WO2016066420A1

WO2016066420A1 - Crystalline forms of palbociclib monohydrochloride

Info

Publication number: WO2016066420A1
Application number: PCT/EP2015/073659
Authority: WO
Inventors: Marijan STEFINOVIC
Original assignee: Sandoz Ag
Priority date: 2014-10-29
Filing date: 2015-10-13
Publication date: 2016-05-06

Abstract

Crystalline forms of palbociclib monohydrochloride useful as CDK4/Cyclin D3 inhibitors & CDK6/Cyclin D3 inhibitors in the treatment of various types of cancers.

Description

CRYSTALLINE FORMS OF PALBOCICLIB MONOHYDROCHLORIDE

FIELD OF THE INVENTION The present invention relates to novel polymorphic forms of palbociclib monohydrochloride and processes for their preparation. It further relates to a pharmaceutical composition comprising said polymorphic forms of palbociclib monohydrochloride, as well of methods of using said polymorphic forms in the treatment of breast cancer and colorectal cancer. BACKGROUND OF THE INVENTION

Palbociclib is a cyclin-dependent kinase 4 and 6 (cdk4 and cdk 6) inhibitor for the potential treatment of cancer, primarily advanced hormone-receptor-positive breast cancer and high-risk early-stage hormone-receptor-positive breast cancer.

Palbociclib is chemically referred to as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(l-piperazinyl)- 2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7-(8H)-one and is represented by following chemical structure:

Palbiciclib and different salts thereof are described in WO 2003/062236 and in WO 2005/005426.

However, the use of Palbociclib in pharmaceutical products has been described in WO 2005/005426 as posing many challenges. For example, palbociclib free base has been described as having poor water solubility and exhibiting low bioavailability in animal studies.

WO 2005/005426 discloses a dihydrochloride salt of palbociclib and states that it exhibits adequate water solubility. But moisture uptake studies revealed that, even at low relative humidity (10 % RH), the dihydrochloride salt absorbs water in an amount greater than about 2 % of its mass, making it unsuitable for use in a solid drug product (WO 2005/005426, page 3, second paragraph).

In the same passage of WO 2005/005426 the monohydrochloride salt of palbociclib is described as a marginally hygroscopic salt, absorbing more than 2% of its mass at a relative humidity above 80%, and WO 2005/005426 goes on to describe potential problems with the process scale-up for the monohydrochloride salt.

Figure 5 in WO 2005/005426 shows a XRPD pattern of palbociclib monohydrochloride crystal form I, wherein crystal form I is characterized by an x-ray powder diffraction pattern (XRPD) comprising peaks at °2Θ values of 4.7, 9.9, 11.19, 15.6, 15.8, 19.2, 22.7 and 24.3, when measured at a temperature of about 20 °C and using CuKai,₂ radiation, and Figure 18 in WO 2005/005426 shows water adsorption/desorption isotherms for various salts of palboclicib such as monohydrochloride, dihydrochloride, monoisethionate, mono-mesylate, di-mesylate, and mono-tosylate. The solid form of the monohydrochloride salt of palbociclib disclosed in WO 2005/005426 exhibits greater than a 2 % change in mass when exposed to humidity levels ranging from 10% RH to 90 % RH at 25°C.

An object of present invention is to provide novel crystalline forms of palbociclib salts exhibiting less than 2.0 change in mass when exposed to humidity levels ranging from 10% RH to 90 % RH at 25°C.

In an attempt to do so, WO 2005/005426 ultimately turns away from chloride salts of palbociclib for pharmaceutical formulation and rather suggests using mono-isethionate salts for the preparation of pharmaceutical formulations.

However, the isethionate counterion adds a lot of unnecessary mass to palbociclib (125Da per isethionate unit), making the identification of stable palbociclib salts having a lower molecular weight desirable from the perspective of drug load and efficiency.

An object of the present invention was thus to provide a stable solid form of a palbociclib salt having a lower molecular weight than the isethionate salt and which is suitable for pharmaceutical formulation. Surprisingly it was found that a novel crystalline form of palbociclib hydrochloride is suitable for pharmaceutical formulation and even provides the below described advantages.

SUMMARY OF THE INVENTION

The present invention provides particular crystalline forms of palbociclib monohydrochloride.

Palbociclib monohydrochloride:

6-Acetyl-8-cyclopentyl-5-methyl-2- { [5-(l -piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyri midin-7(8H)-one monohydrochloride

.HC1

Embodiments of these crystalline forms of the invention include those characterized herein as "Form 2", "Form 3", "Form 4", "Form 5", "Form 6", "Form 7" and "amorphous Form". The names used herein to characterize specific forms, e.g. "Form 2" etc., should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterizing information also presented herein.

The inventors of the present invention have found that polymorphic forms of palbociclib monohydrochloride have properties which make them advantageous for the use in pharmaceutical formulations. For example, Form 2 is significantly less hygroscopic than the crystalline palbociclib monohydrochloride described in WO 2005/005426 Al in Figure 5, as is Form 3. These two crystalline forms are thus much easier to handle under typical pharmaceutical processing conditions and enable standard pharmaceutical processing conditions to be used, such as work in an atmosphere having a relative humidity between 10 to 90 % at 25 °C, with Form 2 being particularly preferred. Furthermore palbociclib monohydrochloride Form 2 and Form 3 need not to be packaged into special containments for proper product quality during storage to be achieved.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 : illustrates the XRPD (Powder X- Ray Powder Diffraction) pattern of crystal Form 2 of palbociclib monohydrochloride.

Figure 2: illustrates the TG/DTA of crystal Form 2 of palbociclib monohydrochloride.

Figure 3: illustrates the XRPD pattern of crystal Form 3 of palbociclib monohydrochloride. Figure 4 : illustrates the TG/DTA of crystal Form 3 of palbociclib monohydrochloride.

DETAILED DESCRIPTION OF THE DISCLOSURE

The disclosure relates to crystalline forms of palbociclib monohydrochloride designated herein as Form 2, Form 3, Form 4, Form 5, Form 6, Form 7 and amorphous palbociclib monohydrochloride which are described and characterized herein. The present invention is further directed to pharmaceutical composition comprising these crystalline palbociclib hydrochloride forms of the present invention and to their use in treating conditions and disorders for which palbociclib is approved, for example breast cancer. The present invention is further directed to methods of preparing the crystalline palbociclib monohydrochloride crystal forms of the present invention.

Definitions

As used herein, the term "polymorphs" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. As used herein, the term "solvate" refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. Solvates may occur as dimers or oligomers comprising more than one molecule or palbociclib monohydrochloride within the crystalline lattice structure.

As used herein, the term "amorphous form" refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.

As used herein, the term "substantially pure," when used in reference to a form, means a compound having a purity greater than 90 weight-%, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight-%, and also including equal to about 100 weight- % of palbociclib monohydrochloride, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of palbociclib monohydrochloride may be deemed substantially pure in that it has a purity greater than 90 weight-%, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight-% of material comprises other form(s) of palbociclib monohydrochloride and/or reaction impurities and/or processing impurities.

The term "essentially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2Θ) will show some inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.

Preferably, the present invention relates to crystalline palbociclib monohydrochloride adsorbing less than 2.0 % water (w/w) in the range of from 10 to 90% relative humidity, when water adsorption is measured at 25 °C. Typically, water adsorption is measured by DVS. Form 2 was found to be non-hygroscopic with about 0.46 % water uptake between 20 and 70 % RH (relative humidity) and about 0.86 % water uptake between 20 and 90 % RH. Whereas Palbociclib monohydrochloride crystal form I (prior art form, figure 5 in WO 2005/005426 ) was found to be hygroscopic with a ca.3% water uptake between 20 and 70% RH and ca.4.3%> water uptake between 20 and 90% RH.

The present invention also relates to a novel polymorph of palbociclib monohydrochloride, palbociclib monohydrochloride Form 2. Palbociclib mohohydrochloride Form 2 can be characterized by showing an XRPD pattern comprising at least four, such as five, six, seven or all of the characteristic peaks described in the table below.

Alternatively, the crystalline form of palbociclib monohydrochloride is characterized by an X-ray powder diffraction pattern comprising peaks at °2Θ values 11.5 +/- 0.2,14.9 +/- 0.2, 16.3 +/- 0.2, 21.7 +/- 0.2, and 22.2 +/- 0.2, wherein the X-ray powder diffractogram is measured at a temperature of 22 °C using

radiation.

Palbociclib mohohydrochloride Form 2 can also be characterized by showing a mass loss of from 0.1 to 0.3 % in the temperature range of from 110 to 175°C. Typically, mass loss during heating is measured by thermogravimetric analysis at a heating rate of 10 K/minute. Examplary conditions for the TGA analysis are shown in the example section hereinbelow.

Preferably, crystalline Form 2 of palbociclib monohydrochloride is provided in substantially pure form. Crystalline Form 2 of palbociclib monohydrochloride, preferably in substantially pure form, may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure. Preferably, crystalline Form 2 of palbociclib monohydrochloride has substantially pure phase homogeneity as indicated by less than 10 %, preferably less than 5 %, more preferably less than 2 % of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. More preferably, crystalline Form 2 of palbociclib monohydrochloride has substantially pure phase homogeneity with less than 1 % of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

The presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (PXRD). For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one polymorph in the sample. The simulated PXRD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963) or TOP AS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).

Further according to the present invention, a composition is provided consisting essentially of crystalline Form 2 of palbociclib monohydrochloride. This composition may comprise at least 90 weight-% of crystalline Form 2 of palbociclib monohydrochloride, based on the weight of palbociclib monohydrochloride in the composition.

Further, a composition is provided comprising crystalline Form 2 of palbociclib monohydrochloride and including less than 10 %, preferably less than 5 %, more preferably less than 3 %, more preferably less than 1 % by weight of palbociclib monohydrochloride crystal form I, wherein crystal form I is characterized by an x-ray powder diffraction pattern (XRPD) comprising peaks at 2Θ values of 4.69, 9.86, 11.12, 15.56, 15.82, 19.21, 22.73 and 24.28, when measured at a temperature of about 20 °C and using

radiation. The present invention also relates to a novel polymorph of palbociclib monohydrochloride, palbociclib monohydrochloride Form 3. Palbociclib mohohydrochloride Form 3 can be characterized by showing an XRPD pattern comprising at least four, such as five, six, seven or all of the characteristic peaks described in the table below:

Alternatively, the crystalline form of palbociclib monohydrochloride is characterized by an X-ray powder diffraction pattern comprising peaks at °29values 9.4 +/- 0.2 , 11.8 +/- 0.2, 16.3 +/- 0.2, 18.8 +/- 0.2, 22.4 +/- 0.2, 22.8 +/- 0.2, and 23.7 +/- 0.2, wherein the X-ray powder diffractogram is measured at a temperature of 22 °C using CuKai_,2 radiation.

Palbociclib mohohydrochloride Form 3 can also be characterized by showing a mass loss of from 0.9 to 1.3 % in the temperature range of from 25 to 240 °C. Typically, mass loss during heating is measured by thermogravimetric analysis at a heating rate of 10 K/minute. Examplary conditions for the TGA analysis are shown in the example section hereinbelow.

Palbociclib mohohydrochloride Form 3 is non-hygroscopic with about 0.70 % water uptake between 20 and 70 % RH (relative humidity) and about 1.0 % water uptake between 20 and 90 % RH when water adsorption is measured by using DVS analysis,

Preferably, palbociclib mohohydrochloride Form 3 is provided in substantially pure form.

Preferably, palbociclib monohydrochloride Form 3 has substantially pure phase homogeneity as indicated by less than 10 %, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. More preferably, crystalline Form 3 of palbociclib monohydrochloride has substantially pure phase homogeneity with less than 1 % of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

Results of further measurements of palbociclib monohydrochloride forms 2 and 3 are shown in the following lists:

Form 2

The TGA showed a 0.2 % weight loss from the outset to about 240 °C.

Form 2 is an anhydrous form.

PLM analysis indicates a needle-like morphology.

IC analysis showed a chloride content of 7.39 %.

Form 3

The TGA showed a 0.7 % weight loss from the outset to about 125 °C, followed by a weight loss of about 0.4 % between about 125 to 240 °C.

In the DTA trace, a very small endotherm was observed at about 208.8 °C.

Form 3 is an anhydrous form.

PLM analysis indicated a needle-like morphology. • Form 3 converts to Form 2 in slurry experiments and can thus be used as an intermediate for Form 2 production

The present disclosure also relates to palbociclib monohydrochloride Form 4, which may be characterized by an X-ray powder diffraction pattern (PXRD) comprising four or more peaks at 2Θ values selected from the group consisting of 3.35, 4.78, 7.80, 12.16, 18.64, 20.16, and 22.18. Palbociclib monohydrochloride Form 4 is obtainable by evaporation of a solution of palbociclib monohydrochloride in an acetonitrile (90%)/water (10%) mixture (v/v). The present disclosure also relates to palbociclib monohydrochloride Form 5, which may be characterized by an X-ray powder diffraction pattern (PXRD) comprising four or more peaks selected from the group consisting of 4.47, 6.45, 17.95, 18.14, 19.46, 22.23 and 22.71. Form 5 is obtainable by crash-cooling a solution of palbociclib monohydrochloride in a tetrohydrofuran (85%): water (15% water v/v) mixture to 2°C.

The present disclosure also relates to palbociclib monohydrochloride Form 6, which may be characterized by an X-ray powder diffraction pattern (PXRD) comprising four or more peaks selected from the group consisting of 2.79, 4.73, 7.62, 8.17, 11.81, 19.63, 20.01 and 21.60. Form 6 is obtainable by evaporation of a solution of palbociclib monohydrochloride in an tetrahydrofuran (85%):water mixture (15% water v/v).

The present disclosure also relates to palbociclib monohydrochloride Form 7, which may be characterized by an X-ray powder diffraction pattern (PXRD) comprising four or more peaks selected from the group consisting of 4.34, 9.88, 10.02, 15.63, 19.85, 21.00 and 23.69.

Preparation process

The present invention also relates to processes for the preparation of crystalline palbociclib monohydrochloride of the invention.

Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of anti-solvents (counter solvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs. Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).

For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An anti-solvent is a solvent in which the compound has low solubility.

In one method to prepare crystals, a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution. The term "slurry", as used herein, means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature. Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph).

A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight-% isolated yield, preferably greater than 90 weight-% isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be comilled or passed through a mesh screen to delump the product, if necessary.

Crystalline forms may be prepared directly from the reaction medium of the final process for preparing palbociclib monohydrochloride. This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which palbociclib monohydrochloride may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.

The processes of the present invention for the preparation of the crystalline forms of palbociclib monohydrochloride of the invention start from amorphous palbociclib monohydrochloride, which may be obtained as follows.

The synthesis and isolation of palbociclib dihydrochloride is described in the prior art. Patent application WO2003/062236 describes the process for the preparation of the dihydrochloride salt of palbociclib. Also example 3 of WO 2005/005426 describes a process for the preparation of palbociclib dihydrochloride. Palbocilib dihydrochloride can be used as the starting material for the preparation of palbociclib free base, for example according to example 1 herein, which can then be converted into amorphous palbociclib monohydrochloride, for example according to examples 2 and 3 herein.

The present invention also relates to a process for the preparation of seed crystals of crystalline palbociclib monohydrochloride crystal Form 2. Seed crystals can be obtained by suspending amorphous palbociclib monohydrochloride in a methanol/water mixture, then stirring the suspension at 35 °C for two hours, cooling the suspension to 5 °C at a constant rate over a period of two hours under stirring, further stirring the suspension at 5 °C for two hours, and heating the suspension to 35 °C at a constant rate over a period of two hours under stirring. After two more cycles of cooling, stirring, heating and stirring, the suspension is finally cooled and stirred, as described above, and then seed crystals of crystalline palbociclib monohydrochloride Form 2 are isolated. Example 4 provides a detailed description of the preparation of Form 2 seed crystals. Further, the present invention relates to a process for the preparation of crystalline palbociclib monohydrochloride Form 2 comprising the steps of

a) dissolving Palbociclib monohydrochloride, preferably amorphous Palbociclib monohydrochloride, in an alcohol/water mixture; then

b) adding an anti-solvent, preferably selected from heptane, tert-butylmethyl ether, acetonitrile and acetone; then

c) allowing palbociclib monohydrochloride to crystallize, such as in the presence of a Form 2 seed crystal. Preferred alcohol/water mixtures for step a) are methanol/water, ethanol/water, n-propanol/water and isopropanol/water. Preferably, steps a) to c) are carried out at ambient temperatures, for example of from 10 to 35 °C, more preferably of from 15 to 30°C. It is preferred that after step a), the solution of palbociclib monohydrochloride in the water/alcohol mixture is filtered before anti-solvent addition. Seed crystals of palbociclib monohydrochloride Form 2 can also be added in order to facilitate crystallization. Preferred alcohol/water mixtures are 95% methanol/ 5% water (v/v), 75 % ethanol/ 25% water, and 80 % 2-propanol/ 20%> water.

The present invention also relates to a process for the preparation of crystalline palbociclib monohydrochloride Form 3 comprising the steps of

a) dissolving Palbociclib monohydrochloride, preferably amorphous Palbociclib monohydrochloride, in an acetonitrile/water mixture; then

c) allowing palbociclib monohydrochloride to crystallize.

Preferably, steps a) to c) are carried out at ambient temperatures, for example of from 10 to 35 °C, more preferably of from 15 to 30°C. It is preferred that after step a), the solution of palbociclib monohydrochloride in the acetonitrile/water mixture is filtered before anti-solvent addition.

The present invention also relates to a process for the preparation of crystalline palbociclib monohydrochloride Form 2 comprising the step of slurrying crystalline palbociclib monohydrochloride Form 3 in an alcohol, ketone or nitrile in the presence of crystalline palbociclib monohydrochloride Form 2.

Pharmaceutical compositions

As mentioned hereinabove, in one aspect the invention relates to a pharmaceutical composition comprising palbociclib monohydrochloride polymorphs as the active ingredient, in particular palbociclib monohydrochloride Form 2. Pharmaceutical compositions according to the invention, in addition to one of the crystalline or amorphous forms according to the invention mentioned hereinabove, can contain a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic and organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard shell capsules. Suitable carriers for soft shell capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules. Suitable carriers for the solutions include, for example, water, polyols, sucrose, invert sugar, glucose, and the like.

These pharmaceutical compositions can be in the form of tablets, coated tablets, dragees, hard and soft shell capsules, emulsions or suspensions. The invention also provides a process for the production of such compositions, which comprises bringing the aforementioned forms into a galenical administration form together with one or more therapeutically inert carriers.

The active ingredient can be formulated at low or high concentrations in a composition further comprising usual pharmaceutically acceptable adjuvants known in the art. A preferred dosage is capsule.

In addition, the pharmaceutical compositions can contain pharmaceutically acceptable preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

The dosage at which the active ingredient, i.e. the crystalline or amorphous forms according to the invention that are administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. Palbociclib monohydrochloride Form 2 and Form 3, and in particular Form 2, possess physical properties that differ from, and are advantageous over crystalline or amorphous forms of palbociclib dihydrochloride. These include, packing properties such as molar volume, hygroscopicity; kinetic properties such as stability under various storage conditions. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use. A contact of the solid phase with water and or water vapour during processing and formulation of the API is a common occurrence. Especially, low hygroscopicity and stability of monohydrochloride salts polymorphic forms of the present invention are advantageous properties, in particular for Form 2, for isolation during downstream processing and secondary manufacturing in FDF.

The various crystalline forms of the disclosure may be used alone or in combination, or formulated with one or more excipients or other active pharmaceutical ingredients to provide formulations suitable for the treatment of the indications identified above. The dosage at which the active ingredient, i.e. the crystalline or amorphous forms according to the invention that are administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg, preferably from about 1 mg to about 500 mg, and still more preferably from about 75 mg to about 300 mg per day. The daily dosage may be administered as a single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. Preferred pharmaceutical composition of Form 2

According to the present invention, a pharmaceutical composition is provided, wherein the active pharmaceutical ingredient consists essentially of crystalline Form 2 of palbociclib monohydrochloride.

Examples of typical capsule formulations which can be prepared according to the invention, and a preferred process for their preparation, are shown in Example 8 hereinbelow.

Packaged pharmaceutical compositions comprising crystalline palbociclib monohydrochloride of the invention

As discussed above, one advantage of Form 2 of the present invention is that it is less hygroscopic than the crystalline palbociclib monohydrochloride described in WO 2005/005426. Thus, palbociclib monohydrochloride Form 2 of the present invention enables the skilled person to package or fill pharmaceutical compositions comprising palbociclib monohydrochloride into inexpensive containers or blisters.

The present invention therefore also relates to a container comprising a pharmaceutical compositions comprising palbociclib monohydrochloride, preferably Form 2 of the present invention. The container container is preferably prepared from a material having a permeability for water vapor (water vapor transmission rate) as measured according to DIN 53122/1 at a foil thickness of 40 μιη of from 1.0 to 500 g*m^~2*d^_1, more preferably of from 1.5 to 100 g*m^~2*d^_1, such as from 2.0 to 40 g*m^~2*d^_1. Preferred examples of such an inexpensive packaging material with relatively high permeability for water vapor are polyvinylchloride, polystyrole, polyamide, polyethylenevinylacetate, cellophane and celluloseacetate. In the above formula d signifies "day", i.e. 1440 minutes. Water vapor transmission rates are to be determined under humid conditions (25 °C, 85 % rel. humidity difference).

The use of these materials for blistering the pharmaceutical compositions of the invention, in particular comprising palbociclib monohydrochloride Form 2, become possible due to the low hygroscopicity of palbociclib monohydrochloride Form 2. This represents a clear economic advantage of palbociclib monohydrochloride Form 2 of the invention. The following non-limiting embodiments and combinations of embodiments as indicated by the respective dependencies and back-references are illustrative of the disclosure and are not intended to be interpreted as limiting the scope of the claims.

1. A crystalline form of palbociclib monohydrochloride adsorbing less than 2.0 % water (w/w), based on the weight of the crystalline form of palbociclib monohydrochloride, wherein water adsorption is measured at 25 °C in the range of from 10 to 90 % relative humidity, in particular as described in the example section hereinbelow.

2. The crystalline form of palbociclib monohydrochloride according to embodiment 1, characterized by an X-ray powder diffraction pattern comprising four or more peaks at

2Θ/⁰ values of the group 9.9 + 0.2, 11.5 + 0.2, 14.9 + 0.2, 16.3 + 0.2, 19.0 + 0.2, 21.7 + 0.2, and 22.2 j_0.2, wherein the X-ray powder diffractogram is measured at a temperature of 22 °C using CuKa_lj2 radiation, in particular as described in the example section hereinbelow.

3. The crystalline form of palbociclib monohydrochloride according to embodiment 2, characterized by a mass loss of from 0.1 to 0.3 % in the temperature range of from 110 to 175 °C determined by thermogravimetric analysis at a heating rate of 10 K/min, in particular as described in the example section hereinbelow.

4. The crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 and 3, including less than 10 %, preferably less than 5 %, more preferably less than 3 % of palbociclib monohydrochloride crystal form I, wherein palbociclib monohydrochloride crystal form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2Θ/⁰ values of the group 4.7 ±_0.2, 9.9 ±_0.2,

11.1 + 0.2, 15.6 + 0.2, 15.8 + 0.2, 19.2 ± 0.2, 22.7 + 0.2, and 24.3 + 0.2, wherein the X-ray powder diffractogram is measured at a temperature of 20 °C using CuKa_lj2 radiation, in particular as described in the example section hereinbelow. 5. The crystalline form of palbociclib monohydrochloride according to embodiment 4, including less than 1 % by weight of palbociclib monohydrochloride crystal form I, wherein palbociclib monohydrochloride crystal form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2Θ/⁰ values of the group 4.7 + 0.2, 9.9+ 0.2, 11.1 +_0.2, 15.6 + 0.2, 15.8 + 0.2, 19.2 +_0.2, 22.7 + 0.2, and 24.3 + 0.2, wherein the X-ray powder diffractogram is measured at a temperature of 20 °C using CuK(Xi,2 radiation, in particular as described in the example section herein below. The crystalline form of palbociclib monohydrochloride according to embodiment 1, characterized by an X-ray powder diffraction pattern comprising four or more peaks at 2Θ/⁰ values of the group 9.4 ±_0.2 , 11.8 + 0.2, 16.3 + 0.2, 18.8 + 0.2, 22.4 + 0.2, 22.8 ± 0.2, and 23.7 j_0.2, wherein the X-ray powder diffractogram is measured at a temperature of 22 °C using CuKa,i,₂ radiation, in particular as described in the example section hereinbelow. The crystalline form of palbociclib monohydrochloride according to embodiment 6, characterized by a mass loss of from 0.9 to 1.3 % in the temperature range of from 25 to 240 °C determined by thermogravimetric analysis at a heating rate of 10 K/min, in particular as described in the example section hereinbelow. A pharmaceutical composition comprising the crystalline form of palbociclib monohydrochloride according to any one of embodiments 1 to 5 and a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition of embodiment 8, comprising the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5 and a pharmaceutically acceptable carrier or diluent. A process for the preparation of seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5, comprising the steps of

a) suspending amorphous palbociclib monohydrochloride in a liquid mixture comprising methanol and water;

b) stirring the suspension obtained from a) at a temperature in the range of from 25 to 45 °C, preferably for 0.5 to 12 hours;

c) cooling the suspension obtained from b) to a temperature in the range of from 1 to 15 °C, preferably over a period in the range of from 0.5 to 12 hours;

d) stirring the suspension obtained from (c) at the temperature in the range of from 1 to 15 °C, , preferably for 0.5 to 12 hours;

e) heating the suspension obtained from d) to a temperature in the range of from 25 to 45 °C, preferably over a period in the range of from 0.5 to 12 hours;

f) stirring the suspension obtained from e) at a temperature in the range of from 25 to 45 °C, preferably for 0.5 to 12 hours;

g) subjecting the suspension obtained from step f) to step c) and repeating the sequence of steps c), d), e), f) at least once;

h) isolating seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5 from the suspension obtained from the final step f).

The process of embodiment 10, comprising the steps of

b) stirring the suspension obtained from a) at a temperature in the range of from 30 to 40 °C, preferably for 1 to 6 hours;

c) cooling the suspension obtained from b) to a temperature in the range of from 2 to 10 °C, preferably over a period in the range of from 1 to 6 hours, wherein during cooling, the suspension is preferably stirred;

d) stirring the suspension obtained from (c) at the temperature in the range of from 2 to 10 °C, preferably for 1 to 6 hours;

e) heating the suspension obtained from d) to a temperature in the range of from 30 to 40 °C, preferably over a period in the range of from 1 to 6 hours, wherein during heating, the suspension is preferably stirred;

f) stirring the suspension obtained from e) at a temperature in the range of from 30 to 40 °C, preferably for 1 to 6 hours;

g) subjecting the suspension obtained from step f) to step c) and repeating the sequence of steps c), d), e), f) at least at least twice, preferably at least three times; h) isolating seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5 from the suspension obtained from the final step f).

A process for the preparation of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5, comprising the steps of

a) dissolving amorphous palbociclib monohydrochloride in a liquid mixture comprising an alcohol and water;

b) adding an anti-solvent to the solution obtained from a), wherein the anti-solvent comprises heptane, tert-butylmethyl ether, acetonitrile, acetone, or a mixture of two or more thereof, preferably heptane, tert-butylmethyl ether, acetonitrile, or acetone;

c) subjecting the mixture obtained from b) to crystallization conditions, obtaining the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5 in its mother liquor.

The process of embodiment 12, comprising the steps of a) dissolving amorphous palbociclib monohydrochloride in a liquid mixture comprising an alcohol and water;

b) adding an anti-solvent to the solution obtained from a), wherein the anti-solvent is heptane, tert-butylmethyl ether, acetonitrile, acetone, or a mixture of two or more thereof, preferably heptane, tert-butylmethyl ether, acetonitrile, or acetone;

c) subjecting the mixture obtained from b) to crystallization conditions, obtaining the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5 in its mother liquor. 14. The process of embodiment 12 or 13, wherein the alcohol comprised in the mixture comprising alcohol and water mixture comprises methanol, ethanol, n-propanol, 2-propanol, or a mixture of two or more thereof, preferably methanol, ethanol, n-propanol, or 2-propanol. 15. The process of embodiment 14, wherein the alcohol comprised in the mixture comprising alcohol and water mixture is methanol, ethanol, n-propanol, 2-propanol, or a mixture of two or more thereof, preferably methanol, ethanol, n-propanol, or 2-propanol. 16. A process for the preparation of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5, comprising slurrying a solid form of palbociclib monohydrochloride in a solvent comprising an alcohol, a ketone, a nitrile, or a mixture of two or more thereof, preferably an alcohol, a ketone, or a nitrile, more preferably an alcohol, in the presence of seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5.

17. The process of embodiment 16, wherein the seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5 are obtainable or obtained by a process according to embodiment 10 or 11.

18. The process of embodiment 16, comprising providing the seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5 by a process according to embodiment 10 or 11. 19. The process of any one of embodiments 16 to 18, wherein the solvent is an alcohol, a ketone, a nitrile, or a mixture of two or more thereof, preferably an alcohol, a ketone, or a nitrile, more preferably an alcohol. 0. The process of any one of embodiments 16 to 19, wherein the solvent is methanol, ethanol, n-propanol and/or 2-propanol. A process for the preparation of the crystalline form of palbociclib monohydrochloride according to embodiment 6 or 7, comprising the steps of

a) dissolving amorphous palbociclib monohydrochloride in liquid mixture comprising acetonitrile and water;

b) adding an anti-solvent to the solution obtained from a), wherein the anti-solvent comprises heptane, tert-butylmethyl ether, acetone, or a mixture of two or more thereof, preferably heptane, tert-butylmethyl ether, or acetone;

c) subjecting the mixture obtained from b) to crystallization conditions, obtaining the crystalline form of palbociclib monohydrochloride according to embodiment 6 or 7 in its mother liquor. process of embodiment 21, comprising the steps of

dissolving amorphous palbociclib monohydrochloride in liquid mixture comprising acetonitrile and water;

adding an anti-solvent to the solution obtained from a), wherein the anti-solvent is heptane, tert-butylmethyl ether, acetone, or a mixture of two or more thereof, preferably heptane, tert-butylmethyl ether, or acetone;

subjecting the mixture obtained from b) to crystallization conditions, obtaining the crystalline form of palbociclib monohydrochloride according to embodiment 6 or 7 in its mother liquor. Use of the crystalline form of palbociclib monohydrochloride according to embodiment 6 or 7 for the preparation of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5. A process for the preparation of the crystalline form of palbociclib monohydrochloride according to any one of embodiments 2 to 5, wherein the crystalline form of palbociclib monohydrochloride according to embodiment 6 or 7 is used as a starting material. The crystalline form of palbociclib monohydrochloride according to any one of embodiments 1 to 7, preferably according to any one of embodiments 2 to 5, or the pharmaceutical composition of embodiment 8 or 9, for use in a method for the treatment of cancer, preferably breast cancer and/or colorectal cancer. A method for treating cancer, preferably breast cancer and/or colorectal cancer, comprising administering the crystalline form of palbociclib monohydrochloride according to any one of embodiments 1 to 7, preferably according to any one of embodiments 2 to 5, or the pharmaceutical composition of embodiment 8 or 9, to a patient in need thereof.

27. A container comprising a pharmaceutical composition according to embodiment 8 or 9, wherein the container is prepared from a material having a permeability for water vapor as measured according to DIN 53122/1 at a foil thickness of 40 μιη of from 1.0 to 500 g*m^"2*d^_1.

28. The container of embodiment 27, wherein the container is a blister package comprising the pharmaceutical composition according to embodiment 8 or 9 as an oral dosage form.

29. The container of embodiment 28, wherein at least one of polyvinylchloride, polystyrole, polyamide, polyethylenevinylacetate, cellophane and celluloseacetate is used in the preparation of the blister package.

The following non-limiting examples are illustrative of the disclosure and are not intended to be interpreted as limiting the scope of the claims.

EXAMPLES

Characterization of polymorphs

Various analytical methods may be used for characterization.

XRPD analysis

XRPD analysis was carried out on a PANalytical X'Pert Pro X-ray Diffractometer, scanning the samples between 2 and 40 ° 2-theta. Material was loaded into a 96-well plate with kapton film as the base. The samples were then loaded into the plate holder of a PANalytical X'Pert Pro X-ray Diffractometer running in transmission mode and analysed, using the following experimental conditions:

Raw Data Origin: XRD measurement (*.XRDML)

Scan Axis: Gonio

Start Position [°2Θ]: 2.0066

End Position [°2Θ]: 39.9796

Step Size [°2Θ]: 0.0130

Scan Step Time [s]: 68.5950

Scan Type: Continuous

PSD Mode: Scanning

PSD Length [°2Θ]: 3.35

Offset [°2Θ]: 0.0000

Divergence Slit Type: Fixed

Divergence Slit Size [°]: 1.0000

Specimen Length [mm] : 10.00

Measurement Temperature [°C]: 25.00

Anode Material: Cu

K-Alphal [A]: 1.54060

K-Alpha2 [A]: 1.54443

K-Beta [A]: 1.39225

K-A2 / K-A1 Ratio: 0.50000

Generator Settings: 40 niA, 40 kV

Diffractometer Type: 0000000011154173

Diffractometer Number: 0

Goniometer Radius [mm] : 240.00

Dist. Focus-Diverg. Slit [mm]: 91.00

Incident Beam Monochromator: No

Spinning: No For some experiments, in order to improve the signal to noise ratio, the scan step time was increased to 5 or 12 seconds and/or a zero background slide was employed.

One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5 % or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X-ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art. Differential Scanning Calorimetry (DSC)

The DSC instrument used to test the crystalline forms was a TA Instrument® Differential Scanning Calorimetry Model 2910, TA Instruments® Modulated Differential Scanning Calorimetry Model 2920, or TA Instruments® Modulated Differential Scanning Calorimetry Model Q1000. The DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about ± 1 °C, and the heat of fusion can be measured within a relative error of about ± 5 %. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. About 2-6 mg of sample powder was placed into the bottom of the pan and lightly tapped down to make contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10 °C per minute in the temperature range between 25 and 300 °C. Approximately 5 mg of material was weighed into an aluminium DSC pan and sealed non-hermetically with a pierced aluminium lid. The sample pan was then loaded into a Seiko DSC6200 (equipped with a cooler). The sample and reference were heated to ca. 260 °C at scan rate of 10 K/min and the resulting heat flow response monitored. The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram ("W/g"). The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.

Thermo gravimetric Analysis (TGA)

The TGA instruments used to test the crystalline forms was a TA Instruments.RTM. High Resolution Thermogravimetric Analyzer Q500 or TA Instruments. RTM. High Resolution Thermogravimetric Analyzer 2950. Samples of 15 to 20 milligrams were analyzed at a heating rate of 10 K per minute in the temperature range between 25 °C and about 300 °C.

Approximately, 5-10 mg of material was accurately weighed into an open aluminium pan and loaded into a simultaneous thermogravimetric/differential thermal analyser (TG/DTA) and held at room temperature. The sample was then heated at a rate of 10 K/min from 25 °C to 300 °C during which time the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas, at a flow rate of 100 cm³/min.

Dynamic Vapor Sorption (DVS)

Approximately 10-20 mg of sample was placed into a vapour sorption balance pan and loaded into a DVS-1 dynamic vapour sorption balance by Surface Measurement Systems. The sample was subjected to a ramping profile from 20 - 90 % relative humidity (RH) at 10 % increments, maintaining the sample at each step until a stable weight had been achieved (99.5 % step completion). After completion of the sorption cycle, the sample was dried using the same procedure, but all the way down to 0 % RH and finally taken back to the starting point of 20 % RH. The weight change during the sorption/desorption cycles were plotted, allowing for the hygroscopic nature of the sample to be determined. Form I palbociclib Form 2 palbociclib Form 3 palbociclib monohydrochloride monohydrochloride monohydrochloride

2.3% water uptake between 0.46 % water uptake between 0.70 % water uptake between 20 and 70% RH and ca.4.3% 20 and 70 % RH (relative 20 and 70 % RH (relative water uptake between 20 and humidity) and about 0.86 % humidity) and about 1.0 % 90% RH. water uptake between 20 and water uptake between 20 and

90 % RH. 90 % RH

Example 1: Preparation of palbociclib free base from palbociclib dihydrochloride

2.5 g of Palbociclib dihydrochloride (as obtained according to example 3 of WO 2005/005426) were slurried in ca. 100 mL of deionised water. The pH of the solution was adjusted to 12.39 using 1 M sodium hydroxide solution. The resulting suspension was then extracted using 100 mL of dichloromethane. The extraction with dichloromethane was repeated 3 times, and the combined organic fractions were washed with brine. The organic fraction was then dried over sodium sulfate, filtered, concentrated under reduced pressure and dried in vacuo for 1 h at 30 °C, providing palbociclib free base.

Example 2: Preparation of the palbociclib monohydrochloride from palbociclib free base

1.6 g of Palbociclib free base were slurried in 19 mL of methanol. 1 equivalent of HC1 (299 of 37 % aq. HC1) was dissolved in 10 mL of methanol and added dropwise to the suspension which was stirred at 35 °C for 18 h. The product was isolated through filtration, washed with methanol (5 mL) and dichloromethane (2 x 5 mL) and then dried in vacuo for 1.5 h at 30 °C, providing palbociclib monohydrochloride. Example 3: Preparation of amorphous palbociclib monohydrochloride

Approximately 1.4 g of palbociclib monohydrochloride from example 2 above was transferred into a large milling jar. Ball milling was used in order to prepare amorphous material from the palbociclib monohydrochloride of example 2. After every hour of ball milling at 50 Hz, the material was analysed by XRPD to determine if completely amorphous material had been obtained. After 2 hours, an amorphous solid was obtained which was characterised by PLM, XRPD, TG/DTA, HPLC and IC analysis.

Example 4: Preparation of Form 2 seed crystals

Approximately 100 mg amorphous Palbociclib monohydrochloride from example 3 above were suspended in a limiting amount of ethanol so as to obtain a slurry. The suspension thus formed was stirred at 30 °C for 120 min. After slowly cooling the suspension to 5 °C at a constant rate over a period of 120 min under stirring, it was further stirred at 5 °C for 120 min. The suspension was again heated to 35 °C at a constant rate over a period of 120 min under stirring and stirred again at 35 °C for 120 min. This process of cooling to 5 °C and stirring for two hours and raising temperature to 35 °C and stirring for two hours was repeated three times. This was followed by nine temperature cycles between 35 °C and 5 °C. Finally seed crystals of crystalline palbociclib monohydrochloride Form 2 were isolated. They were filtered and retained for further experiments. The obtained solid material was analysed by XRPD and PLM.

Example 5: Preparation of palbociclib monohydrochloride Form 2 in methanol

Approximately 500 mg of the amorphous form of Palbociclib monohydrochloride was placed into a vial. 4ml methanol and 0.21ml water were mixed and the mixture containing about 5% water was then added to the material in order to generate a slurry. The slurry thus obtained was subjected to temperature cycling between 35 °C and 5 °C for ca. 24 h (2 h hold period at each temperature, 2 h for heating / cooling). The resulting saturated solution was then filtered and retained for further experiments. The solid material was analysed by XRPD and PLM.

Example 6: Preparation of palbociclib monohydrochloride Form 3 in acetonitrile / water

Approximately 400 mg of the amorphous form of Palbociclib monohydrochloride was placed into a vial. 12 ml of an acetonitrile (80%) / water (20%) mixture (v/v) was then added to the material in order to generate a slurry. The slurry thus obtained was subjected to temperature cycling between 35 °C and 5 °C for ca. 96 h (2 h hold period at each temperature, 2h for heating / cooling). The resulting suspension was then filtered and retained for further experiments. The solid material was analysed by XRPD and PLM. Example 7: X-ray Powder Diffraction (XRPD)

XRPD analysis was carried out as described above. The following table shows the XRPD data obtained for palbociclib monohydrochloride Form 2:

Example 8: X-ray Powder Diffraction (XRPD)

XRPD analysis was carried out as described above. The following table shows the XRPD data obtained for palbociclib monohydrochloride Form 3 :

Example 9: Capsule formulations of palbociclib monohydrochlonde Form 2

Capsule Formulation 1

Capsule Formulation 2

Capsule Formulation 3

Item Ingredients mg/capsule mg/capsule mg/capsule

1 palbociclib 125 100 75 monohydrochloride Form 2

2 Lactose monohydrate 231 150 110

3 Microcrystalline cellulose 10 7 5.4

4 Sodium starch glycolate 4 3 1.8

5 Fumed silicium dioxide 2,5 2 1.4

6 Magnesium stearate 2,5 2 1.4

375 264 195 capsule size 0 capsule size 1 capsule size 2 Capsule Formulation 4

Capsule Formulation 5

Capsule Formulation 6

Item Ingredients mg/capsule mg/capsule mg/capsule

1 palbociclib 125 100 75 monohydrochloride Form 2

2 Mannit 150 120 90

3 Sodium starch glycolate 15 12 9

4 Silicium dioxide 5 4 3

5 Magnesium stearate 4 3 2

299 239 179 capsule size 0 capsule size 1 capsule size 2 Capsule Formulation 7

Manufacturing Procedure:

1. Mix items 1, 2, 3, 4, 5, 6 and 7 in a suitable mixer.

2. Fill the mixture of step 1 into suitable capsule.

3. Manufacturing procedure comprise dry mixing and filling or dry granulation or wet granulation before filling . A manufacturing procedure preferably comprise dry mixing and filling into capsules.

Example 10: Stability of palbociclib monohydrochloride Form 2

Form 2 is the most stable form under slurry conditions at two different temperatures and in three different solvents. Respective reference is made to the following table:

Input polymorphs Temperature Solvent After 120 hr

Forms 2 & 3 RT (room temp.) Acetone Predominantly Form 2

Forms 2 & 3 RT Acetonitrile Predominantly Form 2

Forms 2 & 3 RT Methanol Predominantly Form 2

Forms 2 & 3 50 °C Acetone Predominantly Form 2

Claims

A crystalline form of palbociclib monohydrochloride adsorbing less than 2.0 % water (w/w), based on the weight of palbociclib monohydrochloride, wherein water adsorption is measured at 25 °C in the range of from 10 to 90 % relative humidity.

The crystalline form of palbociclib monohydrochloride according to claim 1, characterized by an X-ray powder diffraction pattern comprising peaks at 2Θ/⁰ values 11.5 +/- 0.2, 14.9 +/- 0.2, 16.3 +/- 0.2, 21.7 +/- 0.2, and 22.2 +/- 0.2, wherein the X-ray powder diffractogram is measured at a temperature of 22 °C using CuKai_,2 radiation.

The crystalline form of palbociclib monohydrochloride according to claim 2, characterized by a mass loss of from 0.1 to 0.3 % in the temperature range of from 110 to 175 °C determined by thermogravimetric analysis at a heating rate of 10 K/min.

The crystalline form of palbociclib monohydrochloride according to any one of claims 2 and 3, including less than 1 % by weight of palbociclib monohydrochloride crystal form I, wherein palbociclib monohydrochloride crystal form I is characterized by an X-ray powder diffraction pattern comprising peaks at 2Θ/⁰ values of the group 4.7 +/- 0.2, 9.9 +/- 0.2, 11.2 +/- 0.2, 15. 6 +/- 0.2, 15.8 +/- 0.2, 19.2 +/- 0.2, 22.7 +/- 0.2, and 24.3 +/- 0.2, wherein the X-ray powder diffractogram is measured at a temperature of 20 °C using CuKa,i_,2 radiation.

The crystalline form of palbociclib monohydrochloride according to claim 1, characterized by an X-ray powder diffraction pattern comprising peaks at 2Θ/⁰ values 9.4 +/- 0.2 , 11.8 +/- 0.2, 16.3 +/- 0.2, 18.8 +/- 0.2, 22.4 +/- 0.2, 22.8 +/- 0.2, and 23.7 +/- 0.2, wherein the X-ray powder diffractogram is measured at a temperature of 22 °C using CuK(Xi,₂ radiation.

The crystalline form of palbociclib monohydrochloride according to claim 5, characterized by a mass loss of from 0.9 to 1.3 % in the temperature range of from 25 to 240 °C determined by thermogravimetric analysis at a heating rate of 10 K/min.

A pharmaceutical composition comprising the crystalline form of palbociclib monohydrochloride according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent.

A process for the preparation of seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of claims 2 to 4, comprising the steps of a) suspending amorphous palbociclib monohydrochloride in a liquid mixture comprising methanol and water;

b) stirring the suspension obtained from a) at a temperature in the range of from 25 to 45 °C for 0.5 to 12 hours;

c) cooling the suspension obtained from b) to a temperature in the range of from 1 to 15 °C over a period in the range of from 0.5 to 12 hours;

d) stirring the suspension obtained from (c) at the temperature in the range of from 1 to 15 °C for 0.5 to 12 hours;

e) heating the suspension obtained from d) to a temperature in the range of from 25 to 45 °C over a period in the range of from 0.5 to 12 hours;

f) stirring the suspension obtained from e) at a temperature in the range of from 25 to 45 °C for 0.5 to 12 hours;

h) isolating seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of claims 2 to 4 from the suspension obtained from the final step f).

A process for the preparation of the crystalline form of palbociclib monohydrochloride according to any one of claims 2 to 4, comprising the steps of

a) dissolving palbociclib monohydrochloride in a liquid mixture comprising an alcohol and water;

b) adding an anti-solvent to the solution obtained from a), wherein the anti-solvent comprises heptane, tert-butylmethyl ether, acetonitrile, acetone, or a mixture of two or more thereof;

c) subjecting the mixture obtained from b) to crystallization conditions, obtaining the crystalline form of palbociclib monohydrochloride according to any one of claims 2 to 4 in its mother liquor.

The process of claim 9, wherein the alcohol comprised in the mixture comprising alcohol and water comprises methanol, ethanol, n-propanol, 2-propanol, or a mixture of two or more thereof.

A process for the preparation of the crystalline form of palbociclib monohydrochloride according to any one of claims 2 to 4, comprising slurrying a solid form of palbociclib monohydrochloride in a solvent comprising an alcohol, a ketone, a nitrile, or a mixture of two or more thereof in the presence of seed crystals of the crystalline form of palbociclib monohydrochloride according to any one of claims 2 to 4. 12. A process for the preparation of the crystalline form of palbociclib monohydrochloride according to claim 5 or 6, comprising the steps of

a) dissolving palbociclib monohydrochloride in a liquid mixture comprising acetonitrile and water;

b) adding an anti-solvent to the solution obtained from a), wherein the anti-solvent comprises heptane, tert-butylmethyl ether, acetone, or a mixture of two or more thereof;

c) subjecting the mixture obtained from b) to crystallization conditions, obtaining the crystalline form of palbociclib monohydrochloride according to claim 5 or 6 in its mother liquor.

13. Use of the crystalline form of palbociclib monohydrochloride according to claim 5 or 6 for the preparation of the crystralline form of palbociclib monohydrochloride according to any one of claims 2 to 4.

14. The crystalline form of palbociclib monohydrochloride according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 7 for use in a method for the treatment of cancer.

15. A container comprising a pharmaceutical composition according to claim 7, wherein the container is prepared from a material having a permeability for water vapor as measured according to DIN 53122/1 of from 1.0 to 500 g*m^~2*d^_1 at a foil thickness of 40 μιη, wherein the container is a blister package comprising the pharmaceutical composition according to claim 7 as an oral dosage form.