Solid state forms of trilaciclib citrate salt

Abstract

The present disclosure encompasses solid state forms of Trilaciclib citrate salt, in embodiments polymorphs of Trilaciclib citrate salt, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

Attorney Docket: API050-WO01 (2222-214 PCT) SOLID STATE FORMS OF TRILACICLIB CITRATE SALT FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Trilaciclib citrate salt, in embodiments polymorphs of Trilaciclib citrate salt, processes for preparation thereof, and pharmaceutical compositions thereof. BACKGROUND OF THE DISCLOSURE

[0002] Trilaciclib, has the following chemical structure:

[0003] Trilaciclib is a small molecule with potential antineoplastic and chemoprotective activities. In particular, it is investigated for myelopreservation (preserving bone marrow function) in patients with small cell lung cancer (SCLC) that receive chemotherapy.

[0004] The compound is described in U.S. Patent No.8,598,165.

[0005] International Publication No. WO 2021 / 257587 discloses crystalline forms of Trilaciclib and Trilaciclib dihydrochloride salt. International Publication Nos. WO 2022 / 076779 and WO 2023 / 164255 describe polymorphs of Trilaciclib; different salts of Trilaciclib and polymorphs thereof; including polymorphs of the citrate salt.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0007] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improvingAttorney Docket: API050-WO01 (2222-214 PCT) formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0008] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical / physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Trilaciclib and of Trilaciclib salts. SUMMARY OF THE DISCLOSURE

[0009] The present disclosure provides crystalline polymorphs of Trilaciclib citrate salt, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other forms of Trilaciclib or of Trilaciclib salts.

[0010] The present disclosure provides crystalline polymorphs of Trilaciclib citrate salt; for use in the preparation of pharmaceutical compositions and / or formulations for use in medicine, in embodiments for the treatment of myelosuppression during chemotherapy.

[0011] The present disclosure provides crystalline polymorphs of Trilaciclib citrate salt for use in medicine, including as a chemoprotective agent (in particular; in patients suffering from SCLC that receive chemotherapy). The crystalline polymorphs of Trilaciclib citrate salt may be used as a chemo protective agent; in particular to reduce chemotherapy-induced bone marrow suppression in patients with SCLC, non-small cell lung cancer (NSCLC), colorectal cancer (particularly metastatic colorectal cancer), breast cancer (particularly metastatic triple-Attorney Docket: API050-WO01 (2222-214 PCT) negative breast cancer), and bladder cancer (particularly advanced / metastatic bladder cancer); and preferably in patients with SCLC.

[0012] The present disclosure also encompasses the use of the solid state forms of Trilaciclib citrate salt of the present disclosure for the preparation of pharmaceutical compositions and / or formulations.

[0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising any one or a combination of the polymorphs of Trilaciclib citrate salt according to the present disclosure.

[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the polymorphs of Trilaciclib citrate salt with at least one pharmaceutically acceptable excipient.

[0015] The polymorphs of Trilaciclib citrate salt as defined herein and the pharmaceutical compositions or formulations of the polymorphs of Trilaciclib citrate salt may be used as medicaments, such as for the treatment of myelosuppression during chemotherapy.

[0016] The present disclosure also provides methods of treating myelosuppression during chemotherapy by administering a therapeutically effective amount of any one or a combination of the polymorphs of Trilaciclib citrate salt of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from myelosuppression, or otherwise in need of the treatment.

[0017] The present disclosure also provides uses of polymorphs of Trilaciclib citrate salt of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating, e.g., myelosuppression. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows a characteristic XRPD of Trilaciclib citrate salt- Form TCT4.

[0019] Figure 2 shows XRPD of Trilaciclib citrate salt which was obtained by slurry of TCT4 in isopropyl acetate.

[0020] Figure 3 shows a characteristic XRPD of Trilaciclib citrate salt- Form TCT5.

[0021] Figure 4 shows a characteristic XRPD of Trilaciclib citrate salt- Form TCT6.

[0022] Figure 5 shows a characteristic XRPD of Trilaciclib citrate salt- Form TCT7.

[0023] Figure 6 shows XRPD of Trilaciclib citrate salt which was obtained by slurry of TCT4 in isopropyl acetate.Attorney Docket: API050-WO01 (2222-214 PCT) DETAILED DESCRIPTION OF THE DISCLOSURE

[0024] The present disclosure encompasses solid state forms of Trilaciclib and Trilaciclib citrate salt, processes for preparation thereof, and pharmaceutical compositions thereof.

[0025] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Trilaciclib or of Trilaciclib salts described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Trilaciclib or of Trilaciclib salt. In some embodiments of the disclosure, the described crystalline polymorph of Trilaciclib or of Trilaciclib salt may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of Trilaciclib and / or of Trilaciclib salt.

[0026] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0027] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sampleAttorney Docket: API050-WO01 (2222-214 PCT) concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Trilaciclib or salt of Trilaciclib referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be to include any crystal forms of Trilaciclib and of Trilaciclib salt characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0028] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Trilaciclib, relates to a crystalline form of Trilaciclib salt which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0029] The term “solvate,” as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a “hydrate.” The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0030] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Kα radiation wavelength 1.5418 Å. XRPD peaks reported herein are measured using CuK α radiation, λ = 1.5418 Å, typically at a temperature of 25 ± 3 °C.

[0031] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.

[0032] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term “v / v” may be used to indicate the number of volumes ofAttorney Docket: API050-WO01 (2222-214 PCT) a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0033] A process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0034] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0035] As used herein and unless indicated otherwise, the term “ambient conditions” refers to atmospheric pressure and a temperature of 22-24 °C.

[0036] In one embodiment, the present disclosure includes a crystalline polymorph of Trilaciclib citrate salt; designated Form TCT4. The crystalline Form TCT4 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 9.9, 14.2, 15.1, 17.9 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0037] Crystalline Form TCT4 of Trilaciclib citrate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.9, 14.2, 15.1, 17.9 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 16.2, 19.8, 24.2 and 27.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0038] Crystalline Form TCT4 of Trilaciclib citrate salt nay be characterized by an X-ray powder diffraction pattern having peaks at 9.9, 14.2, 15.1, 17.9 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one additional peak selected from 16.2, 19.8, 24.2 or 27.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0039] According to any aspect or embodiment, crystalline Form TCT4 of Trilaciclib citrate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 9.9, 14.2, 15.1, 16.2, 17.9, 19.8, 22.7, 24.2 and 27.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0040] Crystalline Form TCT4 of Trilaciclib citrate salt according to any aspect or embodiment may be additionally characterized by an XRPD having an absence of peaks at 5.5 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, crystalline Form TCT4 of Trilaciclib citrate salt according to any aspect or embodiment may be additionally characterized by an XRPD having an absence of peaks at 5.0 to 9.4 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API050-WO01 (2222-214 PCT)

[0041] Crystalline Form TCT4 of Trilaciclib citrate salt may be a hemi citrate salt (i.e., the ratio Trilaciclib:citric acid is 2:1; accordingly). Most preferably, Form TCT4 as described in any aspect or embodiment of the disclosure is a Trilaciclib hemicitrate salt.

[0042] Crystalline Form TCT4 of Trilaciclib citrate salt may be a hydrate form; preferably; hemi-hydrate. Preferably, Form TCT4 as described in any aspect or embodiment of the disclosure, is a hemi-hydrate.

[0043] Form TCT4 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0044] The above crystalline polymorph of Trilaciclib citrate salt can be used to prepare other crystalline polymorphs of Trilaciclib, other Trilaciclib salts and solid state forms thereof; in particular, Form TCT4 can be used in the preparation of other crystalline form of Trilaciclib citrate salt (e.g., Form TCT3 as described in WO2023 / 164255).

[0045] Compared with other forms of Trilaciclib citrate, crystalline Form TCT4 of the present invention may have particularly useful flow and compression properties which makes this form easier to process and handle, for example during filtration and formulation processes.

[0046] In another embodiment, the present disclosure includes a crystalline polymorph of Trilaciclib citrate salt; designated Form TCT5. The crystalline Form TCT5 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 10.4, 17.1, 18.9, 20.8 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0047] Crystalline Form TCT5 of Trilaciclib citrate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 10.4, 17.1, 18.9, 20.8 and 22.1 degrees 2- theta ± 0.2 degrees 2-theta and also having any one, two, or three additional peaks selected from 15.0, 17.9 and 23.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0048] Crystalline Form TCT5 of Trilaciclib citrate salt according to any aspect or embodiment of the disclosure may be characterized by an X-ray powder diffraction pattern having peaks at 10.4, 17.1, 18.9, 20.8 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta and also having any one additional peak selected from 15.0, 17.9 and 23.6 degrees 2-theta ± 0.2 degrees 2-theta. Particularly, according to any aspect or embodiment of the disclosure, crystalline Form TCT5 of Trilaciclib citrate salt may be characterized by an X-ray powder diffraction pattern having peaks at 10.4, 15.0, 17.1, 18.9, 20.8 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta.Attorney Docket: API050-WO01 (2222-214 PCT)

[0049] Crystalline Form TCT5 of Trilaciclib citrate salt according to any aspect or embodiment may be additionally characterized by an XRPD having an absence of peaks at: 3.5 to 5.3 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively crystalline Form TCT5 of Trilaciclib citrate salt according to any aspect or embodiment may be additionally characterized by an XRPD having an absence of peaks at 3.0 to 5.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0050] Crystalline Form TCT5 of Trilaciclib citrate salt may be a hemicitrate salt (i.e., the ratio Trilaciclib:citric acid is 2:1; accordingly). Most preferably, Form TCT5 as described in any aspect or embodiment of the disclosure is a Trilaciclib hemicitrate salt.

[0051] Crystalline Form TCT5 of Trilaciclib citrate salt may be a hydrate form; preferably a monohydrate.

[0052] Form TCT5 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0053] In another embodiment, the present disclosure includes a crystalline polymorph of Trilaciclib citrate salt; designated Form TCT6. The crystalline Form TCT6 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 10.7, 13.5, 18.2, 20.2 and 21.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0054] Crystalline Form TCT6 of Trilaciclib citrate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 10.7, 13.5, 18.2, 20.2 and 21.1 degrees 2- theta ± 0.2 degrees 2-theta and also having any one, two, three, or four additional peaks selected from 15.2, 22.3, 22.7 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0055] Crystalline Form TCT6 of Trilaciclib citrate salt according to any aspect or embodiment may be additionally characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 4.5 degrees 2-theta; and / or an absence of peaks at 5.5 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta; and / or an absence of peaks at 7.8 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta. Particularly, according to any aspect or embodiment, crystalline Form TCT6 of Trilaciclib citrate salt may be additionally characterized by an XRPD pattern having an absence of peaks at 5.5 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta; and / or an absence of peaks at 7.8 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0056] Crystalline Form TCT6 of Trilaciclib citrate salt may be a hemicitrate salt (i.e., the ratio Trilaciclib:citric acid is 2:1; accordingly). Most preferably, Form TCT6 as described in any aspect or embodiment of the disclosure is a Trilaciclib hemicitrate salt.Attorney Docket: API050-WO01 (2222-214 PCT)

[0057] Crystalline Form TCT6 of Trilaciclib citrate salt may be a hydrate form; preferably; dihydrate salt.

[0058] Form TCT6 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0059] In another embodiment, the present disclosure includes a crystalline polymorph of Trilaciclib citrate salt; designated Form TCT7. The crystalline Form TCT7 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG.5; an X-ray powder diffraction pattern having peaks at 3.7, 12.0, 18.5, 26.0 and 29.3 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0060] Crystalline Form TCT7 of Trilaciclib citrate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 3.7, 12.0, 18.5, 26.0 and 29.3 degrees 2- theta ± 0.2 degrees 2-theta and also having any one, two, or three additional peaks selected from 7.4, 11.1 and 14.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0061] Crystalline Form TCT7 of Trilaciclib citrate salt according to any aspect or embodiment may be additionally characterized by an X-ray powder diffraction pattern having an absence of peaks at 4.0 to 5.3 degrees 2-theta; and / or an absence of peaks at 6.3 to 6.9 degrees 2-theta ± 0.2 degrees 2-theta; and / or an absence of peaks at 7.9 to 9.0 degrees 2-theta ± 0.2 degrees 2-theta; and / or an absence of peaks at 12.5 to 14.0 degrees 2-theta ± 0.2 degrees 2-theta. Particularly, according to any aspect or embodiment, crystalline Form TCT6 of Trilaciclib citrate salt may be additionally characterized by an XRPD pattern having an absence of peaks at 4.0 to 5.3 degrees 2-theta ± 0.2 degrees 2-theta; and / or an absence of peaks at 12.5 to 14.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0062] Crystalline Form TCT7 of Trilaciclib citrate salt may be a hemicitrate salt (i.e., the ratio Trilaciclib:citric acid is 2:1; accordingly). Most preferably, Form TCT7 as described in any aspect or embodiment of the disclosure is a Trilaciclib hemicitrate salt.

[0063] Crystalline Form TCT7 of Trilaciclib citrate salt may be a hydrate form; preferably; trihydrate salt.

[0064] Form TCT7 according to any aspect or embodiment of the present disclosure may be polymorphically pure.

[0065] The crystalline Forms TCT4, TCT5, TCT6, and TCT7 of Trilaciclib citrate (preferably hemicitrate) according to any aspect or embodiment of the disclosure, may each be hydrates. The crystalline Forms TCT4, TCT5, TCT6, and TCT7 of Trilaciclib citrate may particularly contain water in an amount of: about 0.3 to about 5 moles, about 0.4 to about 4.5Attorney Docket: API050-WO01 (2222-214 PCT) moles, about 0.5 to about 4 moles, about 0.5 to about 3.5 moles, or about 0.5 to about 3 moles, of water, per mole of Trilaciclib. Crystalline Form TCT4 of Trilaciclib citrate according to any aspect or embodiment of the disclosure may contain water in an amount of: about 0.3 to about 0.7 moles, about 0.4 to about 0.6 moles, about 0.45 to about 0.55 moles, or about 0.5 moles of water per mole of Trilaciclib citrate. Crystalline Form TCT5 of Trilaciclib citrate according to any aspect or embodiment of the disclosure may contain water in an amount of: about 0.8 to about 1.5 moles, about 0.8 to about 1.2 moles, about 0.9 to about 1.1 moles, or about 1.0 moles of water per mole of Trilaciclib citrate. Crystalline Form TCT6 of Trilaciclib citrate according to any aspect or embodiment of the disclosure may contain water in an amount of: about 1.7 to about 2.4 moles, about 1.8 to about 2.2 moles, about 1.9 to about 2.1 moles, or about 2.0 moles of water per mole of Trilaciclib citrate. Crystalline Form TCT7 of Trilaciclib citrate according to any aspect or embodiment of the disclosure may contain water in an amount of: about 2.7 to about 3.5 moles, about 2.8 to about 3.2 moles, about 2.9 to about 3.1 moles, or about 3.0 moles of water per mole of Trilaciclib citrate.

[0066] The present disclosure also encompasses the use of crystalline polymorphs of Trilaciclib or Trilaciclib citrate salt of the present disclosure for the preparation of pharmaceutical compositions of polymorphs of Trilaciclib or Trilaciclib citrate salt.

[0067] The present disclosure includes processes for preparing the above-mentioned pharmaceutical compositions. The processes include combining polymorph of Trilaciclib or Trilaciclib citrate salt of the present disclosure with at least one pharmaceutically acceptable excipient.

[0068] The polymorphs of Trilaciclib or Trilaciclib citrate salt and the pharmaceutical compositions and / or formulations of Trilaciclib and of Trilaciclib salts of the present disclosure, can be used as medicaments.

[0069] The present disclosure also provides methods of treating myelosuppression by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Trilaciclib and / or Trilaciclib salts of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0070] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.Attorney Docket: API050-WO01 (2222-214 PCT) Powder X-ray Diffraction (“XRPD”) method

[0071] X-ray diffraction was performed on X-Ray powder diffractometer: Bruker D8 Advance; CuKα radiation (λ = 1.5418 Å); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring with silicon low background. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass. Measurement parameters: Scan range: 2 – 40 degrees 2-theta; Scan mode: continuous; Step size: 0.05 degrees; Time per step: 0.5 s; Sample spin: 30 rpm; Sample holder: PMMA specimen holder ring with silicon low background. All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample. EXAMPLES Preparation of starting materials

[0072] Trilaciclib can be prepared according to methods known from the literature, for example U.S. Patent No.8598186.

[0073] Crystalline polymorph Form TCT3 of Trilaciclib citrate can be prepared according to the procedure described in International Publication No. WO2023 / 164255. Example 1: Preparation of Trilaciclib citrate salt Form TCT4

[0074] Trilaciclib (0.7 g) and citric acid monohydrate (0.33g) were dissolved in water (5.0 ml) at 50 °C. To the clear solution was added 1mL of sodium hydroxide solution (35 mg / mL of sodium hydroxide in water) at 50 °C and stirred for 30 minutes at this temperature. The reaction mixture was then cooled to 25 °C (during 1 hour) and acetone (6.0 ml) was added, solid material was obtained immediately. The suspension was stirred at 25 °C for 1 hour. The obtained solid was filtered and washed with acetone (1ml) and suction dried for 30 minutes. Further, the solid was dried under vacuum at 50-60 °C for 1 hour. The obtained solid wasAttorney Docket: API050-WO01 (2222-214 PCT) analyzed by XRD and designated as Form TCT4 of Trilaciclib citrate salt; as shown in Figure 1.

[0075] Form TCT4 (0.2 g) was suspended in isopropyl acetate (1.0 ml) at 60 °C. The suspension was stirred at 60 °C for 12 hours. The obtained solid was filtered and suction dried for 30 minutes and further dried under vacuum at 50-60 °C for 1 hour. The obtained solid was analyzed by XRPD; as shown in Figure 2 (peak at 28.4 is the Si standard).

[0076] Form TCT4 (2.0 g) was suspended in isopropyl acetate (10.0 ml) at 60 °C. The suspension was stirred at 60 °C for 12 hours. The obtained solid was filtered and suction dried for 30 minutes and further dried under vacuum at 50-60 °C for 1 hour. The obtained solid was analyzed by XRPD; as shown in Figure 6. Example 2: Preparation of Trilaciclib citrate salt Form TCT5

[0077] Trilaciclib free base (3g) and citric acid monohydrate (1.41 g) were dissolved in water (21.0 ml) at 55 °C. To the clear solution was added 4.5 ml of sodium hydrogen carbonate solution (69 mg / mL of sodium hydrogen carbonate in water) at 55 °C and the mixture was stirred for 30 minutes at this temperature. The clear solution was then filtered and seeded with crystalline polymorph TCT3 (0.033 g) at 55 °C. Acetone (60.0 ml) was added to the reaction mixture at 55 °C (during about 90 minutes) and then the reaction mixture was stirred for 3 hours at 55 °C. The suspension was cooled to 25 °C (during about 100 minutes) and was further stirred for 14 hours. The obtained solid was filtered and washed with acetone (15ml). Further, the solid was dried under vacuum at 50-60 °C for 8 hours under nitrogen atmosphere. The obtained solid was analyzed by XRD and designated as Trilaciclib citrate salt Form TCT5; as shown in Figure 3. Example 3: Preparation of Trilaciclib citrate salt Form TCT6

[0078] Crystalline Form TCT5 was placed at 25 °C in a glass vial and after 2 months solid was analyzed by XRD and designated as Trilaciclib citrate salt- Form TCT6; as shown in Figure 4. Example 4: Preparation of Trilaciclib citrate salt Form TCT6

[0079] Crystalline Form TCT5 was placed at 80%RH humidity chamber at 25 °C and after 24 hours the obtained solid was analyzed by XRD- Form TCT6 was obtained. Example 5: Preparation of Trilaciclib citrate salt Form TCT7

[0080] Trilaciclib free base (0.05g) was suspended in methanol (5 ml) at 25 °C. To the suspension was added a solution of citric acid monohydrate (0.022 g in 1 ml water) at 25 °C. The suspension was stirred for 20 hours at 25 °C. The obtained solid was filtered and driedAttorney Docket: API050-WO01 (2222-214 PCT) under vacuum at 50-60 °C for 1 hour. The obtained solid was analyzed by XRD and designated as Trilaciclib citrate salt- Form TCT7; as shown in Figure 5. Example 6: Bulk Density and Tapped Density Experiments

[0081] Bulk density: A weighed amount of sample material (Form TCT4) was poured along the middle fold of the glassine paper, and gently transferred into a 5 ml graduated cylinder held at a 45 degree angle, whilst avoiding tapping and shaking. The cylinder was moved to the upright position in a single, clean movement, and the mass (M) and volume (V1) of the sample were measured.

[0082] Tapped density: The filled graduated cylinder was subjected to tapping with tapping rate, 250±15 taps / min and the volume (V2) was recorded after 1250 taps.

[0083] The results of the above experiments, are presented below together with the calculated bulk density (BD) and tapped density (TD) and the Hausner ratio: TD Hausner Sample MassV1 V2 BD = M / V2 M(gm)(ml) (ml) = M / V1 (gm\ml) (gm / ml) Ratio (gm\ml) (= TD / BD) Hemi Citrate Salt (TCT4)0.12 2.3 1.9 0.05 0.06 1.21

[0084] The data confirms that Form TCT4 has acceptable flowability for pharmaceutical processing. Example 7: Solubility Experiments

[0085] Aliquots of the test solution (pH 1.2 HCl solution, 10-20 microlitres) were added using a micropipette to accurately weighed samples (about 50 mg) of each of the samples (Forms TCT5, TCT6, and TCT7), and the mixtures were agitated using a vortex following each addition. The experiments were carried out at 37 °C. Further aliquots of the test solution were added to each of the samples, followed by mixing, until clear solutions were obtained. The total volume of test solution required to provide a clear solution in each case, were recorded. The solubility was calculated as: [mass of the sample (mg)] / [volume of test solution (mL)]. The results are presented in the table below:Attorney Docket: API050-WO01 (2222-214 PCT) Sample Solubility (mg / mL) Form TCT5 237 Form TCT6 251 Form TCT7 167

[0086] The results show that the Trilaciclib citrate salt Forms TCT5, TCT6 and TCT7 according to the present disclosure have good solubilities. High solubility is advantageous as it is indicative of a greater bioavailability.

Claims

Attorney Docket: API050-WO01 (2222-214 PCT) Claims 1. A crystalline Trilaciclib hemicitrate salt designated Form TCT4, which is characterized by data selected from one or more of the following: (a) an X-ray powder diffraction pattern substantially as depicted in Figure 1; or (b) an X-ray powder diffraction pattern having peaks at 9.9, 14.2, 15.1, 17.9, and 22.7 degrees 2-theta ± 0.2 degrees 2-theta.

2. The crystalline Trilaciclib hemicitrate salt according Claim 1, which is further characterized by an X-ray powder diffraction pattern having any one, two, three, or four additional peaks selected from 16.2, 19.8, 24.2, and 27.5 degrees 2-theta ± 0.2 degrees 2- theta.

3. The crystalline Trilaciclib hemicitrate salt according Claim 1, which is further characterized by an X-ray powder diffraction pattern having any one additional peak selected from 16.2, 19.8, 24.2, and 27.5 degrees 2-theta ± 0.2 degrees 2- theta.

4. The crystalline Trilaciclib hemicitrate salt according to any of Claims 1.2 or 3, which is characterized by an XRPD pattern having peaks at 9.9, 14.2, 15.1, 16.2, 17.9, 19.8, 22.7, 24.2, and 27.5 degrees 2-theta ± 0.2 degrees 2-theta.

5. The crystalline Trilaciclib hemicitrate salt according to any of Claims 1, 2, 3, or 4, which is substantially free of any other solid state forms of Trilaciclib and / or Trilaciclib salt.

6. The crystalline Trilaciclib hemicitrate salt according to any of Claims 1, 2, 3, 4, or 5, containing about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% (w / w) of any other crystalline forms of Trilaciclib and / or Trilaciclib salt.

7. Use of crystalline Trilaciclib hemicitrate salt according to any of Claims 1-6 for preparing other crystalline forms of Trilaciclib, salts of Trilaciclib or crystalline forms thereof; preferably, crystalline forms of the hemicitrate salt.Attorney Docket: API050-WO01 (2222-214 PCT) 8. A pharmaceutical composition comprising the crystalline Trilaciclib hemicitrate salt according to any of Claims 1-6, and at least one pharmaceutically acceptable excipient.

9. Use of the crystalline Trilaciclib hemicitrate salt according to any of Claims 1-6 in a process for the preparation of a pharmaceutical composition or formulation.

10. The crystalline Trilaciclib hemicitrate salt according to any of Claims 1-6, or a pharmaceutical composition according to Claim 8, for use as a medicament.

11. The crystalline Trilaciclib hemicitrate salt according to any of Claims 1-6, or a pharmaceutical composition according to Claim 8, for use according to Claim 10, as a chemo protective agent; in particular to reduce chemotherapy-induced bone marrow suppression in patients with small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal cancer (particularly metastatic colorectal cancer), breast cancer (particularly metastatic triple-negative breast cancer), and bladder cancer (particularly advanced / metastatic bladder cancer); and preferably in patients with SCLC.

12. A method of treating chemotherapy-induced bone marrow suppression comprising administering a therapeutically effective amount of the crystalline Trilaciclib hemicitrate salt according to any of Claims 1-6, or a pharmaceutical composition according to Claim 8, to a subject in need of the treatment.

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