CA2928286A1 - Solid form of ruxolitinib phosphate - Google Patents

Abstract

A solid, polymorphic form APO-I of Ruxolitinib phosphate is provided.

Description

=

SOLID FORM OF RUXOLITINIB PHOSPHATE
TECHNICAL FIELD
The present invention is directed to Ruxolitinib phosphate and, in particular, to a solid form thereof.
BACKGROUND
Ruxolitinib phosphate (1) is a protein kinase inhibitor indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.
(R) N¨N 0 HO¨P¨OH
OH
hl N
Ruxolitinib phosphate (1) US 7,598,257 B2 relates to heteroaryl substituted pyrrolo[2,3-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
US 2008/0312259 A1 provides salt forms of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile that are useful in the modulation of Janus kinase activity and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.

-2-US 2009/01 81 959 A1 provides heteroaryl substituted pyrrolo[2,3-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
US 7,834,022 B2 provides metabolites of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
WO 2010/039939 A1 provides methods, kits, and compositions for treating dry eye disorders and other related eye diseases are provided, wherein the methods, kits, and compositions utilize a JAK inhibitor.

3 A2 is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-di]pyrimidines, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
WO 2011/146808 A2 relates to pharmaceutical formulations for topical skin application comprising (R)-3-cyclopenty1-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-

4-y1)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and use in the treatment of skin disorders.
WO 2012/112847 A1 provides a combination therapy comprising an mTOR inhibitor and a JAK inhibitor. The combination therapy is useful for the treatment of a variety of cancers, including MPNs. The combination therapy is also useful for the treatment of any number of JAK-associated diseases.
Org. Lett. (2009), 11(9), 1999-2002 relates to an enantioselective synthesis of INCB018424 via organocatalytic asymmetric aza-Michael addition of pyrazoles to (E)-3-cyclopentylacrylaldehyde using diarylprolinol silyl ether as the catalyst. Michael adducts were isolated in good yield and high ee and were readily converted to INCB018424.
CHMP Assessment report; Jakavi; 19 April 2012; EMA/465846/2012 discloses Ruxolitinib phosphate as a white to almost white, non-hygroscopic powder, highly soluble in water, and the solubility is pH dependant.
Ruxolitinib phosphate has the chemical name (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile phosphate or 1H-Pyrazole-1-propanenitrile, 6-cyclopenty1-4-(7H-pyrrolo[2,3-d]pyrimidin-4-, yI)-, (6R)-, phosphate (1:1). Polymorphism has been shown to exist for Ruxolitinib phosphate drug substance and only one anhydrous crystalline form has been used. Anhydrous crystalline form used is the most stable solid form. Ruxolitinib phosphate has one chiral centre in the molecule (R-absolute configuration).
WO 2013/023119 A1 provides a combination therapy comprising a JAK
kinase inhibitor and a dual PBK/mTOR inhibitor, as well as methods of treating various cancers through the use of such a combination therapy.
SUMMARY
The present invention is based, at least in part, on a solid form of Ruxolitinib phosphate, namely a polymorphic form of Ruxolitinib phosphate termed herein APO-1. Processes for preparing this form are also provided.
In illustrative embodiments of the present invention, there is provided APO-1 polymorphic form of Ruxolitinib phosphate.
In illustrative embodiments of the present invention, there is provided a polymorphic form APO-1 of Ruxolitinib phosphate characterized by a powder X-ray diffraction pattern comprising peaks, in terms of degrees 2-theta, at 7.6 0.2 and 8.3 0.2.
In illustrative embodiments of the present invention, there is provided a polymorphic form APO-1 of Ruxolitinib phosphate described herein wherein the powder X-ray diffraction pattern further comprises at least one peak, in terms of degrees 2-theta, at 4.9 0.2, 9.5 0.2, 12.5 0.2, and 13.0 0.2.

In illustrative embodiments of the present invention, there is provided a polymorphic form APO-I of Ruxolitinib phosphate described herein characterized by a DSC thermogram comprising a peak endotherm with an onset temperature of approximately 188 C and a peak maximum of approximately 194 C.
In illustrative embodiments of the present invention, there is provided a polymorphic form APO-I of Ruxolitinib phosphate described herein having a PXRD diffractogram substantially similar to a PXRD diffractogram as depicted in Figure 1.
In illustrative embodiments of the present invention, there is provided a polymorphic form APO-I of Ruxolitinib phosphate described herein having a DSC thermogram substantially similar to a DSC thermogram as depicted in Figure 2.
In illustrative embodiments of the present invention, there is provided a polymorphic form APO-I of Ruxolitinib phosphate described herein in a pharmaceutical formulation.
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS
In drawings which illustrate embodiments of the invention, Figure 1 is a Powder X-Ray Diffraction (PXRD) diffractogram of form APO- I of Ruxolitinib phosphate as prepared in Example 1.
Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of form APO-I of Ruxolitinib phosphate as prepared in Example 1.
Figure 3 is a Powder X-Ray Diffraction (PXRD) diffractogram of Ruxolitinib phosphate disclosed in an affidavit in the file wrapper of US
2008/0312259 A1.

-5-DETAILED DESCRIPTION
When used in reference to a diffractogram, a spectrum and/or data presented in a graph, the term "substantially similar" means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram, spectrum and/or data presented in a graph, but will nevertheless be known to a person of skill in the art.
When used in reference to a peak in a powder X-ray diffraction (PXRD) diffractogram, the term "approximately" and/or "about" means that the peak may vary by 0.2 degrees 2-theta of the subject value.
When used in reference to a peak in a DSC thermogram, the term "approximately" and/or "about" means that the peak may vary by 1 C of the subject value.
As used herein, when referring to a diffractogram, spectrum and/or to data presented in a graph, the term "peak" refers to a feature that one skilled in the art would recognize as not attributable to background noise.
Depending on the nature of the methodology applied and the scale selected to display results obtained from an X-ray diffraction analysis, an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 1% when analyzing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied.
Such variations are known and understood by a person of skill in the art.
As used herein, the term "volumes" refers to the parts of solvent or liquids by volume (mL) with respect to the weight of solute (g). For example, when an experiment is conducted using 1 g of starting material and 100 mL of solvent, it is said that 100 volumes of solvent are used.

-6-As used herein, the term pure means, unless otherwise stated, substantially free from impurities. Often compounds of the present invention are at least 75% pure (w/w), greater than about 90% pure (w/w), or greater than about 95% pure (w/w).
In an illustrative embodiment, the present invention comprises a crystalline form of Ruxolitinib phosphate which is a polymorphic form referred to herein as APO-I which may be characterized by a Powder X-ray Diffraction (PXRD) diffractogram comprising a peak, expressed in degrees 2-theta, at 7.6 0.2 and 8.3 0.2.
In illustrative embodiments, there is provided an APO-I polymorphic form of Ruxolitinib phosphate characterized by at least six peaks, expressed in degrees 2-theta, selected from the group consisting of: 4.9 0.2, 7.6 0.2, 8.3 0.2, 9.5 0.2, 12.5 0.2, and 13.0 0.2.
An illustrative PXRD diffractogram of form APO-I is shown in Figure 1.
Form APO-I may have a reflection ("peak") at any one or more of the values expressed in degrees 2-theta given in Table 1. Although values are given in the tables below, APO-I may be defined by the claimed peaks and a particular claim may be limited to one peak only, or several peaks. The form APO-I does not have to include all or even many of the peaks listed in Table 1. Some illustrative and non-limiting possible observations regarding relative intensities of the peaks are set out in Table 1.
Table 1: Relative peak intensities of form Angle 2-theta Relative intensity %
4.86 19.63

7.56 20.20

8.33 21.03

9.45 13.49 12.07 15.83 12.49 14.55 12.99 7.63 13.74 12.12 14.50 88.52 14.75 39.50 15.19 9.92 Table 1: Relative peak intensities of form Angle 2-theta Relative intensity %
15.91 79.99 16.13 16.47 16.46 18.70 16.75 15.28 17.57 26.27 17.81 17.52 18.80 27.24 19.03 21.76 19.61 14.38 20.21 100.00 20.40 60.01 20.84 51.62 21.73 65.62 22.03 18.05 22.73 33.52 23.24 35.42 23.78 39.12 24.25 9.85 24.87 62.69 25.22 72.03 25.64 17.33 26.28 53.40 27.23 15.61 27.89 16.58 29.61 18.36 = 30.16 11.16 An illustrative DSC thermogram of form APO-I is shown in Figure 2.
The DSC thermogram shown in Figure 2 may be illustrative of the type of results when analysing APO-I by DSC. The DSC thermogram may be further characterized by a peak endotherm with an onset temperature of approximately 188 C and a peak maximum of approximately 194 C.
Form APO-I Ruxolitinib Phosphate may be prepared by a process comprising:
a) Treating a solution of Ruxolitinib with phosphoric acid at a temperature from about room temperature to about 50-75 C to yield a mixture;
b) Isolating a solid form of Ruxolitinib Phosphate from the mixture.

In some embodiments, the solution of Ruxolitinib is comprised of a first and second solvent. The first solvent may be selected from the group consisting of alkyl acetates, such as ethyl acetate and isopropyl acetate, and aromatic hydrocarbons such as toluene. The second solvent may be selected from the group consisting of aliphatic alcohols, such as methanol, ethanol and isopropanol. The volume ratio of the first solvent and the second solvent is typically in the range of 2:98 to about 5:95.
The mixture may be stirred for a suitable amount of time to allow the formation of APO-I. Often, the mixture is stirred for about 1 hour at a temperature of from about 50 C to about 75 C. In some embodiments, the mixture may be cooled down to about 0 C to about 25 C. After cooling, the mixture may be stirred for a suitable amount of time to allow the formation of APO-1. Often, the mixture is stirred for about 3 hours at a temperature of from about 0 C to about 25 C before isolating form APO-I.
Once isolated, the form APO-I may be washed with a suitable volatile organic solvent such as isopropanol.
Following isolation, form APO-1 may be dried in vacuo at a temperature of from about 0 C to about 25 C. The drying time may vary depending on the conditions, with a minimum of about 3 hours often employed.
One method for obtaining the solution of Ruxolitinib is by an extractive work up including treating with base a solution of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)-dibenzoylated tartaric acid salt in the first solvent and water followed by extracting the Ruxolitinib into the first solvent. The second solvent may be added to Ruxolitinib and the first solvent. Distillation and addition of second solvent may be employed as necessary in order to adjust the volume ratio of the first and second solvents into the suitable range of about 2:98 to about 5:95 of first solvent to second solvent, respectively.
Often about 3 volumes to about 5 volumes of the first solvent with respect to the weight of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)-dibenzoylated tartaric acid salt and about 3 volumes to about 5 volumes of water with respect to the weight of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)-dibenzoylated tartaric acid salt may be used to prepare the solution for extraction.
The base may be any suitable base capable of liberating the free base.
The base may be inorganic or organic. The base may be selected from the group consisting of metal hydroxides, carbonates, phosphates, ammonia, ammonium hydroxide, tertiary amines, and aryl amines. The base may be selected of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, lithium carbonate, potassium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, ammonia, ammonium hydroxide, triethyl amine, diisopropylamine, N, N-diisopropylethylamine, N, N-dimethylaniline, N,N-diethylaniline, pyridine and mixtures thereof.
The organic phases of the extractive work-up may be distilled down to about 2 volumes to about 2.5 volumes at a temperature of not more than 30 C.
The second solvent may be added to the extracts of the first solvent following distillation. Often, about 4 volumes to about 6 volumes of the second organic solvent with respect to the weight of (R)-3-(4-(7H-pyrrolo[2,3-cl]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)-dibenzoylated tartaric acid salt may be used. The solution after addition of the second solvent may be distilled down again with additional amounts of the second solvent added until the volume ratio of the first and second solvents are within the suitable range.
In some embodiments, a charcoal treatment may be performed on a solution of Ruxolitinib at any stage. Often the amount of charcoal used is to about 5 % to about 10 % weight / weight ratio with respect to the weight of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)- dibenzoylated tartaric acid salt.
In some embodiments, the charcoal treatment is carried out at a temperature of from about 20 C to about 25 C. The solution may be stirred for a suitable amount of time, often to about 0.5 h to about 1.0 h. After stirring, the solution may be filtered and washed with the second organic solvent, the volume of the second organic solvent used is from about 1 volume to about 2 volumes. A temperature of about 20 C to about 25 C is often used.
EXAMPLES
The following examples are illustrative of some of the embodiments of the invention described herein. These examples do not limit the spirit or scope of the invention in any way Powder X-Ray Diffraction Analysis:
Data were acquired on a PANanalytical X-Pert Powder diffractometer with fixed divergence slits and a Pixcel detector. The diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2-theta range of 4.5 to 40 degrees using CuKa radiation at a power of 40 mA and 45 kV. CuK8 radiation was removed using a divergent beam nickel filter. A step size of 0.013 degrees was used. Samples were rotated to reduce preferred orientation effects. Samples were lightly ground prior to analysis.
Differential Scanning Calorimetry Analysis:
The DSC thermograms were collected on a TA Instruments Q200 instrument. Samples (1 ¨ 5 mg) were weighed into a 40 pL aluminum pan and were crimped closed with an aluminum lid. The samples were analyzed under a flow of nitrogen (ca. 50 mL/min) at a scan rate of 10 C/minute Example 1: Preparation of Form APO-I Ruxolitinib phosphate.
The pH of a suspension of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)-dibenzoylated tartaric acid salt (0.8 g) in a mixture of ethyl acetate (3.2 mL) and water (2.4 mL), was adjusted to 9 to 11 with ammonium hydroxide (0.4 mL) at room temperature and stirred for 30 minutes. The phases were separated and the organic phase was washed with water (2.4 mL) for 5 minutes, and then the phases were separated. The organic phase was concentrated under vacuum to between about 2 to 2.5 volumes at an internal temperature of not more than 25 C. The flask was loaded with isopropanol (4.8 mL) and evaporated to between about 2 to 2.5 volumes under vacuum at an internal temperature of not more than 25 C. The flask was loaded with isopropanol (0.8 mL) and heated to between about 60 to 65 C whereupon a solution of phosphoric acid (0.148 mL) in isopropyl alcohol (1.6 mL) was added over 5 minutes while maintaining an internal temperature of between about 60 to 65 C. During the addition, precipitation was observed and the suspension was maintained for 30 minutes, then the mixture was cooled to between about 20 to 25 C in 2 to 3 hours and maintained overnight. The suspension was filtered, washed with isopropanol (2.4mL) and dried to afford Ruxolitinib phosphate (0.45 g, Molar Yield= 93%, chromatographic purity = 98.9%, enantiomeric purity = 99.2%) as an off white solid. A PXRD diffractogram and DSC thermogram of a sample prepared by this method is shown in Figures 1 and 2, respectively.
Example 2: Preparation of Form APO-I Ruxolitinib phosphate The pH of a suspension of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)-dibenzoylated tartaric acid salt (2 g) in a mixture of ethyl acetate (8 mL) and water (6 mL), was adjusted to a pH of 9 to 11 with ammonium hydroxide (0.9 mL) at room temperature and stirred for 30 minutes. The phases were separated and the organic phase was washed with water (6 mL) for 5 minutes, and then the phases were separated. The organic phase was concentrated under vacuum to between about 2 to 2.5 volumes at an internal temperature of not more than 25 C.
The flask was loaded with ethanol (12 mL) and evaporated to about 2 to 2.5 volumes under vacuum at an internal temperature of not more than 25 C.
The flask was loaded with ethanol (6 mL) and heated to between about 60 to 65 C whereupon a solution of phosphoric acid (1.0 molar equivalents) in ethanol (2 mL) was added over 5 minutes while maintaining an internal temperature of about 60 to 65 C. During the addition precipitation was observed and the suspension was maintained for 30 minutes. The mixture was cooled to about 50 to 55 C and the suspension was filtered, washed with ethanol (6 mL) and dried to afford Ruxolitinib phosphate as an off white solid (1 g).
Example 3: Preparation of Form APO-1 Ruxolitinib phosphate The pH of a suspension of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-y1)-1H-pyrazol-1-y1)-3-cyclopentylpropanenitrile (+)-dibenzoylated tartaric acid salt (12 g) in a mixture of ethyl acetate (36 mL) and water (60 mL) was adjusted to 9 to 11 with ammonium hydroxide (6 mL) at room temperature and stirred for 30 minutes. The phases were separated and the organic phase was washed with water (36 mL) for 5min, and then the phases were separated. The organic phase was concentrated under vacuum to between about 2 to 2.5 volumes at an internal temperature of not more than 25 C.
The flask was loaded with methanol (72 mL) and evaporated to 2 to 2.5 volumes under vacuum at an internal temperature of not more than 25 C.
The flask was loaded with methanol (36 mL) and heated to about 51 to 56 C
whereupon a solution of phosphoric acid (1.0 molar equivalents) in methanol (6 mL) was added over 5 minutes while maintaining an internal temperature of about 51 to 56 C. During the addition, precipitation was not observed and the solution was maintained for 30 minutes, then the mixture was cooled to about 0 to 5 C (precipitation was observed at 44 C). The suspension was filtered, washed with cold methanol (12 mL) and dried to afford Ruxolitinib phosphate as an off white solid (6.24 g, chromatographic purity 98.6%).
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims (6)

What is claimed is:

1. A polymorphic form APO-I of Ruxolitinib phosphate characterized by a powder X-ray diffraction pattern comprising peaks, in terms of degrees 2-theta, at 7.6 ~0.2 and 8.3 ~0.2.

2. The polymorphic form APO-I of Ruxolitinib phosphate of claim 1 wherein the powder X-ray diffraction pattern further comprises at least one peak, in terms of degrees 2-theta, at 4.9 ~0.2, 9.5 ~0.2, 12.5 ~0.2, and 13.0 ~0.2.

3. The polymorphic form APO-I of Ruxolitinib phosphate of claim 1 or 2 characterized by a DSC thermogram comprising a peak endotherm with an onset temperature of approximately 188 °C and a peak maximum of approximately 194 °C.

4. The polymorphic form APO-I of Ruxolitinib phosphate of any one of claims 1 to 3 having a PXRD diffractogram substantially similar to a PXRD
diffractogram as depicted in Figure 1.

5. The polymorphic form APO-I of Ruxolitinib phosphate of any one of claims 1 to 4 having a DSC thermogram substantially similar to a DSC
thermogram as depicted in Figure 2.

6. The polymorphic form APO-I of Ruxolitinib of any one of claims 1 to 5 in a pharmaceutical formulation.