WO2023043869A1 - Solid state forms of ipatasertib citrate - Google Patents

Abstract

The present invention encompasses salts and solid state forms of Ipatasertib and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF IPATASERTIB CITRATE Field of the Invention [0001] The present invention encompasses salts and solid state forms of Ipatasertib and pharmaceutical compositions thereof. Background of the Invention [0002] Ipatasertib, (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(propan-2-ylamino)propan-1-one, having the following formula,

is a An orally bioavailable inhibitor of the serine/threonine protein kinase Akt with potential antineoplastic activity. It is currently under evaluation for treating different types of cancer. [0003] Ipatasertib is described in U.S. Patent No.8,063,050. Solid-state forms of Ipatasertib HCl are described in U.S. Patent No.9,290,458. Different salts of Ipatasertib are described in International Publication No. WO 2013/173784. [0004] 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 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. [0005] 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 improving 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. [0006] Discovering new salts, 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, e.g., 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 salts and solid state forms (including solvated forms) of Ipatasertib. Summary of the Invention [0007] The present invention provides Ipatasertib citrate salt, its solid state forms, processes for preparation thereof, and pharmaceutical compositions thereof. In particular, the present invention provides amorphous Ipatasertib citrate salt, [0008] The present invention also encompasses the use of the disclosed Ipatasertib citrate and its solid state forms for the preparation of pharmaceutical compositions of Ipatasertib and Ipatasertib citrate. [0009] The present invention comprises a process for preparing the above mentioned pharmaceutical compositions. The process comprises combining the Ipatasertib citrate or its solid state forms with at least one pharmaceutically acceptable excipient. [0010] The Ipatasertib citrate and its solid state forms, and the pharmaceutical compositions of the present invention can be used as medicaments, particularly for the treatment of cancer. [0011] The present invention also provides a method of treating cancer, comprising administering a therapeutically effective amount of the Ipatasertib solid state form of the present invention, or at least one of the above pharmaceutical compositions, to a subject suffering from cancer, or otherwise in need of the treatment. [0012] The present invention further provides amorphous Ipatasertib citrate salt for use in the preparation of other solid state forms of Ipatasertib or Ipatasertib salts and solid state forms thereof. Brief Description of the Drawings [0013] Figure 1 shows an X-ray powder diffractogram of amorphous Ipatasertib citrate. [0014] Figure 2 shows a DSC thermogram of amorphous Ipatasertib citrate. [0015] Figure 3 shows an FTIR absorption spectrum of amorphous Ipatasertib citrate. Detailed Description of the Invention [0016] The present invention encompasses Ipatasertib citrate salt and solid state forms thereof processes for their preparation and pharmaceutical compositions thereof. In particular, the present invention discloses amorphous form of Ipatasertib citrate salt. [0017] In some embodiments, the solid state forms of Ipatasertib citrate of the invention are substantially free of any other crystalline forms of Ipatasertib or salts thereof. [0018] 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 (i.e., amorphous Ipatasertib citrate salt) 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 crystalline forms of the subject compound as measured, for example, by XRPD. Thus, an amorphous Ipatasertib citrate salt 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 amorphous Ipatasertib citrate salt. [0019] Depending on which other solid state forms comparison is made with, the amorphous form of Ipatasertib citrate of the present invention has 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. [0020] A solid state form, such as a crystal form or 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 sample 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 solid form of a Ipatasertib referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Ipatasertib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure. [0021] As used herein, the term "isolated" in reference to solid state forms of Ipatasertib of the present invention corresponds to a solid state form of Ipatasertib that is physically separated from the reaction mixture in which it is formed. [0022] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Kα radiation wavelength 1.5418 Å. [0023] 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. [0024] The amount of solvent employed in a chemical process, e.g., a reaction or a 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 of 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. [0025] 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, typically about 16 hours. [0026] 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. [0027] As used herein, and unless indicated otherwise, the terms “wet crystalline form” or "wet form" refer to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow etc. [0028] As used herein, and unless indicated otherwise, the terms “dry crystalline form” or "dry form" refer to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow etc. [0029] In one embodiment, the present invention comprises Ipatasertib citrate salt. [0030] In a further embodiment, the present invention provides Amorphous form of Ipatasertib citrate salt. [0031] In another embodiment, the amorphous form of Ipatasertib citrate salt can be characterized by data selected from one or more of the following: i. an XRPD pattern substantially as depicted in Figure 1; ii. a DSC thermogram substantially as depicted in Figure 2, iii. an FTIR absorption spectrum substantially as depicted in Figure 3; or combinations of these data. Alternatively, the amorphous Ipatasertib citrate salt is characterized by a DSC thermogram having glass transition at about 89.6 ˚C +1 ˚C. [0032] Amorphous Ipatasertib citrate salt may be polymorphically pure. [0033] Amorphous Ipatasertib citrate shows stability when exposed to stress conditions; e.g., under heating, pressure, strong grinding and high humidity. [0034] In a further embodiment, the present disclosure provides a process for preparing amorphous Ipatasertib citrate salt by spray drying a mixture of Ipatasertib and citric acid in a solvent. The mixture is obtained by combining Ipatasertib and citric acid in a solvent, and optionally; heating the mixture. The solvent may be an alcohol; preferably methanol. [0035] The present invention encompasses also the amorphous Ipatasertib citrate obtainable by the described process. [0036] The above described solid state form can be used to prepare other Ipatasertib salts and solid state forms thereof. [0037] The present invention comprises pharmaceutical compositions and formulations comprising amorphous Ipatasertib citrate. Typically, the pharmaceutical composition is a solid composition and the Ipatasertib citrate retains its solid state form. [0038] The pharmaceutical compositions and/or formulation can be prepared by a process comprising combining the solid state form of Ipatasertib citrate of the present invention with at least one pharmaceutically acceptable excipient. [0039] The above solid state form of Ipatasertib citrate of the present invention can also be used as a medicament. [0040] The present invention further encompasses 1) the use of the above-described solid state form of Ipatasertib citrate in the manufacture of a pharmaceutical composition, and 2) a method of treating a subject suffering from cancer, or otherwise in need of the treatment, comprising administration of an effective amount of a pharmaceutical composition comprising the amorphous form of Ipatasertib citrate salt described herein. [0041] Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. X-Ray Powder Diffraction method: [0042] Sample is powdered in a mortar and pestle and applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.5418 Ǻ (Ǻngström), X’Celerator (2.022º 2θ) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan. [0043] The described peak positions were determined without using silicon powder as an internal standard in an admixture with the sample measured. FTIR method: [0044] Sample was prepared as KBr pellet. Empty sample compartment was used for background spectrum acquisition. FTIR spectrum was measured with Nicolet 6700 FTIR spectrometer. The spectra was scanned between: 4000-400 cm^-1, measured in 16 scans with resolution of 4.0 cm^-1 DSC method: [0045] DSC measurements were done using TA Instruments Discovery, DSC unit.1-3 mg of sample was weighted in pan, hermetically closed with the pin hole. Sample was purged with 50 ml/min N₂ flow. Heating range was 25-300 °C with heating rate 2°C/min. Modulated Temperature Amplitude was 0.318℃ with period 60 s. Examples [0046] The starting material-Ipatasertib base may be prepared according to the process described in U.S. Patent No.8,063,050; Example 14. Example 1: Preparation of Ipatasertib citrate, amorphous Form [0047] Ipatasertib base (3.32 grams) was dissolved in 250 mL of methanol at room temperature. Citric acid (1.68 grams) was added to solution. Solution was then spray dried at following conditions: Pump 30%, Aspirator 100% (35 m³/h) Tinl (Tinl=Inlet Temperature) 100°C, Tout 35-40°C. Obtained material was additionally dried under the vacuum at 60°C for 4 hours. Material was analyzed by XRPD and found to be an amorphous material. (Figure 1.)

Claims

Claims: 1. An amorphous form of Ipatasertib citrate salt. 2. The amorphous form of claim 1, characterized by data selected from one or more of the following: i. an XRPD pattern substantially as depicted in Figure 1; ii. a DSC thermogram substantially as depicted in Figure 2., iii. an FTIR absorption spectrum substantially as depicted in Figure 3; or combinations of these data. 3. The amorphous form according to claim 1 or claim 2, characterized by a DSC thermogram having glass transition at about 89.6 ˚C +1 ˚C. 4. A process for the preparation of an amorphous Ipatasertib citrate salt comprising spray drying a mixture of Ipatasertib and citric acid and isolating the formed solid. 5. The process according to claim 4; wherein the mixture is obtained by combining Ipatasertib and citric acid in an organic solvent; and; optionally; heating the mixture. 6. The process according to claims 4 or 5; wherein the solvent is an alcohol; preferably, methanol. 7. An amorphous form of Ipatasertib citrate salt obtainable and/or obtained by the process according to any of claims 4 to 6. 8. An amorphous Ipatasertib citrate salt which is polymorphically pure or which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of crystalline Ipatasertib or its salts. 9. A pharmaceutical composition comprising an amorphous Ipatasertib citrate salt according to any of claims 1 to 3 or claims 7 to 8 and at least one pharmaceutically acceptable excipient. 10. Use of amorphous Ipatasertib citrate salt according to any of claims 1 to 3 or claims 7 to 8 for the preparation of a pharmaceutical composition and/or formulation. 11. A process for preparing the pharmaceutical composition according to claim 9, comprising combining an amorphous Ipatasertib citrate salt according to any of claims 1 to 3 or claims 7 to 8 with at least one pharmaceutically acceptable excipient. 12. An amorphous Ipatasertib citrate salt according to any of claims 1 to 3 or claims 7 to 8 or a pharmaceutical composition according to claim 9 for use as a medicament. 13. An amorphous Ipatasertib citrate salt according to any of claims 1 to 3 or claims 7 to 8, or a pharmaceutical composition according to claim 9, for the treatment of cancer.