or Table 6.

[0125] In one embodiment, deformation H A represents an X-ray powder diffraction pattern having characteristic peaks expressed as °2-θ at angles of 4.7° + / - 0.2°, 18.5° + / - 0.2°, and 22.1° + / - 0.2°. In another embodiment, strain H A represents an X-ray powder diffraction pattern having at least four characteristic peaks represented by °2-θ selected from 4.7° + / - 0.2°, 13.0° + / - 0.2°, 18.5° + / - 0.2°, 20.0° + / - 0.2°, 21.6° + / - 0.2°, and 22.1° + / - 0.2°. In another embodiment, deformation H A represents an X-ray powder diffraction pattern having at least six characteristic peaks represented by °2-θ selected from 4.7° + / - 0.2°, 10.7° + / - 0.2°, 13.0° + / - 0.2°, 16.2° + / - 0.2°, 17.9° + / - 0.2°, 18.5° + / - 0.2°, 20.0° + / - 0.2°, 21.6° + / - 0.2°, 22.1° + / - 0.2°, 26.2° + / - 0.2°, and 28.8° + / - 0.2°. In another embodiment, deformation H Arepresents an X-ray powder diffraction pattern having at least eight characteristic peaks represented by °2-θ selected from 4.7° + / - 0.2°, 8.9° + / - 0.2°, 10.7° + / - 0.2°, 13.0° + / - 0.2°, 16.2° + / - 0.2°, 17.9° + / - 0.2°, 18.5° + / - 0.2°, 20.0° + / - 0.2°, 21.6° + / - 0.2°, 22.1° + / - 0.2°, 26.2° + / - 0.2°, and 28.8° + / - 0.2°. In a further embodiment, the modified H A It substantially represents the X-ray powder diffraction pattern according to Fig. 5 or Table 7.

[0126] In another aspect, the present invention comprises: providing a solution of ribociclib monosuccinate in an organic solvent (e.g., alcohol, e.g., isopropanol) at a concentration of about 0.1 mg / mL to about 1.0 mg / mL (e.g., about 0.2 to 0.8 mg / mL, 0.3 to 0.7 mg / mL, 0.35 to 0.5 mg / mL, 0.4 to 0.6 mg / mL), wherein the solution is substantially free of water and is maintained at a first temperature in the range of about 50°C to about 80°C (e.g., about 55°C to 65°C, about 60°C) for a first time period (e.g., at least about 3, 5, 7, 10, 14 days, or at least about 21 days) (e.g., under shaking); adding a modification A to the solution to form a mixture at the first temperature; The present invention relates to a method for preparing modified E, comprising the step of maintaining the mixture at a first temperature for a second time period (e.g., at least about 12 hours, at least about 1 day, 2 days, 3 days, or at least about 4 days) (e.g., under shaking) and then removing an organic solvent (e.g., isopropanol) from the mixture (e.g., by evaporation) to obtain modified E. In one embodiment, the obtained modified E is a seed material.

[0127] In another aspect, the present invention comprises: (a) providing a succinic acid solution in a first organic solvent (e.g., alcohol, e.g., 2-propanol) at a second temperature in the range of about 70°C to about 85°C (e.g., about 72 to 78°C, about 73 to 77°C, about 74 to 76°C, about 75°C); (b) providing a free base solution of ribociclib in a second organic solvent (e.g., alcohol, e.g., 2-propanol) at a third temperature in the range of about 60°C to about 85°C (e.g., about 62 to 80°C, about 72 to 78°C, about 73 to 77°C, about 74 to 76°C, about 75°C); (c) transferring a free base solution of ribociclib to a crystallization vessel (e.g., through a preheated plate filter, an activated carbon filter cartridge, and a particle filter via a preheated (e.g., about 75°C) transfer line); (d) adding a succinic acid solution to the crystallization vessel at a fourth temperature in the range of about 60°C to about 85°C (e.g., 62 to 80°C, about 72 to 78°C, about 73 to 77°C, about 74 to 76°C, about 75°C) by transferring it to a particle filter; (e) immediately after the addition in (d) is completed, adding a seed crystal of pure Mod E (e.g., using at least 1 mass / % of the seed crystal related to the expected ribociclib succinate yield, as in a 2-propanol suspension) to obtain a turbid mixture (after stirring at a medium to high stirring speed for about 15 minutes); (f) cooling the turbid mixture to a fifth temperature in the range of about 0°C to about 20°C (e.g., about 5°C to 15°C or about 10°C) to obtain modified E; (g) optionally separating modified E from the mixture (e.g., by isolating modified E through filtration), and optionally rinsing the filtered solid with an organic solvent, e.g., 2-propanol;and (h) optionally, a step of drying the deformation E obtained from step (g) at, for example, a jacket temperature of 60°C and, for example, at 20 mbar or less. The invention relates to a method for producing deformation E, comprising the step of drying the deformation E obtained from step (g).

[0128] Specific embodiments of the present invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed only as a method of illustrating the invention and should not be taken as limiting the scope of the invention in any way.

[0129] Example 1 Generation of seed material for deformation E

[0130] It is extremely difficult to generate deformation E in the absence of seed material. To generate Mod. E, the following experiment was performed.

[0131] 3 Å of activated molecular sieve beads with 3 beads was added to 3.5 mL of a solution of ribociclib monosuccinate in dry isopropanol at a concentration ranging from 0.35 to 0.50 mg / mL at 60°C. The resulting mixture was maintained for 2 weeks under gentle shaking (e.g., using a low-frequency vibrating shaker). Approximately 10 mg of ribociclib succinate Mod. A was added to the reaction mixture, and the solution was maintained under shaking at 60°C for an additional 2 days. The molecular sieve beads were removed, and the solution was gently evaporated until dry. The resulting powder, consisting of Mod. E and trace amounts of molecular sieve as confirmed by XRPD analysis, was used for further experiments as described below.

[0132] Example 2 Generation of Mod. E using seed material

[0133] Succinic acid was dissolved in 2-propanol at 72 to 78°C.

[0134] The free base of ribociclib was dissolved in 2-propanol at 72 to 78°C (the free base typically dissolves above 62°C). After stirring for up to 30 minutes, a clear or slightly cloudy solution was obtained.

[0135] A free base solution of ribociclib in 2-propanol was delivered to a crystallization vessel (jacket temperature of 75°C) through a preheated (75°C) delivery line, a preheated plate filter, an activated carbon filter cartridge, and a particle filter. The delivery line was rinsed with warm 2-propanol.

[0136] The succinic acid solution in 2-propanol was passed through a particle filter to the ribociclib free base solution in a crystallization vessel at 73 to 77°C over a period of approximately 60 minutes. Immediately after the addition was completed, a seed crystal suspension of pure Mod E in 2-propanol (at least 1 mass / seed %) relative to the expected ribociclib succinate yield was added. Stirring was continued at a medium to high stirring speed, and after approximately 15 minutes, turbidity was observed. The vessel containing the succinic acid was rinsed with 2-propanol, and the suspension was cooled to an internal temperature of 10°C over approximately 20 hours.

[0137] The product was isolated by filtration through a Nutsche filter, and the wet cake was rinsed with 2-propanol. Subsequently, the wet filter cake was dried at a jacket temperature of 60°C and below 20 mbar.

[0138] Example 3 Modified H, which is ribociclib succinate dihydrate B formation of

[0139] Ribociclib succinate variant A is variant H in the dihydrate form. B It can be converted to. This can occur when exposed to water activity higher than 70% relative humidity (RH). This conversion is observed in large quantities at 40°C / 75% RH. The conversion is observed under solvent-mediated conditions with appropriate water activity.

[0140] Deformation H BIt can also be converted from modification E. Modification H of ribociclib succinate from the suspension equilibrium state of modification E of ribociclib succinate at a water activity (aH2O) of 0.68 or greater at 25°C. B It was obtained. It was found in the suspension equilibrium state of a mixture of ethanol and water at 5°C, 25°C, and 50°C. It can be obtained as the main component of the suspension equilibrium product in pure water at 25°C.

[0141] Example 4 XRPD

[0142] Bruker D8 Advance; LynxEye detector; Cu-Kα radiation; standard measurement conditions: Bragg-Brentano reflection geometry, 40 kV and 40 mA tube power, 0.02° 2θ step size, 37 s step time, 2.5 to 50° 2θ scanning range. Powder samples were measured in a silicon single-crystal sample holder to a depth of 0.1 mm. No special treatment was applied to the samples other than applying slight pressure to obtain a flat surface. An ambient air atmosphere was used for all measurements. All samples were rotated during measurement.

[0143] Example 5 XRPD of ribociclib succinate of variant A

[0144] The deformation A of ribociclib succinate was characterized by XRPD in the reflection method, and the diffraction pattern is presented in Fig. 1.

[0145] Table 3 below shows the XRPD peaks for variant A of ribociclib succinate measured by reflection using a copper K alpha source.

[0146]

[0147] Example 6 XRPD of ribociclib succinate of variant E

[0148] The deformation E of ribociclib succinate was characterized by XRPD in the reflection method (Fig. 2).

[0149] Table 4 below shows the XRPD peaks for the anhydrous strain E of ribociclib succinate measured by the reflection method using a copper K alpha source.

[0150]

[0151] The strain E is characterized by an X-ray powder diffraction pattern having peaks at 11.0° + / - 0.2°, 13.0° + / - 0.2°, and 17.2° + / - 0.2° (CuKα λ= 1.5406 Å).

[0152] The strain E additionally features a powder x-ray diffraction pattern containing four or more 2θ values ​​(CuKα λ= 1.5406 Å) selected from the group consisting of 11.0° + / - 0.2°, 13.0° + / - 0.2°, 17.2° + / - 0.2°, 20.0° + / - 0.2° and 23.0° + / - 0.2° at a temperature of about 22°.

[0153] The strain E additionally features a powder x-ray diffraction pattern containing at least five 2θ values ​​(CuKα λ= 1.5406 Å) selected from the group consisting of 8.8° + / - 0.2°, 11.0° + / - 0.2°, 13.0° + / - 0.2°, 13.7° + / - 0.2°, 15.7° + / - 0.2°, 17.2° + / - 0.2°, 18.7° + / - 0.2°, 20.0° + / - 0.2°, 21.1° + / - 0.2°, 23.0° + / - 0.2° and 24.9° + / - 0.2° at a temperature of about 22°.

[0154] Strain E additionally features a powder X-ray diffraction pattern containing at least six 2θ values ​​(CuKα λ = 1.5406 Å) selected from the group consisting of 7.9° + / - 0.2°, 8.8° + / - 0.2°, 11.0° + / - 0.2°, 12.4° + / - 0.2°, 13.0° + / - 0.2°, 13.7° + / - 0.2°, 15.7° + / - 0.2°, 17.2° + / - 0.2°, 18.7° + / - 0.2°, 20.0° + / - 0.2°, 21.1° + / - 0.2°, 23.0° + / - 0.2°, and 24.9° + / - 0.2°. does.

[0155] Example 7 XRPD of ribociclip hemisuccinate variant F

[0156] The modified F of ribociclib succinate was characterized by XRPD in the reflection method (Fig. 3).

[0157] Table 5 below shows the XRPD peaks for the anhydrous strain F of ribociclib hemisuccinate measured by the reflection method using a copper K alpha source.

[0158]

[0159] The strain F is characterized by an X-ray powder diffraction pattern having peaks at 4.9° + / - 0.2°, 11.9° + / - 0.2°, and 12.6° + / - 0.2° (CuKα λ= 1.5406 Å).

[0160] The strain F additionally features a powder x-ray diffraction pattern containing four or more 2θ values ​​(CuKα λ= 1.5406 Å) selected from the group consisting of 4.9° + / - 0.2°, 11.9° + / - 0.2°, 12.6° + / - 0.2° and 22.8° + / - 0.2° at a temperature of approximately 22°.

[0161] The strain F additionally features a powder x-ray diffraction pattern containing at least five 2θ values ​​(CuKα λ= 1.5406 Å) selected from the group consisting of 4.9° + / - 0.2°, 11.9° + / - 0.2°, 12.6° + / - 0.2°, 22.8° + / - 0.2° and 26.6° + / - 0.2° at a temperature of about 22°.

[0162] The strain F additionally features a powder x-ray diffraction pattern containing at least six 2θ values ​​(CuKα λ= 1.5406 Å) selected from the group consisting of 4.9° + / - 0.2°, 11.9° + / - 0.2°, 12.6° + / - 0.2°, 22.8° + / - 0.2°, 26.6° + / - 0.2° and 29.4° + / - 0.2° at a temperature of about 22°.

[0163] Example 8 Deformation H B XRPD and KF of Ribociclib Succinate

[0164] Variation of ribociclib succinate H B It is characterized by XRPD and shown in Fig. 4.

[0165] Table 6 below shows the deformation H of ribociclib succinate measured by the reflection method using a copper K alpha source. B It shows the XRPD peak for.

[0166]

[0167] The frequent appearance of this form under aqueous conditions gave rise to the hypothesis that it may be a hydrated form. The monohydrate of ribociclib succinate would theoretically contain 3.2 wt% H2O, 4.7 wt% sesquihydrate, and 6.1 wt% dihydrate. Variant H of ribociclib succinate B The Karl-Fischer titration of indicates a water content of 6.1 wt%, with deformation H B It is consistent with the fact that it is monosuccinate dihydrate.

[0168] Example 9 Ribociclip hemisuccinate hydrate modification H A XRPD

[0169] Modification of ribociclib hemisuccinate hydrate H A It was characterized by XRPD using a reflection method with a copper K alpha source. The diffraction pattern is presented in Fig. 5.

[0170]

[0171] Example 10 Differential Scanning Calorimetry (DSC)

[0172] A DSC study was conducted with the following settings.

[0173]

[0174] Example 11 DSC study of ribociclib succinate Mod A

[0175] The DSC curve of ribociclib succinate variant A is strongly influenced by the heating rate regarding decomposition. Since thermal events are related to melting / decomposition, the associated enthalpy values ​​are reported for informational purposes only. Refer to Table 8.

[0176] When deformation A is heated in a DSC at 10 K / min, it exhibits decomposition at approximately 205°C following melting.

[0177] Figure 6 shows the DSC plot of ribociclib succinate variant A at a heating rate of 10°C per minute.

[0178]

[0179] Example 12 DSC study of ribociclib succinate Mod E

[0180] The DSC curve of the deformation E of ribociclib succinate is strongly influenced by the heating rate regarding decomposition. Since the thermal event is related to melting / decomposition, the associated enthalpy values ​​are reported for informational purposes only. Refer to Table 9.

[0181] Figure 7 shows the DSC plot of ribociclib succinate deformation E at a heating rate of 10°C per minute.

[0182]

[0183] Example 13 DSC study of ribociclib succinate variant F

[0184] The DSC curve of the ribociclib succinate variant F is strongly influenced by the heating rate regarding decomposition. Since thermal events are related to melting / decomposition, the associated enthalpy values ​​are reported for informational purposes only. Refer to Table 10.

[0185] Figure 8 shows the DSC plot of ribociclib succinate modified F at a heating rate of 10°C per minute.

[0186]

[0187] Example 14 Ribociclip succinate modification H B DSC study

[0188] Modified H, which is ribociclib succinate dihydrate B The DSC curve is very complex. The first event is likely related to the loss of water molecules occurring in two stages, which is in good agreement with thermogravimetric analysis. These events are likely dependent on kinetic conditions. Other thermal events are difficult to explain.

[0189] When comparing standard DSC data obtained from an Al crucible with data from a sealed gold crucible, ribociclib succinate H B It melts at about 155°C. Decomposition follows the melting.

[0190] Due to the dependence of the melting event as a function of the heating rate of the ribociclib succinate-related phase and typical melt decomposition, it was not possible to impart the phase obtained after dehydration.

[0191] Fig. 9 shows the modified H of ribociclib succinate dihydrate at a heating rate of 10°C / min in a closed gold crucible. B Shows the DSC plot.

[0192]

[0193] Example 15 The thermogravimetric of deformation A

[0194] According to DSC studies, ribociclib succinate variant A undergoes decomposition at approximately 200°C. From 30°C to 180°C, the loss of dryness is less than 0.05%, and decomposition continues.

[0195] Figure 10 shows the thermogravimetric curve of deformation A at a heating rate of 10°C per minute.

[0196] Example 16 The thermogravimetric of deformation E

[0197] In good agreement with DSC studies, ribociclib succinate variant E undergoes decomposition at approximately 200°C. From 30°C to 180°C, the loss of dryness is less than 0.05%.

[0198] Figure 11 shows the thermogravimetric curve of strain E at a heating rate of 10°C per minute.

[0199] Example 17 The thermogravimetric of deformation F

[0200] In good agreement with DSC studies, ribociclib succinate variant F undergoes degradation at approximately 0.9°C. From 30°C to 140°C, the loss of dryness is less than 0.0%.

[0201] Figure 12 shows the thermogravimetric curve of strain F at a heating rate of 10°C per minute.

[0202] Example 18 Deformation H B The thermogravimetric weight of

[0203] In good agreement with the DSC study, the modified H, ribociclib succinate dihydrate B It undergoes water loss at approximately 120°C, corresponding to a mass loss of about 5.8%. This mass loss was found to be consistent with the water (6.1%) determined by Karl Fischer. The substance also decomposes at approximately 200°C.

[0204] Fig. 13 shows deformation H at a heating rate of 10°C per minute. B It shows the thermogravimetric curve.

[0205] Example 19 Hygroscopicity Research

[0206] A. Adsorption / Desorption Isotherm: Anhydrous Variation of Mod A and Mod E

[0207] Anhydrous variants A and E of ribociclib succinate were submitted for DVS analysis.

[0208] The results are reported in Figures 14 and 15 and Table 12.

[0209] Figure 14 shows the DVS isotherms of ribociclib succinate variant A at 25°C.

[0210] Figure 15 shows the DVS isotherm of ribociclib succinate deformation E at 25°C.

[0211]

[0212] As shown above, ribociclib succinate variant A took up to about 0.7% water compared to the dry state (when exposed to 0% RH) when exposed to 95% RH during a DVS cycle at 25°C, whereas ribociclib succinate variant E has a lower mass change (maximum water absorption of 0.1%).

[0213] The dataset indicates that ribociclib succinate variant A can be classified as slightly hygroscopic because the maximum mass change compared to the dry state when exposed to 92% HR is about 0.7% at 25°C.

[0214] In contrast, deformation E is classified as non-hygroscopic.

[0215] B. Adsorption / Desorption Isotherm: Ribociclib Succinate Dehydrate H B

[0216]

[0217] Fig. 16 shows ribociclib succinate dihydrate H at 25°C B Plot the DVS isotherm.

[0218] C. Research on hydrate formation

[0219] i. Exposure to ambient temperatures with varying relative humidity for one day

[0220] A fraction from ribociclib succinate variant A was exposed to a desiccator containing a saturated solution of inorganic salt or drying agent to provide a range of relative humidity.

[0221] Ribociclib succinate variant A is physically stable when exposed to up to 80% RH at ambient temperature for 1 day. When exposed to 92% RH for 1 day, some additional peaks can be detected at approximately 4.7, 6.4, 12.0, and 13.0 degrees 2θ. These peaks correspond to ribociclib hemisuccinate variant H A It can be assigned to.

[0222] Differences in peak shape and peak relative intensity are due to texture effects and sample preparation.

[0223] ii. Exposure to ambient temperatures with varying relative humidity for 10 days

[0224] Similar behavior was observed after 10 days, but complete conversion is achieved when exposed to 92% RH. The material indicates poor crystallinity and loss upon thermogravimetric drying, which is evaluated at 3.9%, in contrast to the starting material having a value lower than 0.05%.

[0225] It was found that ribociclib succinate variant A begins to deliquate upon exposure for a sufficient period at relative humidity close to or higher than 92%. When this deliquent material (corresponding to a highly concentrated solution of ribociclib succinate) dries, for example, by exposure to lower relative humidity, it can recrystallize into this other crystalline form. This crystalline form is additionally variant H A It can be verified as. This form H AFurther characterization confirmed that this refers to the hydrated form of the hemisuccinate salt of ribociclib with a ribociclib:succinic acid:water ratio of 2:1:1. Although the water content of this phase may vary depending on the sample formulation (e.g., the ribociclib:succinic acid:water ratio is not exactly 2:1:1), Mod. H A The XRPD pattern of appears to remain substantially the same as the pattern in Fig. 5.

[0226] D. Long-term exposure of Mod A to high relative humidity

[0227] During long-term stability studies of various batches exposed to 75% RH at various temperatures and less protective packaging materials, ribociclib succinate variant A was physically unstable at 40 or 50°C, causing the appearance of additional diffraction peaks when analyzed by XRPD.

Claims

Claim 1 A step of providing a solution of ribociclib monosuccinate in isopropanol at a concentration of 0.1 mg / mL to 1.0 mg / mL, wherein the solution is substantially water-free and maintained at a first temperature in the range of 50°C to 80°C for a first time period; a step of mixing modification A with the solution to form a mixture at the first temperature; A method for preparing a crystalline form of succinate of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide of the following formula I, which is a form of modified E, comprising the step of removing isopropanol from the mixture after maintaining the mixture at the first temperature for a second time period to obtain modified E, wherein the form of modified E is characterized by an X-ray powder diffraction pattern having peaks at 11.0° + / - 0.2°, 13.0° + / - 0.2°, and 17.2° + / - 0.2° (CuKα λ= 1.5406 Å) at a temperature of 22°, and the form of modified A is characterized by peaks at 7.6° + / - 0.2°, 14.4° + / - A method for manufacturing characterized by an X-ray powder diffraction pattern having peaks at 0.2°, 17.9° + / - 0.2°, 19.8° + / - 0.2° and 23.0° + / - 0.2° (CuKα λ= 1.5406 Å). [Chemical Formula I] Claim 2 (a) a step of providing a succinic acid solution in isopropanol at a second temperature in the range of 70°C to 85°C; (b) a step of providing a free base solution of ribociclib in isopropanol at a third temperature in the range of 60°C to 85°C; (c) a step of transferring the free base solution of ribociclib to a crystallization vessel; (d) a step of adding the succinic acid solution to the crystallization vessel at a fourth temperature in the range of 60°C to 85°C; (e) a step of adding a seed crystal of pure modified E immediately after the addition in (d) is completed to obtain a turbid mixture; (f) a step of cooling the turbid mixture to a fifth temperature in the range of 0°C to 20°C to obtain modified E; (g) a step of optionally separating modified E from the mixture and optionally rinsing the separated solid with isopropanol; A method for preparing a crystalline form of succinate of 7-cyclopentyl-2-(5-piperazine-1-yl-pyridine-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide of the following formula I, wherein the form of modified E comprises the step of (h) optionally drying the modified E obtained from step (g), the method wherein the modified E is characterized by an X-ray powder diffraction pattern having peaks at 11.0° + / - 0.2°, 13.0° + / - 0.2°, and 17.2° + / - 0.2° (CuKα λ= 1.5406 Å) at a temperature of 22°. [Formula I] Claim 3 A method for manufacturing, wherein, in claim 1 or 2, the form of deformation E comprises a powder X-ray diffraction pattern including four or more 2θ values ​​(CuKα λ= 1.5406 Å) selected from the group consisting of 11.0° + / - 0.2°, 13.0° + / - 0.2°, 17.2° + / - 0.2°, 20.0° + / - 0.2° and 23.0° + / - 0.2° at a temperature of 22°. Claim 4 A method of manufacturing according to claim 1 or 2, wherein the shape of deformation E comprises a powder X-ray diffraction pattern including at least five 2θ values ​​(CuKα λ= 1.5406 Å) selected from the group consisting of 8.8° + / - 0.2°, 11.0° + / - 0.2°, 13.0° + / - 0.2°, 13.7° + / - 0.2°, 15.7° + / - 0.2°, 17.2° + / - 0.2°, 18.7° + / - 0.2°, 20.0° + / - 0.2°, 21.1° + / - 0.2°, 23.0° + / - 0.2°, and 24.9° + / - 0.2° at a temperature of 22°. Claim 5 In claim 1 or 2, the form of deformation E comprises at least six 2θ values ​​(CuKα λ = 1.5406 Å) selected from the group consisting of 7.9° + / - 0.2°, 8.8° + / - 0.2°, 11.0° + / - 0.2°, 12.4° + / - 0.2°, 13.0° + / - 0.2°, 13.7° + / - 0.2°, 15.7° + / - 0.2°, 17.2° + / - 0.2°, 18.7° + / - 0.2°, 20.0° + / - 0.2°, 21.1° + / - 0.2°, 23.0° + / - 0.2°, and 24.9° + / - 0.2° at a temperature of 22°. A manufacturing method characterized by a powder X-ray diffraction pattern. Claim 6 A manufacturing method according to claim 1 or 2, characterized by a differential scanning calorimetry thermogram in which the form of deformation E is endothermic at 210℃ (± 2.5). Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete

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