PHARMACEUTICAL COMPOSITION CONTAINING Akt PROTEIN KINASE INHIBITOR

Abstract

To provide a pharmaceutical composition containing Akt protein kinase inhibitor having therapeutic activity to diseases such as cancer.SOLUTION: A pharmaceutical composition contains Akt inhibitor, and one or more pharmaceutically acceptable additives selected from filler, binder and disintegrator.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions comprising Akt protein kinase inhibitors having therapeutic activity against diseases such as cancer, as well as methods for their preparation and their use as medicaments. [Background technology]

[0002] Protein kinase B (PKB), also known as Akt, is a serine / threonine kinase overexpressed in certain human tumors. International Patent Application Publication No. 2008 / 006040(A1) and U.S. Patent No. 8,063,050(B2) discuss several Akt inhibitors, including ipatasertib (WHO Drug Information Vol. 27, No. 3, 2013, Recommended INN: List 70), a compound with a recommended INN of 70, (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one, which is being investigated in clinical trials for the treatment of various cancers. TIFF2025170249000002.tif84170

[0003] Stable, effective, and convenient pharmaceutical compositions are needed for active pharmaceutical ingredients. The present invention provides pharmaceutical compositions comprising an Akt inhibitor, particularly ipatasertib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0004] Very few crystalline forms of ipatasertib have been described to date. For example, WO 2013 / 173784A1 describes crystalline besylate and tosylate salts of ipatasertib. Both benzenesulfonic acid and p-toluenesulfonic acid are less preferred anions for pharmaceutical salts.

[0005] The best pharmaceutically acceptable solid form of ipatasertib described to date is the amorphous anhydrous monohydrochloride salt, as described, for example, in WO 2013 / 173811 A1.

[0006] Ipatasertib monohydrochloride has been found to exhibit unique mechanical behavior with very brittle deformation characteristics (three times more brittle than lactose), making processing by mechanical compression very difficult. Mechanical compression during tableting of conventional pharmaceutical compositions containing ipatasertib results in loss of compressibility, followed by elastic recovery of the tablet upon decompression. Therefore, conventional pharmaceutical compositions containing ipatasertib monohydrochloride are not suitable for direct compression due to compression cracking issues (crack formation during decompression), which are detectable (e.g., using X-ray microtomography) as small cracks and fissures in the tablet core. Industrially required high-speed tableting processes may not be achievable.

[0007] Ipatasertib has been found to exhibit very high solubility (greater than 1 g per g of water, greater than 2 g per g of 1:1 water / ethanol) and very high wettability (~6% at 50% RH, greater than 35% at 95% RH). While low solubility is often a limiting factor in the development of galenical formulations of other APIs (active pharmaceutical ingredients), high solubility can equally pose problems for processing performance. Due to the very high intrinsic wettability of this API, ipatasertib drug substance tends to autodissolve into a honey-like viscous liquid as humidity increases. Such high solubility and wettability can pose significant problems not only for processing but also for the stability and shelf life of the final product. Therefore, conventional pharmaceutical compositions containing ipatasertib and methods for producing pharmaceutical compositions that involve wetting (e.g., wet granulation) are challenging due to the high solubility and high wettability of this API.

[0008] Alternative granulation processes for ipatasertib, such as high shear processes involving sequential wetting and drying, have further been found to be difficult to control, do not result in a consistent high quality product, and require large amounts of moisture absorbent (at least 10-15 wt%).

[0009] Due to the high solubility and wettability of ipatasertib, conventional methods for preparing amorphous ipatasertib monohydrochloride require prolonged drying at high temperatures and forced removal of pharmaceutically unfavorable solvents, which can cause partial crystallization. Conventional methods for preparing amorphous ipatasertib monohydrochloride are not suitable for providing a homogeneous, amorphous, and stable API that exhibits suitable particle characteristics for use in formulation processes without further conditioning or reprocessing. Therefore, there is a need for an improved method for preparing amorphous ipatasertib monohydrochloride that can be easily used in the preparation of pharmaceutical compositions. Summary of the Invention

[0010] The present invention provides a pharmaceutical composition comprising ipatasertib and a method for producing the same, which solves the problems described above.

[0011] The inventors of the present invention have discovered that a pharmaceutical composition comprising ipatasertib and a certain amount of intragranular material with plastic deformation characteristics prevents the formation of brittle cracks during compression. Therefore, tablet cores comprising ipatasertib and pharmaceutically acceptable excipients with plastic deformation characteristics substantially improve processability.

[0012] The inventors of the present invention have found that a pharmaceutical composition comprising ipatasertib and a certain amount of an intragranular moisture absorbent can prevent processing problems in the dissolution of ipatasertib during granulation. Thus, the pharmaceutical composition comprising ipatasertib and a certain amount of an intragranular moisture absorbent substantially improves processability.

[0013] The inventors of the present invention have surprisingly found that fluidized bed granulation is a well-controllable process suitable for providing granules containing ipatasertib of high and consistent quality.

[0014] As described above, the only solid form of ipatasertib known to date that is suitable for pharmaceutical development and manufacturing is the amorphous anhydrous monohydrochloride salt (ipatasertib·HCl).

[0015] Conventional drying processes for ipatasertib have been found to produce only moderate results due to the high solubility and wettability of the API and complex desolvation. Long drying times at high temperatures and the forced removal of pharmaceutically undesirable or even unacceptable solvents are required to comply with the standards of the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Furthermore, conventional drying processes result in a mixture of amorphous and partially crystalline material.

[0016] Ipatasertib monohydrochloride ethyl acetate monosolvate has a defined stoichiometry containing one ethyl acetate molecule per ipatasertib molecule. Through conventional drying processes, the amount of ethyl acetate per ipatasertib in ipatasertib monohydrochloride ethyl acetate monosolvate can be reduced to a residual solvent content of 2-10 wt% ethyl acetate, typically 5-7 wt% ethyl acetate. Further reduction of the ethyl acetate content, for example, below 0.5 wt%, can only be achieved through harsh and prolonged drying conditions.

[0017] Ipatasertib monohydrochloride can be obtained from ipatasertib monohydrochloride ethyl acetate. Humidity was found here to be the primary driving force in the conversion of ipatasertib·HCl·EtOAc to amorphous ipatasertib·HCl.

[0018] Drying / wetting cycles using vacuum drying and humidified nitrogen in a conical screw dryer allowed for the removal of EtOAc and the achievement of amorphous conversion. However, drying time was not significantly improved, and several additional days were required for the completion of a conventional batch on an industrial scale. Furthermore, variations in the solid state were observed in the XRPD patterns. The additional particle size distribution was not controlled, resulting in only inconsistent particle size distribution profiles.

[0019] WO 2013 / 173811A1 discloses the preparation of amorphous ipatasertib monohydrochloride by spray drying using a two-fluid nozzle spray dryer (Examples 12A-C,

[0138] ). It was found that the spray drying process as disclosed in the prior art only yields moderate results in terms of particle size and particle shape, i.e., a bimodal particle size distribution with a large number of submicrometer particles is obtained. Therefore, the flowability and processability of the material so obtained are very limited.

[0020] The present invention further provides an improved spray-drying process, lacking problematic solvents, for the production of solid ipatasertib, particularly ipatasertib solvates, most particularly amorphous ipatasertib·HCl from ipatasertib·HCl·EtOAc, which results in a chemically stable, uniform amorphous material with improved flowability, bulk density, particle shape, and particle size distribution that can be used in the methods of manufacturing pharmaceutical compositions as disclosed herein without additional treatment, conditioning, or reprocessing. The product obtained by the methods of the present invention results in consistent and robust quality across batches.

[0021] It was surprisingly found that spray drying from water as the solvent gave particularly beneficial results, since ipatasertib was found not to form hydrates or other crystalline forms from water, the high solubility of ipatasertib in water allows for high API concentrations, and water is considered safer than many organic solvents.

[0022] It has been found that a spray drying process using a rotary wheel type atomizer as described in the Examples can provide amorphous ipatasertib·HCl of purity up to >99.4%.

[0023] The spray drying process of the present invention, using a rotating wheel atomizer as described in the Examples, offers the advantage that both residual EtOAc and water are immediately controlled: ICH Q3C(R5) limits are not required to be reached after drying.

[0024] The material as obtained by the spray drying process of the present invention, using a rotating wheel atomizer, exhibits exceptional powder properties according to flow behavior, PSD profile and SEM images.

[0025] The increased particle size of the material obtained from the spray drying process of the present invention compared to material obtained from conventional processes improves the processability of the API and improves the disintegration of tablets containing the material.

[0026] The bulk density of the material obtained by the spray drying process of the present invention using a rotating wheel atomizer is increased by nearly 2 times compared to the material obtained by other conventional processes. Bulk density also shows a very high impact in, for example, continuous tableting processes. [Brief explanation of the drawings]

[0027] [Figure 1] 1 shows a flow diagram of the manufacturing process of the pharmaceutical composition of the present invention. [Figure 2] 1 is a graph showing the effect of filler on tablet hardness with compression force. [Figure 3] 1 is a scanning electron micrograph (SEM) obtained from granules of Composition 11 containing colloidal silica. [Figure 4] 1 is a scanning electron micrograph (SEM) taken of granules of Composition 12 lacking colloidal silica. [Figure 5]1 is a graph showing the effect of binder grade on drug dissolution time. [Figure 6] 1 is a graph of the particle size distribution of the material of Example 6C (Batch HQ00003) spray dried using a two-fluid nozzle as obtained by laser diffraction. A bimodal particle size distribution is evident. [Figure 7] Figure 16 is an SEM micrograph of the material of Example 6C (batch HQ00003) spray dried with two feed nozzles. Nanoparticles of 1-10 μm diameter and a bimodal particle size distribution are evident. The sample was sputtered with gold. [Figure 8] 1 shows a flow diagram of the spray drying process by general means in Example 7. [Figure 9] Figure 2 is a graph of the particle size distribution of material spray dried using a rotating wheel nozzle, i.e., material from batch BS1506SA03 of Example 13 (Table 20), obtained using a Malvern Mastersizer2000 equipped with a Hydro2000S wet sample dispersion unit (Malvern Instruments Ltd, Malvern / UK). A unimodal particle size distribution is evident. [Figure 10] Figure 2 shows an SEM micrograph of material spray-dried with a rotating wheel nozzle obtained using a Zeiss Sigma VP (Carl Zeiss Microscopy GmbH, Oberkochen / DE), namely the material of batch BS1506SA07 of Example 13 (Table 20). Spherical particles of approximately uniform size are visible. DETAILED DESCRIPTION OF THE INVENTION

[0028] As used herein, the term "ipatasertib·HCl·EtOAc" refers to ipatasertib monohydrochloride salt having ethyl acetate in the crystal lattice, particularly having more than 0.5 wt% ethyl acetate in the crystal lattice, more particularly having more than 2 wt% ethyl acetate in the crystal lattice, and most particularly having more than 5 wt% ethyl acetate in the crystal lattice.

[0029] The term "tablet compression cracking" refers to the (partial) separation of a tablet into two or more distinct layers. Compression cracking can be caused by air entrapment during compression and subsequent release from extrusion, or by over-compression during tableting, which can lead to distortion of granules because they are no longer held together. Compression cracking can also occur when groups of fine and light particles are no longer held together.

[0030] The designation "wt%" indicates the mass percentage relative to the total weight of the tablet core (or relative to the total weight of the final film-coated tablet, if indicated).

[0031] A "fluidized bed" occurs when a quantity of solid particles is placed under conditions suitable to cause the mixture to behave as a fluid. This is typically done by passing compressed air, gas, or other fluid through a bed of solid particles. This causes the solid medium to acquire properties that are thought to be similar to those of a normal fluid, resulting in what is known as fluidization. Fluid beds are commonly used in the pharmaceutical industry to dry, granulate and coat many different active pharmaceutical ingredients (APIs), excipients or other formulations.

[0032] The "fluidized bed granulation" process involves suspending particles in an air stream (i.e., fluidized granulation) and spraying a liquid into the fluidized bed either downward from the top of the system (top spray granulator) or upward from the bottom (bottom spray granulator or Wilstar process). Particles in the path of the atomizing gas become slightly wetted and sticky. The sticky particles collide with other particles in the bed of material and adhere to them to form granules. There are two different modes of fluidized bed granulation: wet stage and dry stage. In dry stage granulation, the particles only need to be slightly wetted and become sticky and adherent to each other. The granulating solution is applied at a rate less than or equal to its evaporation rate. Thus, the particles remain "dry" throughout the entire process.

[0033] In wet stage granulation, the particles require a significant amount of moisture or granulation solution before they become sticky enough to adhere to each other. The granulation solution is applied at a rate higher than the evaporation rate until the particles have accumulated enough moisture to granulate. Note: The characteristics of the particles when wet and the type of granulation solution used will determine which mode of granulation is most appropriate. Wet stage granulation allows for a concentrated product, while dry stage is more common. A particular fluid bed granulator of the present invention is a top spray granulator in dry stage mode.

[0034] The terms "atomization" and "nebulization" both refer to a method of preparing an aerosol, i.e., a dispersion of solid particles or liquid droplets in a gas, especially a colloidal dispersion.

[0035] The term "aqueous mist" refers to an aerosol comprising small droplets (diameter less than 10 μm, particularly less than 5 μm, most particularly less than 1 μm) of water suspended in a gas, particularly air or nitrogen, most particularly nitrogen.

[0036] The term "atomizer" refers to a device that facilitates the atomization of a dispersion of solid particles or liquid droplets into an aerosol. Atomizers and their applications are described, for example, in Nasr, GG et al., Industrial Sprays and Atomization: Design, Analysis and Applications, Springer, 2002, ISBN 978-1852334604.

[0037] Atomizers can be categorized based on the energy input used to create the atomization and the breakup of the fluid into droplets. Single-fluid nozzles such as flat plate orifice nozzles, geometric orifice nozzles, surface impingement single-fluid nozzles, pressure vortex single-fluid atomizing nozzles, solid cone single-fluid nozzles and compound nozzles Two-fluid nozzles such as internal mixing two-fluid nozzles and external mixing two-fluid nozzles Rotary sprayer ·Ultrasonic sprayer Electrostatic sprayer Includes:

[0038] Particular atomizers of the present invention are two-fluid nozzles and rotary atomizers. Most particular atomizers of the present invention are rotary atomizers.

[0039] The term "rotary wheel type atomizer," also referred to as "rotary wheel atomizer" or "rotary atomizer," refers to a device used for atomization, where the feed is accelerated by centrifugal force due to the high velocity at the atomizer. The degree of atomization depends on the peripheral velocity, feed rate, liquid properties, and atomizer wheel design.

[0040] The term "rotating wheel spray dryer," also known as "rotating wheel spray dryer" or "rotary spray dryer," refers to an apparatus containing a rotary atomizer. Rotary spray dryers are used for atomization and drying, where the feed is centrifugally accelerated to high speeds in an atomizer wheel before being discharged into a hot drying gas. The degree of atomization and particle morphology depend on the peripheral velocity, feed rate, liquid properties, and atomizer wheel design. Particle size is controlled by varying the peripheral velocity. A particular rotating wheel spray dryer contains 24 holes.

[0041] The term "two-fluid nozzle" or "two-fluid nozzle atomizer" refers to a device used for atomization, where atomization is achieved pneumatically by high velocity compressed gas (e.g., air or nitrogen, especially nitrogen) to impinge on a liquid supply.

[0042] The term "two-fluid nozzle spray dryer" refers to a device used for atomization and drying, where atomization is achieved pneumatically with high-velocity compressed gas (e.g., air or nitrogen, especially nitrogen) and impinging on the liquid feed. Particle size is controlled by varying the nozzle flow ratio between the atomizing gas and the feed. Two-fluid nozzle spray dryers can be operated in a) co-current mode or b) fountain (counter-current) mode. a) When operated in co-current mode, the flow direction of the material to be sprayed and the drying gas are the same, and the nozzle tip is located near the outlet of the sealing gas distributor. The co-current mode is selected when drying heat-sensitive products. b) In fountain or counter-flow mode, the flow directions of the material to be sprayed and the drying gas are in opposite directions. Two-fluid nozzles in fountain mode are suitable when a non-thermally sensitive feed of coarse particles is required, and two-fluid nozzles can be further grouped into 1) internal mixing two-fluid nozzles and 2) external mixing two-fluid nozzles according to the mixing point of the gas and liquid streams relative to the nozzle face. 1) Internal mixing two-fluid nozzles contact the fluids inside the nozzle. The shear between the high-velocity gas and the low-velocity liquid breaks the liquid stream into droplets, creating a high-velocity spray. This type of nozzle tends to use less atomizing gas than an external mix atomizer and is better suited to higher flow velocities. 2) External mixing two-fluid nozzles (or outer mixing two-fluid nozzles) contact the fluids outside the nozzle. This type of atomizing nozzle can require more atomizing air and a higher atomizing air pressure drop because the liquid mixing and atomization occurs outside the nozzle. The liquid pressure drop is lower than with this type of nozzle, and liquid is often drawn into the nozzle due to suction caused by the atomizing air nozzle (siphon nozzle).

[0043] The term "single-fluid nozzle spray dryer" or "pressure nozzle spray dryer" refers to a device used for atomization and drying, where atomization is the result of converting pressure energy in a liquid feed into kinetic energy of a moving thin liquid sheet. There is no compressed atomizing gas. Pressure applied to the liquid in the nozzle forces the liquid out of the orifice, creating a spray. Pressure nozzles can be operated in co-current or fountain mode. Particle size is adjusted by varying the feed pressure and nozzle size. Pressure nozzles will generally deliver narrower particle size distributions and coarser particles than other atomizer types. The choice of nozzle type depends on the feed characteristics and powder specifications.

[0044] The term "cyclone separation" refers to a filter-free method of removing solid particles from a gas or liquid stream through vortex separation, i.e., through rotational effects and gravity. A high-velocity, rotating flow is established in a cylindrical or conical vessel called a cyclone. The flow follows a spiral pattern, beginning at the top (wide end) of the cyclone and terminating at the bottom (narrow) end before exiting the cyclone. Dense particles in the rotating flow have too much momentum along the flow's rigid curve and hit the outer wall, then enter the bottom of the cyclone, where they can be removed.

[0045] In a conical system, as the rotating flow moves toward the narrow end of the cyclone, the flow's radius of gyration decreases, causing it to separate into progressively smaller particles. The cyclone geometry, along with the flow velocity, defines the cyclone's cutoff point, which is the size of particles that will be removed from the flow at 50% efficiency. Particles larger than the cutoff point are removed with greater efficiency, and smaller particles are removed with less efficiency.

[0046] The term "solid form" or "form" is a general term that refers to a solid substance in crystalline and / or amorphous form.

[0047] The terms "crystalline form" and "crystalline form" can be used interchangeably to refer to polymorphs and pseudo-polymorphs of a crystalline solid.

[0048] The terms "polymorph" and "modification" can be used synonymously to mean one particular crystal structure in which a compound can crystallize. Various polymorphs have different arrangements or conformations of the molecules in the crystal lattice, but all share the same elemental composition.

[0049] The term "polymorphism" refers to the ability of a compound to form more than one polymorphic form.

[0050] The terms "solvate" and "pseudopolymorph" can be used synonymously to refer to a crystal having either a stoichiometric or non-stoichiometric amount of solvent incorporated into the crystal lattice. When the incorporated solvent is water, the solvate formed is a "hydrate." When the incorporated solvent is alcohol, the solvate formed is an "alcoholate."

[0051] The term "salt" refers to a substance consisting of two components, an acid and a base, with a well-defined stoichiometric ratio of the two salts. Salt crystals are formed by ionic bonding interactions with complete transfer of hydrogen ions between the acid and base.

[0052] The term "agglomerate" means an assemblage of primary particles that are tightly bonded together, such as by fusion, sintering, or growth. Agglomerates cannot be well dispersed. The term "agglomeration" refers to the process by which primary particles join together to form aggregates.

[0053] The term "agglomerate" refers to a collection of primary particles that are loosely attached to one another by contact. The agglomerates may be well dispersed. The term "aggregation" refers to the process by which primary particles adhere to one another to form agglomerates.

[0054] The term "amorphous form" refers to a solid material that does not have a discernible crystal lattice, and the molecular arrangement of the molecules lacks any significant order. In particular, amorphous refers to a material that does not exhibit a Bragg diffraction peak. Bragg's law describes the diffraction of crystalline materials with the equation "2d sin(theta) = n·lambda," where "d" refers to the perpendicular distance (in angstroms) between a pair of adjacent planes in the crystal ("d-spacing"), "theta" refers to the Bragg angle, "lambda" refers to the wavelength, and "n" refers to an integer. When Bragg's law is satisfied, the reflected beam is in a phase that interferes with the Bragg diffraction peaks observed in the X-ray diffraction pattern. At angles of incidence other than the Bragg angle, the reflected beam is out of phase, and destructive interference or cancellation occurs. Amorphous materials do not satisfy Bragg's law, and no sharp Bragg diffraction peaks are observed in the X-ray diffraction pattern. The XRPD pattern of amorphous material is further characterized by one or more amorphous halos.

[0055] The term "XRPD" refers to the analytical method of X-ray powder diffraction. The repeatability of angle values ​​is in the range of 2 theta ± 0.2°, more particularly in the range of 2 theta ± 0.1°. The term "approximately" in combination with an angle value refers to a variance in the range of 2 theta ± 0.2°, particularly in the range of 2 theta ± 0.1°. Relative XRPD peak intensities depend on many factors, such as structure factors, temperature factors, crystallinity, polarization factors, diversity, and Lorentz factors. Relative intensities can vary considerably from one measurement to another due to preferred orientation effects. According to USP 941 (US Pharmacopoeia, 37th Edition, General Chapter 941), the relative intensity between two samples of the same material can vary considerably due to "preferential orientation" effects. Anisotropic materials that adopt preferred orientation will lead to anisotropic distributions of properties such as modulus, strength, ductility, toughness, conductivity, thermal expansion, etc., as described, for example, by Kocks UF et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In XRPD, as well as in Raman spectroscopy, preferred orientation causes changes in the intensity distribution. Preferential orientation effects are particularly pronounced in crystalline APIs with relatively large particle sizes.

[0056] The term “d 50 The terms "d(0.5)-value" (often referred to as "d(0.5)-value") and "mass median diameter" (or MMD) can be used interchangeably and refer to the average particle size by mass, i.e., the average equivalent diameter of the particles, which is defined as the diameter at which 50% (w) of the particles in the population have a larger equivalent spherical diameter and the other 50% (w) have a smaller equivalent spherical diameter. Similarly, the term "d 10 "d -value" refers to the particle diameter at which 10% (w) of the particles in the population have a smaller equivalent spherical diameter. 90 "-value" means the particle diameter at which 90% (w) of the particles in the population have a smaller equivalent spherical diameter.

[0057] Mass-based particle size distribution (PSD) through sieve analysis (also known as grade testing) is a widely used sieving method for determining particle size and particle size distribution. The mass of material retained on a particular sieve (typically 50 μm to 800 μm sieve sizes in 20 μm-200 μm increments) is weighed and expressed as a percentage of all extracted material, i.e., the cumulative percent weight of particles having a size smaller than the corresponding sieve. Thus, a mass-based PSD is generated.

[0058] The value "characteristic particle size" (d''), obtained through sieve analysis, corresponds to a fictitious sieve size where 63.2 wt% of the total sieved material passes through the screen.

[0059] The term "as / is" yield indicates that no adjustment was made, for example, to account for the amount of solvent in the crystallization, i.e., the yield relative to the amount of ipatasertib·HCl·EtOAc originally used.

[0060] The term "corrected" yield refers to the yield relative to the original solids on a dry basis (anhydrous ipatasertib HCl).

[0061] As used herein, the term "anhydrous" means a solid form lacking water or other solvate molecules in the crystal lattice.

[0062] The terms "screening" and "sieving" both refer to the process of reducing particles in size by mechanically induced abrasion through a screen. This process is generally referred to as milling or deagglomeration.

[0063] Active Pharmaceutical Ingredients (API) (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) has been found to be a safe, potent, and effective inhibitor of Akt suitable for use in the treatment of hyperproliferative disorders such as cancer. Dosage strengths of 100 mg or 200 mg of ipatasertib free base have been found to be optimal for achieving the desired efficacy for various clinical indications.

[0064] In one particular embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) or a pharmaceutically acceptable salt thereof.

[0065] In one particular embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) in amorphous form or a pharmaceutically acceptable salt thereof.

[0066] In one particular embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) as the free base.

[0067] In one particular embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one as the monohydrochloride salt (ipatasertib·HCl).

[0068] In one particular embodiment of the invention, the Akt inhibitor is anhydrous (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib).

[0069] In one particular embodiment of the invention, the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one as the monohydrochloride salt (ipatasertib·HCl) in amorphous form.

[0070] In one particular embodiment of the invention, the Akt inhibitor is anhydrous (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one as the monohydrochloride salt (ipatasertib·HCl) in amorphous form.

[0071] In one particular embodiment of the invention, the pharmaceutical composition comprises 50 mg-1000 mg of an Akt inhibitor.

[0072] In one particular embodiment of the invention, the pharmaceutical composition comprises 100 mg-800 mg of an Akt inhibitor.

[0073] In one particular embodiment of the invention, the pharmaceutical composition comprises 100 mg-300 mg of an Akt inhibitor.

[0074] In one particular embodiment of the invention, the pharmaceutical composition comprises 100 mg, 200 mg or 300 mg of an Akt inhibitor.

[0075] Filler (intragranular) As described above, amorphous ipatasertib monohydrochloride is a very brittle API, making it very difficult to process using direct compression. It has been found that microcrystalline cellulose, which has high plastic deformation characteristics, as a filler advantageously compensates for the brittle properties of ipatasertib. It has further been found that a combination of microcrystalline cellulose and pregelatinized starch as fillers together with ipatasertib provides a composition with improved granulation performance when compared to a composition of microcrystalline cellulose and API alone, due to the moisture absorption properties of pregelatinized starch and also due to the improved compression performance.

[0076] Alternative fillers such as mannitol and lactose have further been found to reduce tablet hardness.

[0077] It has further been found that alternative combinations of fillers, such as microcrystalline cellulose together with lactose, increase the risk of tablet compression cracking.

[0078] In one particular embodiment of the invention, the pharmaceutical composition comprises one or more fillers selected from microcrystalline cellulose, pregelatinized starch, corn starch, lactose, mannitol, calcium phosphate, hydroxypropyl cellulose, polyethylene glycol, sorbitol, maltodextrin, and dextrose.

[0079] In one particular embodiment of the invention, the pharmaceutical composition comprises one or two fillers selected from microcrystalline cellulose and pregelatinized starch.

[0080] In one particular embodiment of the invention, the pharmaceutical composition comprises microcrystalline cellulose and pregelatinized starch as fillers.

[0081] In one particular embodiment of the invention, the pharmaceutical composition comprises 20-75 wt%, more particularly 30-70 wt%, even more particularly 40-65 wt%, and most particularly 50-60 wt% of filler.

[0082] In one particular embodiment of the invention, the pharmaceutical composition comprises 20-75 wt%, more particularly 30-70 wt%, even more particularly 40-65 wt%, and most particularly 50-60 wt% of intragranular filler.

[0083] In one particular embodiment of the invention, the pharmaceutical composition comprises 20-65 wt%, more particularly 30-55 wt%, even more particularly 40-50 wt%, and most particularly 40-45 wt% of crystalline cellulose as a filler.

[0084] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-50 wt%, more particularly 0-30 wt%, even more particularly 5-15 wt%, and most particularly 10-15 wt% of pregelatinized starch as a filler.

[0085] In one particular embodiment of the invention, the pharmaceutical composition comprises 20-65 wt% microcrystalline cellulose and 0-50 wt% pregelatinized starch as fillers, more particularly 30-55 wt% microcrystalline cellulose and 0-30 wt% pregelatinized starch as fillers, even more particularly 40-50 wt% microcrystalline cellulose and 5-15 wt% pregelatinized starch as fillers, and most particularly 40-45 wt% microcrystalline cellulose and 10-15 wt% pregelatinized starch as fillers.

[0086] Binder (intragranular) It has been surprisingly found that the particulate properties of granules can be substantially improved by adding one or more binders to the intragranular matrix. Povidone K90 (polyvinylpyrrolidone K90 with an average Mw of 360,000) improves binding capacity, increases granule particle size distribution (PSD), and improves particle shape (reduced amount of fines) without affecting dissolution performance and hardness. It has been found that granules containing povidone K90 exhibit improved properties such as improved binding capacity (significantly better binding of API), reduced granule friability, increased granule PSD, and reduced amount of fines, while maintaining similar dissolution and disintegration performance at comparable hardness, when compared to povidone K30.

[0087] In one embodiment of the invention, the pharmaceutical composition comprises one or more binders selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl acetate, polyvinyl alcohol, gelatin, and gum arabic.

[0088] In one embodiment of the invention, the pharmaceutical composition comprises one or more binders selected from povidone K90, povidone K30, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl acetate, polyvinyl alcohol, gelatin, and gum arabic.

[0089] In one particular embodiment of the invention, the binder is polyvinylpyrrolidone.

[0090] In one particular embodiment of the invention, the binder is povidone K90.

[0091] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 1.5-3.5 wt% of a binder.

[0092] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 1.5-3.5 wt% of an intragranular binder.

[0093] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 1.5-3.5 wt% of povidone K90 as binder.

[0094] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 1.5-3.5 wt% of intragranular povidone K90 as binder.

[0095] Disintegrants (intraglanin and / or extragranular) It has surprisingly been found by the inventors of the present invention that the disintegration characteristics and drug release profile can be improved by the additional use of a disintegrant. Croscarmellose sodium has been found to be a particularly advantageous (super)disintegrant that does not introduce any peroxides into the pharmaceutical composition.

[0096] In one embodiment of the invention, the pharmaceutical composition comprises one or more disintegrants selected from croscarmellose sodium (internally cross-linked sodium carboxymethylcellulose, E468), crospovidone (polyvinylpolypyrrolidone, PVPP, E1202, a highly cross-linked modification of polyvinylpyrrolidone (PVP)), sodium starch glycolate, sodium alginate, starch, pectin, cellulose derivatives, and croscarmellose calcium.

[0097] In one embodiment of the present invention, the pharmaceutical composition comprises croscarmellose sodium as a disintegrant.

[0098] In one particular embodiment of the invention, the pharmaceutical composition comprises 3-10 wt%, more particularly 4-8 wt%, even more particularly 5-7 wt% disintegrant.

[0099] In one particular embodiment of the invention, the pharmaceutical composition comprises 3-10 wt%, more particularly 4-8 wt%, even more particularly 5-7 wt% of intragranular disintegrant.

[0100] In one particular embodiment of the invention, the pharmaceutical composition comprises 3-10 wt%, more particularly 4-8 wt%, even more particularly 5-7 wt% of extragranular disintegrant.

[0101] In one particular embodiment of the invention, the pharmaceutical composition comprises 3-10 wt%, more particularly 4-8 wt%, even more particularly 5-7 wt% of croscarmellose sodium as a disintegrant.

[0102] In one particular embodiment of the invention, the pharmaceutical composition comprises 3-10 wt%, more particularly 4-8 wt%, even more particularly 5-7 wt% of intragranular croscarmellose sodium as disintegrant.

[0103] In one particular embodiment of the invention, the pharmaceutical composition comprises 3-10 wt%, more particularly 4-8 wt%, even more particularly 5-7 wt% of extragranular croscarmellose sodium as disintegrant.

[0104] In one particular embodiment of the invention, the disintegrant is extragranular.

[0105] Lubricant (extragranular) It has been found by the inventors of the present invention that efficient lubrication to support robust tablet compression can be achieved by the additional use of a lubricant. Stearic acid or magnesium stearate has been found to be a particularly advantageous lubricant suitable for achieving an acceptable lubricating effect during tablet compression while simultaneously providing a targeted drug release profile.

[0106] In one embodiment of the invention, the pharmaceutical composition further comprises one or more lubricants.

[0107] In one embodiment of the invention, the pharmaceutical composition further comprises one or more lubricants selected from magnesium stearate, sodium stearyl fumarate, stearic acid, talc, calcium stearate, and stearyl alcohol.

[0108] In one embodiment of the invention, the pharmaceutical composition further comprises magnesium stearate as a lubricant.

[0109] In one embodiment of the invention, the pharmaceutical composition further comprises stearic acid as a lubricant.

[0110] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, and even more particularly 0.5-1.5 wt% of a glidant.

[0111] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, even more particularly 0.5-1.5 wt% of an extragranular flow enhancer.

[0112] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, even more particularly 0.5-1.5 wt% magnesium stearate as a glidant.

[0113] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, even more particularly 0.5-1.5 wt% extragranular magnesium stearate as a glidant.

[0114] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, even more particularly 0.5-1.5 wt% extragranular stearic acid as a glidant.

[0115] Moisture absorbent (intragranular) As described above, amorphous ipatasertib monohydrochloride exhibits consistently high solubility and very high wettability, which poses significant challenges for processing and for the stability and shelf life of the final product.

[0116] The inventors of the present invention have surprisingly found that a pharmaceutical composition comprising amorphous ipatasertib monohydrochloride and a hygroscopic agent (intragranular) can prevent dissolution of amorphous ipatasertib monohydrochloride during granulation. Thus, a pharmaceutical composition comprising amorphous ipatasertib monohydrochloride and a hygroscopic agent substantially improves processability by reducing the risk of over-wetting and over-granulation and by improving process robustness.

[0117] In one particular embodiment of the present invention, the pharmaceutical composition comprises one or more moisture absorbing agents.

[0118] In one particular embodiment of the present invention, the pharmaceutical composition comprises one or more moisture-absorbing agents selected from colloidal silica, fumed silica, non-fumed silica (Syloid®), pregelatinized starch, corn starch, and croscarmellose.

[0119] In one particular embodiment of the present invention, the moisture absorbent is colloidal silica.

[0120] In one particular embodiment of the present invention, the moisture absorbent is colloidal fumed silica.

[0121] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 2-4 wt% of a moisture absorbing agent.

[0122] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 2-4 wt% of intragranular moisture absorbent.

[0123] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 2-4 wt% colloidal silica as a hygroscopic agent.

[0124] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-10 wt%, more particularly 0-5 wt%, even more particularly 2-4 wt% of intragranular colloidal silica as a hygroscopic agent.

[0125] Glidant (extragranular) Glidant properties (e.g., blend flow) can be improved and tablet compression cracking reduced with the additional use of extragranular glidants. Colloidal silica has been found to be a particularly useful glidant for achieving adequate final blend flow and reducing the risk of compression cracking. Glidants have been found to improve particle flow, which supports a robust tablet compression process and target content uniformity.

[0126] Magnesium stearate has been found to be a particularly useful glidant for achieving an appropriate lubricating effect during tablet compression and drug release profile. The use of colloidal silica in the presence of magnesium stearate is particularly effective in reducing the risk of tablet compression cracking.

[0127] In one embodiment of the invention, the pharmaceutical composition comprises one or more glidants. In one embodiment of the invention, the pharmaceutical composition comprises one or more glidants selected from colloidal silica, talc, magnesium stearate, polyethylene glycol, calcium stearate, and cetyl alcohol.

[0128] In one embodiment of the invention, the pharmaceutical composition comprises colloidal silica as a glidant.

[0129] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, and even more particularly 0.5-1.5 wt% of a glidant.

[0130] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, and even more particularly 0.5-1.5 wt% of an extragranular flow enhancer.

[0131] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, even more particularly 0.5-1.5 wt% colloidal silica as a glidant.

[0132] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-5 wt%, more particularly 0-3 wt%, even more particularly 0.5-1.5 wt% of extragranular colloidal silica as a glidant.

[0133] In one particular embodiment of the present invention, the pharmaceutically acceptable intragranular excipients comprise one or more of a filler, a hygroscopic agent and a binder.

[0134] In one particular embodiment of the present invention, the pharmaceutically acceptable extragranular excipients comprise one or more of a disintegrant, a lubricant and a glidant.

[0135] In one particular embodiment of the present invention, the pharmaceutically acceptable intragranular excipients include one or more fillers, hygroscopic agents and binders, and the pharmaceutically acceptable extragranular excipients include one or more disintegrants, lubricants and glidants.

[0136] In one particular embodiment of the present invention, the pharmaceutically acceptable intragranular excipients include microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide and povidone K90.

[0137] In one particular embodiment of the present invention, the pharmaceutically acceptable extragranular excipients comprise croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0138] In one embodiment of the invention, the pharmaceutically acceptable intragranular excipients include microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, and povidone K90, and the pharmaceutically acceptable extragranular excipients include croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.

[0139] Film Coating Stability, appearance, swallowability, and taste masking can be improved by the additional use of non-functional film coatings. Opadry II®, especially low titanium dioxide Opadry II®, a PVA (polyvinyl alcohol) based film coating system, has been found to be a particularly beneficial film coating suitable for achieving uniformity of coat color and coat thickness.

[0140] In one embodiment of the invention, the pharmaceutical composition further comprises a film coating selected from a PVA-based film coating or an HPMC-based film coating.

[0141] In one embodiment of the invention, the pharmaceutical composition further comprises a film coating selected from an Opadry® PVA-based film coating or an Opadry® HPMC-based film coating.

[0142] In one embodiment of the invention, the pharmaceutical composition further comprises an Opadry II® PVA-based film coating, particularly a low titanium dioxide grade Opadry II® PVA-based film coating.

[0143] In one particular embodiment of the invention, the pharmaceutical composition comprises 0-7 wt%, more particularly 1-6 wt%, and even more particularly 3-5 wt% of an Opadry II® PVA-based film coating.

[0144] Pharmaceutical Compositions Oral immediate-release film-coated tablets have been found to be a particularly suitable dosage form containing amorphous ipatasertib monohydrochloride due to their safety, efficacy and excellent patient compliance, e.g., they are easy to swallow as well as tasteless and odorless.

[0145] The pharmaceutical compositions of the present invention exhibit good stability for more than 24 months without complex storage requirements.

[0146] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders, and disintegrants.

[0147] One embodiment relates to a pharmaceutical composition comprising (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from fillers, binders, and disintegrants.

[0148] One embodiment relates to a pharmaceutical composition as described herein comprising (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) or a pharmaceutically acceptable salt thereof, one or more fillers, binders, and disintegrants.

[0149] One embodiment relates to a pharmaceutical composition as described herein, wherein the intragranular matrix comprises (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected from fillers, binders, and disintegrants.

[0150] One embodiment relates to a pharmaceutical composition as described herein comprising 50 mg-1000 mg of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) or a pharmaceutically acceptable salt thereof.

[0151] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor and one or more fillers.

[0152] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor and a binding agent.

[0153] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor, one or more fillers and binders.

[0154] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor, one or more fillers, binders, and disintegrants.

[0155] One embodiment relates to a pharmaceutical composition comprising an Akt inhibitor, one or more fillers, binders, disintegrants, and lubricants.

[0156] One embodiment relates to a pharmaceutical composition wherein the intragranular matrix comprises an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0157] One embodiment relates to a pharmaceutical composition wherein the intragranular matrix comprises an Akt inhibitor and one or more fillers.

[0158] One embodiment relates to a pharmaceutical composition wherein the intragranular matrix comprises an Akt inhibitor and a binding agent.

[0159] One embodiment relates to a pharmaceutical composition wherein the intragranular matrix comprises an Akt inhibitor, one or more fillers and binders.

[0160] One embodiment relates to a pharmaceutical composition wherein the intragranular matrix comprises an Akt inhibitor, one or more fillers, binders, and disintegrants.

[0161] One embodiment relates to a pharmaceutical composition wherein the extragranular matrix comprises a disintegrant.

[0162] In one particular embodiment of the invention, the pharmaceutical composition further comprises a lubricant.

[0163] In one particular embodiment of the present invention, the pharmaceutical composition further comprises an extragranular lubricant.

[0164] In one particular embodiment of the present invention, the pharmaceutical composition further comprises a moisture absorbing agent.

[0165] In one particular embodiment of the present invention, the pharmaceutical composition further comprises an intragranular moisture absorbent.

[0166] In one particular embodiment of the invention, the pharmaceutical composition further comprises a glidant.

[0167] In one particular embodiment of the present invention, the pharmaceutical composition further comprises an extragranular flow promoter.

[0168] In one particular embodiment of the present invention, the pharmaceutical composition further comprises a film coating.

[0169] In one particular embodiment of the invention, the pharmaceutical composition is suitable for oral administration.

[0170] In one particular embodiment of the invention, the pharmaceutical composition is in solid form.

[0171] In one particular embodiment of the invention, the pharmaceutical composition is a tablet, capsule or sachet comprising granules, which comprise an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

[0172] In one particular embodiment of the invention, the pharmaceutical composition is a tablet, capsule or sachet comprising granules comprising an Akt inhibitor and one or more fillers.

[0173] In one particular embodiment of the invention, the pharmaceutical composition is a tablet, capsule or sachet comprising granules comprising the Akt inhibitor and a binder.

[0174] In one particular embodiment of the invention, the pharmaceutical composition is a tablet, capsule or sachet comprising granules comprising an Akt inhibitor, one or more fillers and a binder.

[0175] In one particular embodiment of the invention, the pharmaceutical composition is a tablet, capsule or sachet comprising granules comprising an Akt inhibitor, one or more fillers, binders and a disintegrant.

[0176] In one particular embodiment of the invention, the pharmaceutical composition is a tablet.

[0177] In one particular embodiment of the present invention, the pharmaceutical composition is an immediate release film coated tablet.

[0178] In one particular embodiment of the invention, the pharmaceutical composition comprises: 20-40 wt% ipatasertib or a pharmaceutically acceptable salt thereof 20-65wt% microcrystalline cellulose as a filler 0-50wt% pregelatinized starch as filler 0-10wt% colloidal silica as a moisture absorbent 1-10wt% polyvinylpyrrolidone as a binder 0-5wt% colloidal silica as a glidant 3-10 wt% croscarmellose sodium as a disintegrant 0-5wt% magnesium stearate as a lubricant Includes:

[0179] In one particular embodiment of the invention, the pharmaceutical composition comprises: 20-40 wt% ipatasertib or a pharmaceutically acceptable salt thereof 20-65wt% microcrystalline cellulose as a filler 0-50wt% pregelatinized starch as filler 0-10wt% colloidal silica as a moisture absorbent 1-10wt% polyvinylpyrrolidone as a binder 0-5wt% colloidal silica as a glidant 3-10 wt% croscarmellose sodium as a disintegrant 0-5wt% magnesium stearate as a lubricant Including, The net weight of ipatasertib free base is 50 mg-800 mg.

[0180] In one particular embodiment of the invention, the pharmaceutical composition comprises: 20-40 wt% of ipatasertib free base or ipatasertib monohydrochloride 40-45wt% microcrystalline cellulose as filler 10-15wt% pregelatinized starch as a filler 2-4 wt% colloidal silica as a moisture absorbent 1.5-3.5 wt% polyvinylpyrrolidone as a binder 0.5-1.5 wt% colloidal silica as a glidant 5-7 wt% croscarmellose sodium as a disintegrant 0.5-1.5 wt% magnesium stearate as a lubricant Includes:

[0181] In one particular embodiment of the invention, the pharmaceutical composition comprises: 20-40 wt% of ipatasertib free base or ipatasertib monohydrochloride 40-45wt% microcrystalline cellulose as filler 10-15wt% pregelatinized starch as a filler 2-4 wt% colloidal silica as a moisture absorbent 1.5-3.5 wt% polyvinylpyrrolidone as a binder 0.5-1.5 wt% colloidal silica as a glidant 5-7 wt% croscarmellose sodium as a disintegrant 0.5-1.5 wt% magnesium stearate as a lubricant Including, The net mass of ipatasertib free base is 50 mg-300 mg.

[0182] In one particular embodiment of the invention, the pharmaceutical composition comprises: 95-105 mg of ipatasertib free base or the corresponding amount of ipatasertib monohydrochloride 150-155mg microcrystalline cellulose as a filler 40-45mg pregelatinized starch as a filler 8-12mg colloidal silica as a moisture absorbent 7-10mg polyvinylpyrrolidone as a binder 2-5mg colloidal silica as a glidant 20-22mg croscarmellose sodium as a disintegrant 2-5mg magnesium stearate as a lubricant Includes:

[0183] In one particular embodiment of the invention, the pharmaceutical composition comprises: 99-101 mg of ipatasertib free base or the corresponding amount of ipatasertib monohydrochloride 151.5-153.5mg microcrystalline cellulose as a filler 41-43mg pregelatinized starch as a filler 9.5-11.5mg colloidal silica as a moisture absorber 7.75-9.75mg polyvinylpyrrolidone as a binder 2.5-4.5mg colloidal silica as a glidant 20-22mg croscarmellose sodium as a disintegrant 2.5-4.5mg magnesium stearate as a lubricant Includes:

[0184] In one particular embodiment of the invention, the pharmaceutical composition comprises: 195-205 mg of ipatasertib free base or the corresponding amount of ipatasertib monohydrochloride 300-310mg microcrystalline cellulose as a filler 80-90mg pregelatinized starch as a filler 19-23mg colloidal silica as a moisture absorbent 15-20mg polyvinylpyrrolidone as a binder 5-10mg colloidal silica as a glidant 40-44mg croscarmellose sodium as a disintegrant 5-10mg magnesium stearate as a lubricant Includes:

[0185] In one particular embodiment of the invention, the pharmaceutical composition comprises: 199-201 mg of ipatasertib free base or the corresponding amount of ipatasertib monohydrochloride 304.5-306.5mg microcrystalline cellulose as a filler 83-85mg pregelatinized starch as a filler 20-22mg colloidal silica as a moisture absorbent 16.5-18.5mg polyvinylpyrrolidone as a binder 6-8mg colloidal silica as a glidant 41-43mg croscarmellose sodium as disintegrant 6-8mg magnesium stearate as a lubricant Includes:

[0186] Method for producing pharmaceutical compositions The present invention further provides methods for the manufacture of pharmaceutical compositions as described herein. In particular, the present invention provides methods for the manufacture of pharmaceutical compositions according to Figure 1.

[0187] One embodiment of the present invention is a method for the preparation of granules suitable for further use in a pharmaceutical composition as described herein, comprising the steps of: a) optionally sieving the filler, optionally the disintegrant and (if present) the moisture absorbing agent by passing them through a mill; b) preparing a pre-blend by mixing the filler and moisture absorbent (if present) together with the API, followed by introducing the pre-blend into a fluid bed granulator; c) preparing a granulation solution by dissolving a binder in a solvent followed by stirring until a clear solution is obtained, alternatively the binder may have already been added during the pre-blend preparation in step b), in which case the granulation solution consists of the solvent; d) spraying the granulation solution onto the fluidized pre-blend in a fluid bed granulator to obtain wet granules; e) Optionally drying the wet granules obtained in the fluid bed granulator The present invention relates to a method, comprising:

[0188] One embodiment of the present invention is a method for preparing a pharmaceutical composition as described herein, comprising: a) optionally sieving the filler and (if present) moisture absorbent by passing through a mill; b) preparing a pre-blend by mixing the filler and moisture absorbing agent (if present) together with the API, followed by introducing the pre-blend into a fluid bed granulator; c) preparing a granulation solution by dissolving a binder in a solvent followed by stirring until a clear solution is obtained, alternatively the binder may have already been added during the pre-blend preparation in step b), in which case the granulation solution consists of the solvent; d) spraying the granulation solution onto the fluidized pre-blend in a fluid bed granulator to obtain wet granules; e) optionally drying the wet granules obtained from the fluid bed granulator; f) optionally sieving the granules obtained by passing them through a mill; g) optionally sieving the disintegrant and glidant (if present) by passing them through a mill; h) preparing a first blend by mixing a disintegrant and, if present, a glidant together with the dry granules in a blender, wherein alternatively or additionally, the disintegrant may have already been added during the preparation of the pre-blend in step b), i) optionally sieving the lubricant by passing it through a mill; j) preparing a second blend by mixing a lubricant with the first blend in a blender; k) compressing the second blend into tablets using a tablet press and punches; l) Optionally coating the tablets in a pan coater The present invention relates to a method, comprising:

[0189] In a particular embodiment of the invention, the milling in step a) has a sieve size of 1.0 mm-2.0 mm, more particularly 1.5 mm.

[0190] In a particular embodiment of the invention, the sieved material in step a) further comprises a binder.

[0191] In a particular embodiment of the invention, the sieved material in step a) further comprises a disintegrant.

[0192] In a particular embodiment of the invention, the sieved material in step a) further comprises a binder and a disintegrant.

[0193] In a particular embodiment of the present invention, the pre-blend in step b) further comprises a binder.

[0194] In certain embodiments of the invention, the pre-blend in step b) further comprises a disintegrant.

[0195] In a particular embodiment of the invention, the pre-blend in step b) further comprises a binder and a disintegrant.

[0196] In a particular embodiment of the present invention, the fluid bed granulator in step b) is a top spray granulator or a bottom spray granulator.

[0197] In a particular embodiment of the present invention, the fluid bed granulator in step b) is a top spray granulator.

[0198] In a particular embodiment of the present invention, the fluid bed granulator in step b) is a bottom spray granulator.

[0199] In a particular embodiment of the present invention, the pre-blend in b) is further mixed during a pre-heating phase at elevated temperature, in particular at 30-80°C or 40-80°C.

[0200] In certain embodiments of the present invention, the pre-blend in b) is further mixed at an elevated temperature during a pre-heating phase, wherein the pre-heating phase lasts for less than 15 minutes, or less than 10 minutes, or less than 5 minutes.

[0201] In a particular embodiment of the invention, the granulation solution in step c) is prepared with a solvent comprising water.

[0202] In a particular embodiment of the invention, the granulation solution in step c) is prepared using water as the solvent.

[0203] In a particular embodiment of the invention, the granulation solution in step c) is prepared at a temperature of 5-60°C, in particular at 20-30°C, most particularly at 25°C.

[0204] In a particular embodiment of the invention, the spraying in step d) is carried out at a spray pressure of the granulation solution of 0.1-5 bar, or 2-4 bar, in particular 1-3 bar.

[0205] In a particular embodiment of the invention, the spraying in step d) is carried out at a spray rate of the granulation solution of 50-250 g / min, or 50-200 g / min, in particular 75-125 g / min.

[0206] In a particular embodiment of the invention, the spraying in step d) is carried out using a spray nozzle with a diameter of 0.8-2 mm, or 1.0-1.6 mm, in particular 1.0-1.4 mm.

[0207] In a particular embodiment of the invention, the drying in step e) is carried out with air, in particular at a temperature of 50-80°C, most particularly at 65°C.

[0208] In a particular embodiment of the present invention, the drying step in step e) is carried out over a period of 300-600 m 3 / hour or 360-560m 3 This is done using air at / hour airflow.

[0209] In a particular embodiment of the invention, the drying step in step e) occurs for less than 1 hour.

[0210] In a particular embodiment of the invention, the mill in step f) has a sieve size of 1.0 mm-2.0 mm, more particularly 1.5 mm.

[0211] In a particular embodiment of the invention, the mill in step g) has a sieve size of 1.0 mm-2.0 mm, more particularly 1.5 mm.

[0212] In a particular embodiment of the invention, the mill in step i) has a sieve size of 1.0 mm-2.0 mm, more particularly 1.5 mm.

[0213] In a particular embodiment of the invention, the step of compression in step k) takes place with a main compression force of 6-20 kN, in particular 8-15 kN or 10-14 kN.

[0214] In one particular embodiment of the invention, the pharmaceutical composition comprises 95-105 mg of ipatasertib free base (or a corresponding amount of ipatasertib monohydrochloride), and the compression step in step k) occurs at a main compression force of 6-14 kN, in particular 8-10 kN.

[0215] In one particular embodiment of the invention, the pharmaceutical composition comprises 195-205 mg of ipatasertib free base (or a corresponding amount of ipatasertib monohydrochloride), and the compression step in step k) occurs at a main compression force of 9-20 kN, in particular 13-15 kN.

[0216] In a particular embodiment of the present invention, the coating step in step l) is carried out in a pan coater where the aqueous coating suspension is sprayed onto the tablets.

[0217] In a particular embodiment of the invention, the coating step in step l) is carried out in a pan coater, in which the aqueous coating suspension is sprayed onto the tablets using a spray nozzle with a diameter of 0.5-1.5 mm, or with a diameter of 0.8-1.5 mm, in particular with a diameter of 0.8-1.2 mm.

[0218] In a particular embodiment of the present invention, the coating step in step l) is carried out in a pan coater, in which the aqueous coating suspension is sprayed onto the tablets at a spray pressure of 1.5-3 bar, in particular 2-2.5 bar.

[0219] In a particular embodiment of the present invention, the coating process in step l) is carried out at an inlet temperature of 50-75°C, in particular 60°C, and a temperature of 400-800m 3 / hour, especially 450m 3Followed by drying using air in the inlet flow for 1 hour.

[0220] Spray Drying Process The present invention also provides a spray drying process, devoid of problematic solvents, for the production of homogeneous and stable amorphous ipatasertib monohydrochloride particles with improved particle size, particle shape and particle properties, such as improved flowability and bulk density, which can be further used in the manufacture of pharmaceutical compositions without additional treatment, conditioning or reprocessing.

[0221] Ipatasertib solvates are listed below: Methyl acetate Ethyl acetate n-Propyl acetate Isopropyl acetate n-Butyl acetate Isobutyl acetate tert-Butyl acetate Amyl acetate Glycerol triacetate Ethyl propionate Methyl ethyl ketone 2-Pentanone Methyl butyl ketone Methyl isobutyl ketone Diisopropyl ketone Diisobutyl ketone Dimethyl carbonate Diethyl carbonate Diethyl ether Methyl tert-butyl ether Methyl tert-butyl ether (water saturated (approximately 1%)) Cyclopentyl methyl ether 1,2-Dimethoxyethane 1,2-diethoxyethane 2,2-Dimethoxypropane 2-Methyltetrahydrofuran Tetrahydropyran Chloroform Carbon tetrachloride 1,2-Dichloroethane 1,1,1-trichloroethane Trichloroethene Tetrachloroethylene ·benzene ·toluene Ethylbenzene Chlorobenzene Kumen o-xylene m-Xylene p-xylene Tetralin This has been successfully achieved with a solvent selected from:

[0222] An ideal solvate would be based on a solvent classified as a USP Class 3 solvent (based on hazard assessment or on their potential toxicity level), which would be water-miscible, have a high vapor pressure and high volatility, and should not form genotoxic by-products.

[0223] A particular solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib HCl) is an ipatasertib solvate that contains in the crystalline lattice a solvent selected from the list of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl propionate, methyl ethyl ketone, 2-pentanone, methyl butyl ketone, methyl isobutyl ketone, diisopropyl ketone, diisobutyl ketone, and methyl tert-butyl ether.

[0224] The most particular solvates of ipatasertib suitable as starting materials for the preparation of ipatasertib monohydrochloride (ipatasertib HCl) are ipatasertib solvates that contain a solvent in the crystalline lattice selected from the list of ethyl acetate, n-propyl acetate, n-butyl acetate, and methyl ethyl ketone.

[0225] A particularly preferred solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib HCl) is ipatasertib ethyl acetate, also known as ipatasertib ethyl etanoate, which is characterized by a single crystal X-ray diffraction pattern containing peaks at diffraction angles 2-theta of 6.6°, 13.9°, 16.6°, 17.4°, 18.2°, 19.0°, 20.5°, 21.4°, 22.4°, and 22.6° (±0.2°).

[0226] A particularly preferred solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib HCl) is ipatasertib ethyl acetate, also known as ipatasertib ethyl ethanoate, which is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction 2-theta angles of 6.6°, 8.4°, 10.5°, 13.6°, 16.4°, 17.2°, 18.8°, 20.0°, 21.1°, and 22.1° (±0.2°).

[0227] A particularly preferred solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib HCl) is ipatasertib n-propyl acetate, also known as ipatasertib n-propyl etanoate. One particular solid form of ipatasertib n-propyl acetate is characterized by an XRPD diffraction pattern containing peaks at diffraction 2-theta angles of 6.2°, 6.9°, 9.5°, 14.4°, 16.9°, 17.4°, 18.0°, 19.8°, 20.7°, and 22.1° (±0.2°).

[0228] Another particular solid form of ipatasertib n-propyl acetate is characterized by an XRPD diffraction pattern comprising peaks at diffraction 2-theta angles of 6.5°, 7.5°, 9.9°, 12.2°, 14.5°, 16.6°, 17.0°, 19.6°, 20.6° and 24.5° (±0.2°).

[0229] Another particular solid form of ipatasertib n-propyl acetate is characterized by an XRPD diffraction pattern comprising peaks at diffraction 2-theta angles of 5.8°, 6.9°, 12.3°, 14.1°, 17.4°, 18.1°, 18.7°, 19.3°, 20.4° and 20.6° (±0.2°).

[0230] A particularly preferred solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib HCl) is ipatasertib n-butyl acetate, also known as ipatasertib n-butyl ethanoate, which is characterized by an XRPD diffraction pattern comprising peaks at diffraction 2-theta angles of 5.8°, 7.5°, 12.0°, 13.7°, 14.8°, 16.9°, 18.8°, 19.1°, 21.8°, and 22.7° (±0.2°).

[0231] A particularly preferred solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib HCl) is ipatasertib methyl ethyl ketone, also known as ipatasertib 2-butanone, which is characterized by an XRPD diffraction pattern comprising XRPD peaks at diffraction 2-theta angles of 5.8°, 7.6°, 12.0°, 13.8°, 14.7°, 16.3°, 17.1°, 18.8°, 19.1°, and 22.8° (±0.2°).

[0232] A particularly preferred solvate of ipatasertib suitable as a starting material for the preparation of ipatasertib monohydrochloride (ipatasertib·HCl) is ethyl ipatasertib acetate.

[0233] A particularly preferred solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib·HCl) is ipatasertib monohydrochloride ethyl acetate solvate (ipatasertib·HCl·EtOAc) which contains less than 10 wt % ethyl acetate.

[0234] A particularly preferred solvate of ipatasertib suitable as a starting material for the preparation of ipatasertib monohydrochloride (ipatasertib·HCl) is ipatasertib monohydrochloride ethyl acetate solvate (ipatasertib·HCl·EtOAc) which contains less than 8 wt % ethyl acetate.

[0235] A particularly preferred solvate of ipatasertib suitable as a starting material in the preparation of ipatasertib monohydrochloride (ipatasertib·HCl) is ipatasertib monohydrochloride ethyl acetate solvate (ipatasertib·HCl·EtOAc) which contains less than 7 wt % ethyl acetate.

[0236] One embodiment of the present invention is a process for preparing amorphous ipatasertib monohydrochloride, comprising: a) dissolving a solvate of ipatasertib in a solvent; b) feeding the resulting feed solution into a spray dryer unit; c) atomizing the solution in a drying chamber to obtain a mist; d) mixing the generated mist with a dry gas, thereby evaporating the solvent; e) separating the obtained amorphous ipatasertib monohydrochloride powder from the drying gas; and f) collecting the resulting amorphous ipatasertib monohydrochloride powder. The present invention relates to a method, comprising:

[0237] One embodiment of the present invention is a process for preparing amorphous ipatasertib monohydrochloride, comprising: g) dissolving ipatasertib monohydrochloride ethyl acetate solvate (ipatasertib·HCl·EtOAc) in a solvent; h) feeding the resulting feed solution into a spray dryer unit; i) atomizing the solution in a drying chamber to obtain a mist; j) mixing the produced mist with a dry gas, thereby evaporating the solvent; k) separating the resulting amorphous ipatasertib monohydrochloride powder from the drying gas; and l) collecting the resulting amorphous ipatasertib monohydrochloride powder. The present invention relates to a method, comprising:

[0238] Optionally, the substantially powder-free dry gas containing evaporated solvent may be recycled as follows: m) directing the dry gas from the cyclone into a filter bag housing, where very fine particles are retained in the bag filter; n) cooling the dry gas in a condenser to cause solvent condensation; o) Reheating and recycling the redried drying gas into the drying chamber.

[0239] In particular, the method relates to the preparation of amorphous ipatasertib monohydrochloride (ipatasertib·HCl) from ipatasertib monohydrochloride ethyl acetate solvate (ipatasertib·HCl·EtOAc) using a spray dryer with a rotating wheel atomizer.

[0240] In particular, the method relates to the preparation of amorphous ipatasertib monohydrochloride (ipatasertib·HCl) from ipatasertib solvate using a spray dryer with a rotating wheel atomizer.

[0241] In a particular embodiment, the dissolving in step a) is carried out at a temperature of 5°C-50°C, more particularly at a temperature of 20°C-25°C. In a particular embodiment, the solvent in step a) comprises water, in particular is water, most particularly purified water.

[0242] In a particular embodiment, the feed solution obtained in step a) is an aqueous solution.

[0243] In a particular embodiment, the feed solution obtained in step a) comprises 5-35% (w / w) ipatasertib·HCl·EtOAc, or more particularly 10-30% (w / w) ipatasertib·HCl·EtOAc, and most particularly 18-22% (w / w) ipatasertib·HCl·EtOAc.

[0244] In a particular embodiment, the feed solution in step b) is fed at a feed rate of 7-20 kg / h, in particular 10-12 kg / h.

[0245] In a particular embodiment, the spray dryer unit in step b) is a rotating wheel or two-fluid nozzle atomizer.

[0246] In a particular embodiment, the spray dryer unit in step b) is a rotating wheel type pressure-swirl single-fluid atomizing nozzle.

[0247] In a particular embodiment, the spray dryer unit in step b) is a rotary wheel atomizer.

[0248] In a particular embodiment, the spray dryer unit in step b) is a rotary wheel atomizer operated at 10,000-30,000 RPM, or 10,000-28,000 RPM, particularly 15,000-25,000 RPM, or 20,000 RPM, most particularly 18,000-20,000 RPM.

[0249] In a particular embodiment, the rotary wheel atomizer has a diameter of 100 mm and 24 holes.

[0250] In a particular embodiment, the spray dryer unit in step b) is a two-fluid nozzle atomizer, more particularly an internally mixed two-fluid nozzle atomizer, most particularly a co-current, internally mixed two-fluid nozzle atomizer.

[0251] In a particular embodiment, the spray dryer unit in step b) allows a water evaporation capacity of 5-30 kg / hour.

[0252] In a particular embodiment, the spray dryer unit in step b) is a GEA Niro Production Minor™ Spray Dryer (DK-2860 Soeborg) manufactured by GEA Process Engineering.

[0253] In a particular embodiment, the two-fluid nozzle spray dryer is operated in step c) using nitrogen as the atomizing gas.

[0254] In a particular embodiment, the two-fluid nozzle spray dryer is operated in step c) at an atomizing gas pressure of 0.5-3 bar, or 1.5-3 bar, in particular 1.5-2.6 bar, or 2.2-2.6 bar, most particularly 2.3-2.5 bar.

[0255] In a particular embodiment, the drying gas in step d) is nitrogen.

[0256] In a particular embodiment, the dry gas in step d) is dry nitrogen having a water content of less than 100 ppm, in particular less than 67 ppm.

[0257] In a particular embodiment, the drying gas in step d) is in the form of a gas stream.

[0258] In particular embodiments, the nominal drying gas flow in step d) is 100-1000 kg / h, in particular 300-600 kg / h, most particularly 350-450 kg / h, or 400-450 kg / h, most particularly in closed cycle mode.

[0259] In a particular embodiment, the drying gas in step d) has an initial temperature of 150°C-200°C, in particular 160°C-190°C or 160°C-180°C, most particularly 170-180°C.

[0260] In a particular embodiment, the mixture of fine aqueous mist with drying gas in step d) has an outlet temperature of 70-150°C, in particular 90°C-120°C, most particularly 100°C-110°C.

[0261] In a particular embodiment, the temperature difference between the initial temperature of the drying gas in step b) and the outlet temperature of the mixture of aqueous mist and drying gas in step d) is between 50°C and 90°C, in particular between 60°C and 80°C.

[0262] In a particular embodiment, the separation in step e) is carried out in a cyclone.

[0263] In a particular embodiment, the separation in step e) is carried out in a conical cyclone at a flow rate of 350-450 kg / h.

[0264] In a particular embodiment, the separation in step e) is carried out in a cyclone with a cutoff of 5 μm-10 μm.

[0265] In a particular embodiment, the amorphous ipatasertib monohydrochloride powder is transferred from the drying chamber into a cyclone in step e) using a flow of drying gas.

[0266] In certain embodiments, the amorphous ipatasertib monohydrochloride powder is collected in step f) in a drum by gravity.

[0267] In a particular embodiment, the humidified dry gas in step h) is cooled to -10°C-20°C, in particular to 0°C-10°C, most particularly to 5°C-9°C.

[0268] In a particular embodiment, the process for the preparation of amorphous ipatasertib monohydrochloride comprises the following process parameters: Feed solution: 20-25% (w / w) ipatasertib·HCl·EtOAc 75-80% (w / w) water Sprayer: Rotating wheel type sprayer or two-fluid nozzle Sprayer speed: 10000-28000RPM for rotary wheel sprayers Atomizing gas pressure: 2.2-2.6 bar for two-fluid nozzles Drying gas inlet temperature: 160-180℃ Drying gas outlet temperature: 90-120℃ Dry gas (nitrogen): 450 kg / hour, especially in closed cycle mode Condensation temperature (process h): 5-9℃ It is held at.

[0269] In certain embodiments, the process for the preparation of amorphous ipatasertib monohydrochloride comprises the following process parameters: Feed solution composition: 20% (w / w) ipatasertib·HCl·EtOAc 80% (w / w) purified water Spray mode: Rotating wheel type sprayer or two-fluid nozzle Sprayer speed: 19000 RPM for rotary wheel sprayer Spray pressure: 2.4 bar for two-fluid nozzles Drying gas inlet temperature: 175℃ Drying gas outlet temperature: 105℃ Dry gas (nitrogen): 400 kg / hour, closed cycle mode Condensation temperature: 5-9℃ It is held at.

[0270] These optimized conditions allow excellent yields of 90-94% as / is and 96-100% "corrected".

[0271] use A particular embodiment of the present invention relates to a pharmaceutical composition as defined above for use in the treatment of hyperproliferative disorders, in particular for the treatment of cancer.

[0272] A particular embodiment of the present invention relates to a method for the treatment of a hyperproliferative disorder, in particular for the treatment of cancer, comprising administering to a subject a pharmaceutical composition as defined above.

[0273] A particular embodiment of the present invention relates to the use of a pharmaceutical composition as defined above for the treatment of hyperproliferative disorders, in particular for the treatment of cancer. [Example]

[0274] The following Examples 1-14 are provided to illustrate the present invention and should not be considered as limiting the scope of the invention, but merely as being representative thereof.

[0275] Example 1 Pharmaceutical composition of ipatasertib HCl The following 15 pharmaceutical compositions were prepared according to the present invention as described in the flow diagram of Figure 1, followed by the procedures detailed below, and the ingredient concentrations in Tables 1-7 below.

[0276] General measures: 1) Sifting the filler, hygroscopic agent (if present) and intragranular disintegrant (if present) by passing through a mill (1.5 mm sieve size). 2) Preparing a preblend by mixing the filler and moisture absorbent (if present) together with the API, followed by introducing this preblend into a fluidized bed granulator (top spray granulator in drying stage mode, Diosna Fluid Bed Dryer CCSP150, Diosna Dierks & Sohne GmbH, Osnabruck / DE). 3) Preparing the granulation solution by dissolving the binder in water at 25°C followed by stirring until a clear solution is obtained. 4) Spraying the granulation solution onto the fluidized pre-blend in a fluidized bed granulator to obtain wet granules (atomization pressure 3 bar, spray rate of granulation solution 100-125 g / min, spray nozzle diameter 1.2 mm). 5) 360-560 m for 0-45 (mainly 15-30) minutes using air at 65°C. 3 Drying the wet granules obtained in the fluid bed granulator with an air stream for 1 / hour. 6) Sieving the obtained granules by passing them through a mill (sieve size of 1.5 mm). 7) Sifting the extragranular disintegrant and glidant (if present) by passing through a mill (1.5 mm sieve size). 8) Preparing a first blend by mixing the extragranular disintegrant and glidant (if present) together with the dry particles in a blender. 9) Sifting the lubricant by passing it through a mill (1.5 mm sieve size). 10) Preparing a second blend by mixing a lubricant with the first blend in a blender. 11) Compressing the second blend into tablets using a tablet press and punches (100 mg API content: 10 kN main compression force, 200 mg API content: 14 kN main compression force). 12) If applicable, coating the tablets in a pan coater, where an aqueous coating suspension comprising Opadry II 85F240172 PVA-based film coat (pink) is sprayed onto the tablets using a spray nozzle with a diameter of 1.2 mm and a spray pressure of 2-2.5 bar. 13) At an inlet temperature of 60°C, if applicable, and 450m 3 A process for drying film-coated tablets (fct) using air at an inlet flow rate of 1 / hour. JPEG2025170249000003.jpg169170JPEG2025170249000004.jpg163170JPEG2025170249000005.jpg163170JPEG20251702490 00006.jpg156170JPEG2025170249000007.jpg190170JPEG2025170249000008.jpg187170JPEG2025170249000009.jpg194170

[0277] Example 2 Effect of fillers on pharmaceutical compositions containing ipatasertib HCl Tablet hardness was measured by compressing tablets at various compression forces (8-24 kN, 2 kN each). At each compression force, 10 tablets were tested in a tablet hardness tester (Sotax AG, Aesch / CH), and the resulting breaking forces were recorded and averaged. Each point in Figure 2 represents the average hardness of n = 10 tablets at a particular compression force.

[0278] FIG. 2 provides the compression force / hardness curves of five tablet cores of the present invention. GPV0006 / 03 corresponds to composition 1 containing 36.27 wt% microcrystalline cellulose, 12.00 wt% pregelatinized starch and 6.00 wt% lactose as fillers (weight ratio 6:2:1). · GPV0004 / 09 corresponds to composition 3, which contains 38.50 wt% microcrystalline cellulose and 18.00 wt% mannitol as fillers (ratio by weight of about 2:1). · GPV0004 / 10 corresponds to composition 4, which contains 38.50 wt% microcrystalline cellulose and 18.00 wt% corn starch as fillers (ratio by weight of about 2:1). · GPV0004 / 07 corresponds to composition 5 containing 56.50 wt% microcrystalline cellulose as the sole filler. GMP0147 / 03 corresponds to composition 7, which contains 43.65 wt% microcrystalline cellulose and 12.00 wt% pregelatinized starch as fillers (ratio by weight of approximately 78:22).

[0279] Ideally, a tablet hardness of between 200N and 350N is achieved with a compression force of 12-20kN (depending on the particle size and punch type). Therefore, a compression force / hardness profile that is not too broad is preferred. Compositions 1, 3, 4, and 7 of the present invention have been found to ideally satisfy this requirement. Microcrystalline cellulose (Avicel PH101) as a filler favorably compensates for the brittle properties of ipatasertib HCl. Microcrystalline cellulose as a filler alone (as in Composition 5) does not produce adequate compression behavior when the compression force / hardness profile is too broad.

[0280] It has further been found that a combination of microcrystalline cellulose and pregelatinized starch (Starxx 1500) together with ipatasertib HCl as a filler, such as in composition 7, provides a composition with improved fluid bed granulation process performance due to the water absorption properties of the pregelatinized starch and also due to improved compression performance when compared to a composition containing microcrystalline cellulose as the filler alone.

[0281] Mannitol as a filler (as in composition 3) was further found to be less compatible and present potential tablet robustness issues (e.g., sticking during tablet compression), as tablets obtained with mannitol as a filler were found to require very high ejection forces from a tablet press.

[0282] Corn starch as a filler (as in composition 4) was further found to be less beneficial as corn starch has inherent elastic mechanical properties that increase the risk of tablet compression cracking.

[0283] Lactose as a filler (as in composition 12) was found to be less beneficial, as tablets obtained with lactose as a filler were found to exhibit increased dissolution times. Furthermore, lactose has inherently brittle mechanical properties that increase the risk of tablet compression cracking. The combination of microcrystalline cellulose and lactose as a filler was found to increase the risk of tablet compression cracking, as evidenced by the data provided at the bottom of Table 5.

[0284] To check for tablet compression cracking, tablets were tested in a standard tablet hardness tester. For each compression force, 10 tablets were tested, and the tablet breaking direction was visually observed. Tablets with no tendency to compression cracking exhibited a vertical breaking direction. The number of tablets exhibiting a horizontal breaking direction (indicating compression cracking) was recorded.

[0285] The combination of microcrystalline cellulose and pregelatinized starch as fillers showed good granulation process robustness, yielding an acceptable compression force / hardness profile with adequately low tablet wear at lower hardnesses, and also yielding acceptable disintegration times at higher hardnesses.

[0286] Example 3 Effect of hygroscopic agents on pharmaceutical compositions containing ipatasertib HCl Compositions 11 and 12 were prepared to evaluate the effect of moisture absorbers. Granules could be obtained with or without intragranular colloidal silica as a moisture absorber. However, the granulation process without colloidal silica as a moisture absorber was observed to be less robust, i.e., the granules appeared to be more sensitive to higher spray rates. As can be seen from Table 6, granules without intragranular colloidal silica (e.g., Compound 12: d' = 285 μm, 16.9% fine particles) exhibit significantly increased PSD d' (+45%) and decreased fine particle content (-51%) compared to granules containing 5 wt% colloidal silica (e.g., Compound 11: d' = 197 μm, 25.5% fine particles). It was further found that the removal of intragranular colloidal silica resulted in lower tablet hardness and higher tablet wear. It was further found that granules without colloidal silica exhibited a 15% higher disintegration time (Compound 12: 14 min 43 sec, Compound 11: 12 min 42 sec) despite lower tablet hardness. It was further observed that colloidal silica had only a minimal effect on bulk density (Compound 12: 0.21 g cm -3 , compound 11:0.25gcm -3 ).

[0287] Figure 3 provides a scanning electron micrograph obtained from Composition 11. It is evident that the round particles (amorphous API) are layered with colloidal silica (small dots on the round particles).

[0288] Figure 4 provides a scanning electron micrograph obtained from Composition 12. The rounded API particles are fused with a matrix of other excipients. Due to the high aqueous solubility of the API, it is hypothesized that the API dissolves during granulation and precipitates along with the other excipients.

[0289] Colloidal silica (Aerosil200 Pharma) is used as an intragranular moisture absorbent. Supports robust fluid bed granulation process performance.

[0290] Example 4 Effect of binders on pharmaceutical compositions containing ipatasertib HCl The particle size, bulk density and disintegration time of three tablets (Compositions 11, 13 and 5) were investigated as presented in Table 8. Figure 5 provides the drug dissolution profiles of these three compositions. TIFF2025170249000010.tif57170

[0291] In compositions 11 and 13, a different binder grade with a smaller binding capacity was used (PVP K30) compared to composition 5 (PVP K90). Similar process robustness was observed for all three compositions, but the particle size distribution was shifted to smaller sizes and higher doses of fine particles for compositions containing PVP K30 as the binder.

[0292] 2.5% PVPK90 resulted in larger granule particle size when compared to 2.5% and 5% PVP K30. Furthermore, the amount of fine fraction (fine particles) in the granules could be substantially reduced by using PVP K90 when compared to PVP K30, which is believed to be beneficial in reducing the risk of tablet compression cracking.

[0293] The effect of binder grade on tablet disintegration time and drug dissolution was not significant. At similar compression forces used in tableting (approximately 16 kN), the data show that PVP K90 (composition 5) leads to similar dissolution performance from the tablets than PVP K30 (compositions 11 and 13), as can be seen in Figure 5.

[0294] In conclusion, PVP K90 leads to larger granules and reduced fines content while maintaining the same beneficial dissolution performance at comparable hardness. Polyvinylpyrrolidone K90 (Kollidon K90) as a binder promotes the formation of an appropriate granule size distribution for robust downstream process performance.

[0295] Example 5 Effect of lubricants on pharmaceutical compositions containing ipatasertib HCl The lubricant has the purpose of lubricating the tablet compression tooling, which supports a robust tablet compression process. Two additional tablets were prepared by the method of Example 1 to investigate the effect of the lubricant on the robustness of tablet compression performance. In contrast to Example 1, the intragranular matrix of Composition 14 was sieved through a 2.0 mm sieve in step 6 of the general procedure to obtain coarse granules. In contrast to Example 1, the extragranular matrix of Composition 15 was sieved through a 2.0 mm sieve and through a 0.8 mm sieve in step 6 of the general procedure to obtain fine particle granules.

[0296] The particle size distribution of such resulting granules was subsequently investigated before being mixed with the extragranular matrix, as provided in Table 9. TIFF2025170249000011.tif40170

[0297] Composition 14 can be considered an extreme example of an over-lubricated final blend, as it combines coarser, and therefore lower surface area, granules with an above-target magnesium stearate concentration.

[0298] Composition 15 can be considered an extreme example of a poorly lubricated final blend, as it combines particulate, and therefore higher surface area, granules with a magnesium stearate concentration below target.

[0299] The tablet compression performance, i.e., adhesion and compression cracking behavior, of Compositions 14 and 15 were subsequently evaluated. Across all compression runs, ejection forces were found to be within the normal range for both 100 mg (100-130 N) and 200 mg (-200 N) tablet sizes, with no increase observed. Interestingly, both extremes reveal robust tablet compression performance, indicating a low risk of adhesion and compression cracking. The robust tablet compression and absence of microcracks (as confirmed by μCT imaging) confirm that 1 wt% magnesium stearate corresponds to the optimal lubricant concentration in the extragranular matrix for both 100 mg and 200 mg tablet dose strengths.

[0300] Example 6 Amorphous ipatasertib monohydrochloride prepared using a two-fluid nozzle spray dryer WO 2013 / 173811A1 describes, on pages 33-35 (Examples 12A-12C), a number of spray drying processes for producing amorphous ipatasertib monohydrochloride. Amorphous ipatasertib monohydrochloride was prepared by spray drying solutions of different free forms of ipatasertib monohydrochloride using a two-fluid nozzle spray dryer. The conditions and results are shown below in Table 10. TIFF2025170249000012.tif190170

[0301] The materials as given in Table 10 were further investigated with additional analytical methods. The results obtained for the materials as described in Examples 12A-C in WO 2013 / 173811 A1 are set out below in Tables 11 and 12. TIFF2025170249000013.tif187170TIFF2025170249000014.tif68170

[0302] The following conclusions were drawn from analytical investigations of the materials according to Examples 6A, 6A', 6B, 6B', 6C and 6C', which were obtained as described in WO 2013 / 173811 A1, pages 33-35. The bulk density of the powder of Example 6C' is 0.262 g cm -3 The tap density is 0.423 gcm -3 , resulting in a Carr index of 38%, indicating very poorly flowing material. Shear cell tests (ffc approx. 1.1 over all pre-shear stresses, see Table 12) show that the powder has very poor flowability. Shear tests show that the poor flow is primarily due to the small particle size and high cohesion (high stickiness) of the particles, despite the rounded morphology of the particles. The particle size analysis of the powder of Example 6C was d<8.1 μm. 90 The bimodal particle size distribution was revealed (see Figure 6). Optical and scanning electron microscopy (see Figure 7) reveal that the resulting material of the powder of Example 6C consists of rounded particles in two size ranges: submicron-sized nanoparticles and particles with a diameter of 1-10 μm.

[0303] Example 7 General procedure for the conversion of ipatasertib monohydrochloride ethyl acetate solvate to amorphous ipatasertib monohydrochloride using a rotating wheel spray dryer Anhydrous ipatasertib monohydrochloride ethyl acetate solvate (typically containing 2-8 wt% EtOAc) was dissolved in purified water at 15-30°C. The resulting solution, containing 10-30 wt% solids, was then fed into a spray dryer unit (a Niro Production Minor™ spray dryer obtained from GEA Process Engineering, Soeborg, DK) and atomized in a drying chamber using suitable rotating wheel atomization conditions or, alternatively, suitable two-fluid nozzle atomization conditions. The fine mist produced by the atomizer was mixed with a hot nitrogen stream as a drying gas to initiate evaporation of water from the droplets. The solution feed rate was adjusted to reach the desired gas outlet temperature. The drying gas carried the fine powder through the drying chamber and out of a cyclone. The cyclone separated the powder from the drying gas, and the powder was collected in a drum by gravity. The substantially powder-free gas flowed into a filter bag housing, where very fine particles were retained in a bag filter. The powder-free gas was cooled in a condenser where water condensation occurred and after reheating the dried gas was recycled to the drying chamber (flow diagram in Figure 8).

[0304] Example 8 Preparation of amorphous ipatasertib monohydrochloride Five batches of amorphous ipatasertib HCl (130710450, 130710451, 130710452, 130810453, and 130810454) were prepared according to the general procedure of Example 7, except that batch 130810454 was prepared using a two-fluid nozzle spray dryer instead of a rotating wheel spray dryer. The amounts of reactants used, process parameters, and analytical results are presented in Table 13. All five batches were obtained within 1-2 hours. Four batches using the rotating wheel spray mode (batch numbers 130710450, 130710451, 130710452, and 130810454) showed improved processability in subsequent drug product manufacturing. TIFF2025170249000015.tif193170

[0305] Example 9 Preparation of amorphous ipatasertib monohydrochloride Five additional batches of amorphous ipatasertib monohydrochloride (140110401, 140110402, 140110403, 140110404, 140110405) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are presented in Table 14. TIFF2025170249000016.tif195170

[0306] Example 10 Preparation of amorphous ipatasertib monohydrochloride Five additional batches of amorphous ipatasertib monohydrochloride (140110406, 140110407, 140110408, 140110409, 140110410) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are presented in Table 15. TIFF2025170249000017.tif183170

[0307] Example 11 Preparation of amorphous ipatasertib monohydrochloride One additional batch (140110411) of amorphous ipatasertib monohydrochloride was prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are presented in Table 16. TIFF2025170249000018.tif184170

[0308] Example 12 Preparation of amorphous ipatasertib monohydrochloride Three additional batches of amorphous ipatasertib monohydrochloride (140210412, 140210413, 140210414) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters, and analytical results are presented in Table 17. TIFF2025170249000019.tif162170

[0309] Example 13 Preparation of amorphous ipatasertib monohydrochloride Twenty additional batches of amorphous ipatasertib monohydrochloride (140910415-141210426 and BS1506SA01-BS1506SA08) were prepared according to the general procedure of Example 7. The amounts of reactants used, process parameters and analytical results are presented in Tables 18, 19 and 20.

[0310] For example, the process conditions as used in Table 20 allowed excellent yields of 90-94% "as is" and 96-100% "corrected." TIFF2025170249000020.tif231170TIFF2025170249000021.tif246170TIFF2025170249000022.tif250170

[0311] Example 14 Characterization of amorphous ipatasertib monohydrochloride As obtained in Tables 18 and 20 of Example 13, various amorphous ipatencetib monohydrochloride batches prepared using a rotary wheel type spray dryer were further characterized by shear cell tests similar to those in Example 6 of amorphous ipatencetib monohydrochloride prepared using a two-fluid nozzle spray dryer (Table 12).

[0312] Similar to the classification used by Jenike (Dietmar Schulze, Pulver und Schuttguter, 2009 Springer Verlag Berlin / DE), the flow behavior can be defined as follows based on the flow function constant (ffc). ffc < 1 No fluidity 1 < ffc < 2 Very sticky 2 < ffc < 4 Sticky 4 < ffc < 10 Flows easily 10 < ffc Flows freely

[0313] The larger the flow function constant ffc, that is, the smaller the ratio of the unconfirmed yield stress (σc) to the consolidation stress (σ1), the better the flow of the bulk solid.

[0314] As is immediately apparent from the data in Table 21, amorphous ipatencetib monohydrochloride prepared using a rotary wheel type spray dryer exhibits substantially improved flow behavior (up to ffc 4.0) compared to amorphous ipatencetib monohydrochloride prepared using the two-fluid nozzle spray dryer of Example 6C' (Table 12, ffc 1.08). TIFF2025170249000023.tif130170

Claims

1. A pharmaceutical composition comprising an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders and disintegrants.

2. 10. The pharmaceutical composition of claim 1, comprising an Akt inhibitor, one or more fillers, a binder, and a disintegrant.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the intragranular matrix comprises an Akt inhibitor and one or more pharmaceutically acceptable excipients selected from fillers, binders, and disintegrants.

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the Akt inhibitor is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) or a pharmaceutically acceptable salt thereof.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, comprising 50 mg to 1000 mg of an Akt inhibitor.

6. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein amorphous monohydrochloride salt of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib) is used.

7. 7. The pharmaceutical composition of claim 1, further comprising one or more fillers selected from microcrystalline cellulose, pregelatinized starch, corn starch, lactose, mannitol, calcium phosphate, hydroxypropyl cellulose, polyethylene glycol, sorbitol, maltodextrin and dextrose.

8. 8. The pharmaceutical composition according to claim 1, comprising one or two fillers selected from microcrystalline cellulose and pregelatinized starch.

9. 9. The pharmaceutical composition of claim 1, comprising one or more binders selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl acetate, polyvinyl alcohol, gelatin, and gum arabic.

10. 10. The pharmaceutical composition of claim 1, wherein the binder is polyvinylpyrrolidone.

11. 11. The pharmaceutical composition of claim 1, comprising one or more disintegrants selected from croscarmellose sodium, crospovidone, sodium starch glycolate, sodium alginate, starch, pectin, cellulose derivatives and croscarmellose calcium.

12. 12. The pharmaceutical composition of claim 1, comprising croscarmellose sodium as a disintegrant.

13. 13. The pharmaceutical composition of claim 1, further comprising one or more lubricants.

14. 14. The pharmaceutical composition of claim 13, comprising one or more lubricants selected from magnesium stearate, sodium stearyl fumarate, stearic acid, talc, calcium stearate, and stearyl alcohol.

15. 15. The pharmaceutical composition of claim 12, comprising magnesium stearate as a lubricant.

16. 16. The pharmaceutical composition of claim 1, further comprising one or more moisture-absorbing agents.

17. 17. The pharmaceutical composition of claim 16, wherein the moisture absorbing agent is intragranular.

18. 18. The pharmaceutical composition of claim 17, comprising one or more moisture-absorbing agents selected from colloidal silica, fumed silica, non-fumed silica, pregelatinized starch, corn starch, and croscarmellose.

19. 19. The pharmaceutical composition of claim 17 or 18, wherein the moisture absorbent is colloidal silica.

20. 20. The pharmaceutical composition of claim 1, further comprising one or more glidants.

21. 21. The pharmaceutical composition of claim 20, comprising one or more glidants selected from colloidal silica, talc, magnesium stearate, polyethylene glycol, calcium stearate, and cetyl alcohol.

22. 22. The pharmaceutical composition of claim 20 or 21, comprising colloidal silica as a glidant.

23. 23. The pharmaceutical composition of claim 1, further comprising a film coating.

24. 24. The pharmaceutical composition of claim 23, comprising a film coating selected from a PVA-based film coating or an HPMC-based film coating.

25. 20-40 wt% ipatasertib or a pharmaceutically acceptable salt thereof; 20-65 wt% microcrystalline cellulose as a filler; 0-50 wt % pregelatinized starch as a filler; 0-10 wt% colloidal silica as a moisture absorbent; 1-10 wt % polyvinylpyrrolidone as a binder; 0-5 wt % colloidal silica as a glidant; 3-10 wt% croscarmellose sodium as a disintegrant, and 0-5 wt% magnesium stearate as a lubricant 25. The pharmaceutical composition of claim 1, comprising:

26. 20-40 wt% of ipatasertib free base or ipatasertib monohydrochloride, 40-45 wt% microcrystalline cellulose as a filler; 10-15 wt % pregelatinized starch as a filler; 2-4 wt% colloidal silica as a moisture absorbent; 1.5-3.5 wt % polyvinylpyrrolidone as a binder; 0.5-1.5 wt % colloidal silica as a glidant; 5-7 wt% croscarmellose sodium as a disintegrant, and 0.5-1.5 wt% magnesium stearate as a lubricant 26. The pharmaceutical composition of any one of claims 1 to 25, comprising:

27. 27. The pharmaceutical composition of any one of claims 1 to 26, which is a tablet, capsule or sachet.

28. 27. The pharmaceutical composition of any one of claims 1 to 26, which is an immediate release film-coated tablet.

29. 29. A method for the manufacture of granules suitable for further use in a pharmaceutical composition according to any one of claims 1 to 28, comprising the steps of: a) optionally sieving the filler, optionally the disintegrant and the moisture absorbing agent (if present) by passing them through a mill; b) preparing a pre-blend by mixing the filler and moisture absorbing agent (if present) together with the API, followed by introducing the pre-blend into a fluid bed granulator; c) preparing a granulation solution by dissolving a binder in a solvent followed by stirring until a clear solution is obtained; alternatively, the binder may have already been added during the pre-blend preparation in step b), in which case the granulation solution consists of the solvent; d) spraying the granulation solution onto the fluidized pre-blend in a fluid bed granulator to obtain wet granules; e) Optionally drying the wet granules obtained in the fluid bed granulator A method comprising:

30. 29. A method for the preparation of a pharmaceutical composition according to any one of claims 1 to 28, comprising: a) optionally sieving the filler and (if present) moisture absorbent by passing through a mill; b) preparing a pre-blend by mixing the filler and moisture absorbing agent (if present) together with the API, followed by introducing the pre-blend into a fluid bed granulator; c) preparing a granulation solution by dissolving a binder in a solvent followed by stirring until a clear solution is obtained; alternatively, the binder may have already been added during the pre-blend preparation in step b), in which case the granulation solution consists of the solvent; d) spraying the granulation solution onto the fluidized pre-blend in a fluid bed granulator to obtain wet granules; e) optionally drying the wet granules obtained in the fluid bed granulator; f) optionally sieving the granules obtained by passing them through a mill; g) optionally sieving the disintegrant and glidant (if present) by passing through a mill; h) preparing a first blend by mixing a disintegrant and, if present, a glidant together with the dry granules in a blender, wherein alternatively or additionally, the disintegrant may have already been added during the preparation of the pre-blend in step b); i) optionally sieving the lubricant by passing it through a mill; j) preparing a second blend by mixing a lubricant with the first blend in a blender; k) compressing the second blend into tablets using a tablet press and punches; l) Optionally coating the tablets in a pan coater A method comprising:

31. 29. A process for the preparation of amorphous ipatasertib monohydrochloride suitable for the pharmaceutical composition of any one of claims 1 to 28, comprising: a) dissolving a solvate of ipatasertib in a solvent; b) feeding the resulting feed solution into a spray dryer unit; c) atomizing the solution in a drying chamber to obtain a mist; d) mixing the created mist with a dry gas, thereby evaporating the solvent; e) separating the resulting amorphous ipatasertib monohydrochloride powder from the drying gas; and f) collecting the resulting amorphous ipatasertib monohydrochloride powder. A method comprising:

32. g) directing the dry gas from the cyclone into a filter bag housing, where very fine particles are retained in the bag filter; h) cooling the dry gas in a condenser to cause solvent condensation; i) reheating and recycling the re-dried drying gas into the drying chamber.

32. The method of claim 31 , further comprising:

33. 33. The method of claim 31 or 32, wherein the solvate of ipatasertib in step a) comprises in the crystal lattice a solvent selected from the list of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl propionate, methyl ethyl ketone, 2-propanone, methyl butyl ketone, methyl isobutyl ketone, diisopropyl ketone, diisobutyl ketone and methyl tert-butyl ether.

34. 34. The method of any one of claims 31 to 33, wherein the solvate of ipatasertib in step a) is ipatasertib monohydrochloride ethyl acetate solvate (ipatasertib.HCl.EtOAc).

35. 35. The method according to any one of claims 31 to 34, wherein the spray dryer unit in step b) is a rotating wheel type or a two-fluid nozzle atomizer.

36. The process parameters are as follows: Feed solution: 20-25% (w / w) Ipatasertib·HCl·EtOAc 75-80% (w / w) water, Sprayer: Rotating wheel type sprayer or two-fluid nozzle; Sprayer speed: 10,000-28,000 RPM for rotary wheel sprayers; Atomizing gas pressure: 2.2 to 2.6 bar for two-fluid nozzles; Drying gas inlet temperature: 160-180°C, Drying gas outlet temperature: 90-120°C, Dry gas (nitrogen): 450 kg / h, especially in closed cycle mode; Condensation temperature (process h): 5-9℃ 36. The method of any one of claims 31 to 35, wherein the method is carried out by

37. 30. A pharmaceutical composition according to any one of claims 1 to 28 for use in the treatment of a hyperproliferative disorder.

38. 30. A method for the treatment of a hyperproliferative disorder, comprising administering to a subject a pharmaceutical composition of any one of claims 1 to 28.

39. 30. Use of a pharmaceutical composition according to any one of claims 1 to 28 for the treatment of a hyperproliferative disorder.

40. 10. The invention as hereinbefore described.

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