STEFINOVIC MARIJAN (AT)
MÜHLEGGER ISABELLA (AT)
| WO2017066775A1 | 2017-04-20 | |||
| WO2018056269A1 | 2018-03-29 | |||
| WO2011068881A1 | 2011-06-09 | |||
| WO2017066775A1 | 2017-04-20 |
SHELDRICK, ACTA CRYST., vol. A71, 2015, pages 3 - 8
ACTA CRYST, vol. C71, 2015, pages 3 - 8
| CLAIMS 1) A solvate comprising upadacitinib and acetic acid. 2) Upadacitinib acetic acid solvate of claim 1, characterized by the chemical structure according to Formula (II) (P), wherein n is in the range of from 0.8 to 1.2. 3) Upadacitinib acetic acid solvate (Form BHOAC) of claim 1 or 2, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (11.3 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. 4) Upadacitinib acetic acid solvate (Form BHOAC) of claim 3, characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (9.8 ± 0.2)° and (13.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. 5) Upadacitinib acetic acid solvate of claim 1, characterized by the chemical structure according to Formula (II) wherein n is in the range of from 1.8 to 2.2. 6) Upadacitinib acetic acid solvate (Form AHOAC) of claim 1 or 5, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (3.3 ± 0.2)°, (11.0 ± 0.2)° and (27.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. 7) Upadacitinib acetic acid solvate of claim 6 characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (17.7 ± 0.2)° and (22.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. 8) Use of the upadactinib acetic acid solvate (Form AHOAC) as defined in any one of claims 5 to 7 for the preparation of the upadacitinib acetic acid solvate (Form BHOAC) as defined in any one of claims 2 to 4. 9) Use of the upadacitinib acetic acid solvate as defined in any one of claims 1 to 7 for the preparation of a pharmaceutical composition. 10) A pharmaceutical composition comprising the upadacitinib acetic acid solvate as defined in any one of claims 1 to 4 and at least one pharmaceutically acceptable excipient. 11) The pharmaceutical composition of claim 10, wherein the at least one pharmaceutically acceptable excipient comprises a release control polymer. 12) The pharmaceutical composition of claim 10 or 11, wherein the at least one pharmaceutically acceptable excipient does not comprise a pH-modifier. 13) The pharmaceutical composition as defined in any one of claims 10 to 12, wherein the pharmaceutical composition is an oral solid dosage form. 14) The pharmaceutical composition as defined in any one of claims 10 to 13, comprising 15 or 30 mg of the upadacitinib acetic acid solvate (Form BHOAC) as defined in any one of claims 1 to 4, calculated as upadacitinib. 15) The pharmaceutical composition as defined in any one of claims 10 to 14 for use in the treatment of rheumatoid arthritis. |
FIELD OF THE INVENTION
The present invention relates to acetic acid solvates of upadacitinib and processes for their preparation. The invention also relates to a pharmaceutical composition comprising an upadacitinib acetic acid solvate, preferably in a predetermined and/or effective amount and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment and/or prophylaxis of rheumatoid arthritis.
BACKGROUND OF THE INVENTION
Janus kinases (JAKs) belong to the superfamily of tyrosine kinase proteins and consist of four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Upadacitinib is an investigational oral agent engineered to selectively inhibit JAK1 and is currently tested in clinical studies to treat rheumatoid arthritis and various other chronic diseases. It can be chemically designated as (3S , ,4i?)-3-ethyl-4-(3iT-imidazo[l,2-a]pyrrolo[2,3-e]pyraz in-8-yl)-A-(2,2,2- trifluoroethyl)pyrrolidine-l -carboxamide and is represented by the following chemical structure according to Formula (I)
The compound upadacitinib is disclosed in WO 2011/068881 Al. Various solid-state forms of upadacitinib free base as well as different acid addition salts of upadacitinib are disclosed in WO 2017/066775 Al. The described solid-state forms of the free compound include besides amorphous upadacitinib several crystalline forms designated Form A (isopropyl acetate/water solvate), Form B (hydrate), Form C (hemihydrate) and Form D (anhydrate). Although solvate formation, with pharmaceutically acceptable organic solvents may be used as a means for customizing the physicochemical properties of active pharmaceutical ingredients with a process or clinical need, the isopropyl acetate/water solvate Form A of WO 2017/066775 A1 suffers from certain drawbacks, which to a certain degree compromizes its utility for formulation into a pharmaceutical dosage form. For example, according to the teaching of WO 2017/066775 Al, the solvate Form A is not physically stable but readily desolvates and converts to amorphous upadacitinib upon drying and therefore does not exhibit pharmaceutically acceptable physical stability for use as an active ingredient in a pharmaceutical dosage form (see WO 2017/066775 Al, page 85, paragraph [00385] and page 337, paragraph [001458]).
Alternatively, salt formation might be used as a means for improving the physicochemical properties of a drug substance. However, the tartarte hydrate salt disclosed in WO 2017/066775 Al tends to release its crystal water fairly quickly already at moderate temperature stress leading to amorphization (see WO 2017/066775 Al page 357, paragraph [001506] and corresponding Figure 4E as well as page 358 paragraph [001517]). Dehydration followed by amorphization also occurs when the tartarate hydrate is exposed to dry conditions (see WO 2017/066775 Al page 359, paragraph [001528]). In addition, the needle-shaped morphology of the tartrate hydrate (see WO 2017/066775 Al page 342, Table 15-A) is not preferred since such material often shows poor powder properties such as low bulk density as well as poor flow properties and compressability.
Hence, there remains a need for improved solid-state forms of upadacitinib possessing physicochemical properties which allow for the stable formulation of upadacitinib into a pharmaceutical dosage form such that reliable quality and efficacy are achieved throughout shelf-life.
SUMMARY OF THE INVENTION
The present invention relates to an upadacitinib acetic acid solvate. In particular, the present invention relates to crystalline forms of upadacitinib acetic acid solvate. One form of the present invention, also designated as Form AHOAC, contains about 2 mol equivalents of acetic acid and another form of the present invention, herein also designated as Form BHOAC, comprises about 1 mol equivalent of acetic acid. While Form AHOAC is a useful intermediate allowing for the first time the preparation of Form BHOAC, the latter possesses favorable physicochemical properties for a drug substance intended for use in an oral solid dosage form with regards to chemical stability, physical stability, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, compactibility and wettability.
In particular, the upadacitinib acetic acid solvate (Form BH O A C ) of the present invention is physically and chemically stable and can thus be reliably formulated into a pharmaceutical dosage form and safely stored. For example, in contrast to the upadacitinib isopropyl acetate/water solvate Form A or the upadacitinib tartrate salt of WO 2017/066775 A1 the upadacitinib acetic acid solvate (Form BHOA C ) of the present invention is physically stable upon drying, against moderate temperature stress and at dry conditions (see also Comparative Examples 1 and 2 hereinafter).
Abbreviations
PXRD powder X-ray diffractogram
DSC differential scanning calorimetry
TGA thermogravimetric analysis
MS mass spectrometry
GC gas chromatography
SXRD single crystal X-ray diffraction
RT room temperature
RH relative humidity
w-% weight percent
Definitions
In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:
As used herein the term“room temperature” refers to a temperature in the range of from 20 to 30 °C.
As used herein, the term“measured at a temperature in the range of from 20 to 30 °C” refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30 °C, i.e. at room temperature. Standard conditions can mean a temperature of about 22 °C. Typically, standard conditions can additionally mean a measurement under 20-80% relative humidity, preferably 30-70% relative humidity, more preferably 40-60% relative humidity and most preferably 50% relative humidity. The term“reflection” with regards to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see“Fundamentals of Powder Diffraction and Structural Characterization of Materials” by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).
The term“essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably in the range of ± 0.1° 2-Theta. Thus, a reflection that usually appears at 11.0° 2- Theta for example can appear between 10.8° and 11.2° 2-Theta, preferably between 10.9 and 11.1° 2-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
The crystalline upadacitinib acetic acid solvate of the present invention may be referred to herein as being characterized by a powder X-ray diffractogram "as shown in" a figure. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration, sample purity, sample history and sample preparation may lead to variations, for example relating to the exact reflection and peak positions and their intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for an unknown physical form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.
The term“solid-state form” as used herein refers to any crystalline and/or amorphous phase of a compound. The term“solvate” as used herein, refers to a crystalline solid wherein either one or more organic solvent(s) is/are cooperated in or accommodated by the crystal structure e.g. is/are part of the crystal structure or entrapped into the crystal (solvent inclusions). Thereby, the one or more organic solvent(s) can be present in a stoichiometric or non-stoichiometric amount. When the one or more organic solvent(s) is/are present in stoichiometric amount(s), the solvate may be referred to by adding greek numeral prefixes. For example, a solvate may be referred to as a /lew/solvate or as a /wwosolvate depending on the solvent(s)/compound stoichiometry. The solvent content can be measured/determined, for example, by GC, NMR, SXRD and/or TGA/MS.
A“predetermined amount” as used herein with regards to the upadacitinib acetic acid solvate of the present invention refers to the initial amount of the upadacitinib acetic acid solvate used for the preparation of a pharmaceutical composition having a desired dosage strength of upadacitinib.
The term“effective amount” as used herein with regards to the upadacitinib acetic acid solvate of the present invention encompasses an amount of upadacitinib acetic acid solvate, which causes the desired therapeutic and/or prophylactic effect.
As used herein, the term“about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.
As used herein, the term“mother liquor” refers to the solution remaining after crystallization of a solid from said solution.
The term“antisolvent” as used herein refers to liquids which reduce the solubility of the upadacitinib acetic acid solvates of the present invention in a solvent.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: illustrates a representative PXRD of the upadacitinib acetic acid solvate (Form AHOAC) prepared according to Example 1 of the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.
Figure 2: illustrates a representative TGA curve of the upadacitinib acetic acid solvate (Form AHOA C ) prepared according to Example 1 of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the mass (loss) of the sample in weight percent (w-%).
Figure 3: illustrates a representative DSC curve of the upadacitinib acetic acid solvate (Form AHOA C ) prepared according to Example 1 of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Milliwatt per gram (mW/g) with endothermic peaks going up.
Figure 4: illustrates a representative PXRD of the upadacitinib acetic acid solvate (Form BHOA C ) prepared according to Example 3 of the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.
Figure 5: illustrates a representative DSC curve of the upadacitinib acetic acid solvate (Form BHOA C ) prepared according to Example 3 of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Milliwatt per gram (mW/g) with endothermic peaks going up.
Figure 6: illustrates a representative TGA curve of the upadacitinib acetic acid solvate (Form BHOA C ) prepared according to Example 3 of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis the mass (loss) of the sample in weight percent (w-%).
Figure 7: illustrates an overlay comparison of the DSC curves of the upadacitinib acetic acid solvate Form BHOA C of the present invention (bottom) and the upadacitinib tartrate hydrate of WO 2017/066775 A1 (top). The x-axis shows the temperature in degree Celsius (°C). The DSC curve of the tartrate salt was shifted toward the y-axis for clarity reasons, hence the y-axis is not labeled. Endothermic peaks are going up.
Figure 8: illustrates a comparison of representative GMS isotherms of upadacitinib acetic acid solvate Form BHOA C of the present invention (solid line with squares) and the upadacitinib tartrate hydrate of WO 2017/066775 A1 (solid line with triangles) during the desorption cycle from 25 to 0% relative humidity. The x-axis displays the relative humidity in percent (%) measured at a temperature of (25.0 ± 0.1) °C, the y-axis displays the equilibrium mass change in percent (%). The sample weight at 25% relative humidity was used as reference weight. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a solvate comprising upadacitinib and acetic acid. In particular, the present invention relates to upadacitinib acetic acid solvate. More precisely, the present invention relates to crystalline forms of upadacitinib acetic acid solvate, herein also designated as“Form AHOA C ” and“Form BHOA C ”, respectively.
Upadacitinib acetic acid solvate Form AHOA C
The present invention relates to upadacitinib acetic acid solvate (Form AHOA C ) characterized by the chemical structure according to Formula (II)
Formula (II), wherein n is in the range of from 1.7 to 2.3, preferably in the range of from 1.8 to 2.2, more preferably in the range of from 1.9 to 2.1, even more preferably in the range of from 1.95 to 2.05 and most preferably n is about 2.0. For example, n is selected from the group consisting of about 1.7, 1.8, 1.9, 1.95, 2.0, 2.05, 2.1, 2.2 and 2.3. The upadacitinib acetic acid solvate (Form AHOA C ) of the present invention is a rZ/solvate e.g. a solvate having a molar ratio of upadacitinib and acetic acid in the range of from 1.0: 1.7 to 2.3, preferably of from 1.0: 1.8 to 2.2, more preferably of from 1.0: 1.9 to 2.1, even more preferably of from 1.00: 1.95 to 2.05 and most preferably the molar ratio is about 1.0 to 2.0.
The upadacitinib acetic acid solvate (Form AHOA C ) of the present invention as defined in any one of the above described embodiments may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. It may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the upadacitinib acetic acid solvate (Form AHOA C ) of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
The present invention relates to upadacitinib acetic acid solvate (Form AHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of:
(3.3 ± 0.2)°, (11.0 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (11.0 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (11.0 ± 0.2)°, (17.7 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (11.0 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (11.0 ± 0.2)°, (13.1 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ±
0.2)°; or
(3.3 ± 0.2)°, (11.0 ± 0.2)°, (13.1 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (18.1 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (11.0 ± 0.2)°, (13.1 ± 0.2)°, (17.1 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (18.1 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (11.0 ± 0.2)°, (13.1 ± 0.2)°, (13.3 ± 0.2)°, (17.1 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (18.1 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (6.5 ± 0.2)°, (11.0 ± 0.2)°, (13.1 ± 0.2)°, (13.3 ± 0.2)°, (17.1 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (18.1 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°; or
(3.3 ± 0.2)°, (6.5 ± 0.2)°, (9.8 ± 0.2)°, (11.0 ± 0.2)°, (13.1 ± 0.2)°, (13.3 ± 0.2)°, (17.1 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (18.1 ± 0.2)°, (22.4 ± 0.2)° and (27.3 ± 0.2)°;
when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
Alternatively, the present invention relates to upadacitinib acetic acid solvate (Form AHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of:
(3.3 ± 0.1)°, (11.0 ± 0.1)° and (27.3 ± 0.1)°; or
(3.3 ± 0.1)°, (11.0 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ± 0.1)°; or
(3.3 ± 0.1)°, (11.0 ± 0.1)°, (17.7 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ± 0.1)°; or
(3.3 ± 0.1)°, (11.0 ± 0.1)°, (17.3 ± 0.1)°, (17.7 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ± 0.1)°; or
(3.3 ± 0.1)°, (11.0 ± 0.1)°, (13.1 ± 0.1)°, (17.3 ± 0.1)°, (17.7 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ±
0.1)°; or (3.3 ± 0.1)°, (11.0 ± 0.1)°, (13.1 ± 0.1)°, (17.3 ± 0.1)°, (17.7 ± 0.1)°, (18.1 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ± 0.1)°; or
(3.3 ± 0.1)°, (11.0 ± 0.1)°, (13.1 ± 0.1)°, (17.1 ± 0.1)°, (17.3 ± 0.1)°, (17.7 ± 0.1)°, (18.1 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ± 0.1)°; or
(3.3 ± 0.1)°, (11.0 ± 0.1)°, (13.1 ± 0.1)°, (13.3 ± 0.1)°, (17.1 ± 0.1)°, (17.3 ± 0.1)°, (17.7 ± 0.1)°, (18.1 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ± 0.1)°; or
(3.3 ± 0.1)°, (6.5 ± 0.1)°, (11.0 ± 0.1)°, (13.1 ± 0.1)°, (13.3 ± 0.1)°, (17.1 ± 0.1)°, (17.3 ± 0.1)°, (17.7 ± 0.1)°, (18.1 ± 0.1)°, (22.4 ± 0.1)° and (27.3 ± 0.1)°; or
when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In addition, the present invention relates to upadacitinib acetic acid solvate (Form AHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of (11.0 ± 0.2)°, (13.1 ± 0.2)°, (17.3 ± 0.2)°, (17.7 ± 0.2)°, (20.3 ± 0.2)°, (21.1 ± 0.2)°, (22.4 ± 0.2)° (27.3± 0.2)°, (27.4 ± 0.2)° and (27.7 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
Alternatively, the present invention relates to upadacitinib acetic acid solvate (Form AHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of (11.0 ± 0.1)°, (13.1 ± 0.1)°, (17.3 ± 0.1)°, (17.7 ± 0.1)°, (20.3 ± 0.1)°, (21.1 ± 0.1)°, (22.4 ± 0.1)° (27.3± 0.1)°, (27.4 ± 0.1)° and (27.7 ± 0.1)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
The present invention also relates to upadacitinib acetic acid solvate (Form AHOA C ) characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
The present invention also relates to upadacitinib acetic acid solvate (Form AHOA C ) characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (75 ± 5)°C, preferably of (75 ± 3)°C, even more preferably of (75 ± 2)°C and most preferably of (75 ± 1)°C, when measured a heating rate of 10 K/min.
In another embodiment, the present invention relates to upadacitinib acetic acid solvate (Form AHOA C ), characterized by having a TGA curve showing a mass loss of not more than 0.5 w-% based on the weight of the upadacitinib acetic acid solvate, when heated from 25 to 75 °C at a rate of 10 K/min.
In still a further embodiment, the present invention relates to upadacitinib acetic acid solvate
(Form AHOA C ) characterized by having the orthorhombic space group symmetry P 2i 2i 2 and the following unit cell parameters:
a = 8.4059 Angstrom;
b = 53.747 Angstrom;
c = 5.1541 Angstrom;
alpha = 90°;
beta = 90°;
gamma = 90°;
when measured at a temperature of 173 K with Mo-Kalphai,2 radiation having a wavelength of 0.71073 Angstrom.
In another aspect, the invention relates to a process for the preparation of the upadacitinib acetic acid solvate (Form AHOA C ) as defined in any one of the above described embodiments comprising:
(a) providing a solution comprising upadacitinib and acetic acid; and
(b) allowing the solvent to evaporate.
Upadacitinib may be prepared according to the teachings of WO 2011/068881 A1 or WO 2017/066775 Al, in particular it may be prepared according to Example 3 or Example 4 of WO 2017/066775 Al . Acetic acid is commercially available and may be applied as concentrated acetic acid (e.g. from Sigma-Aldrich ® ’ assay > 99.8%) or as aqueous acetic acid (e.g. acetic acid having an assay of 96%).
The upadacitinib concentration of the solution in step (a) is in the range of from 50 - 180 g/L, preferably of from 100 - 170 g/L and most preferably of from 160 - 170 g/L.
In step (b) the solvent is allowed to evaporate at RT e.g. the solution is open stored at RT for a period in the range of from several days to several weeks. For example, the solution is stored at RT for a period in the range of from about 2 days to 8 weeks, preferably of from about 4 days to 4 weeks, e.g. of from about 7 days to 2 weeks. Storage is continued until an essential part, preferably all of the solvent is evaporated. Optionally, the obtained crystals are further dried, wherein drying may be performed at a temperature in the range of from about 20 to 60 °C, preferably of from about 20 to 40 °C , even more preferably drying is performed at RT. The optional additional drying step may be performed at ambient pressure and/or under reduced pressure. Preferably, it is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less for example a vacuum of about 30 mbar or less. The drying may be performed for a period in the range of from about 1 to 24 hours, preferably of from about 1 to 12 hours and most preferably of from about 2 to 6 hours. However, most preferably the drying step is omitted.
Upadacitinib acetic acid solvate Form BHOA C The present invention also relates to upadacitinib acetic acid solvate (Form BHOA C ) characterized by the chemical structure according to Formula (II)
Formula (II), wherein n is in the range of from 0.7 to 1.3, preferably in the range of from 0.8 to 1.2, more preferably in the range of from 0.9 to 1.1, even more preferably in the range of from 0.95 to 1.05 and most preferably n is about 1.0. For example, n is selected from the group consisting of about 0.7, 0.8, 0.9, 0.95, 1.0, 1.05, 1.1, 1.2 and 1.3. The upadacitinib acetic acid solvate Form BHOA C of the present invention is a /ww solvate e.g. a solvate having a molar ratio of upadacitinib and acetic acid in the range of from 1.0: 0.7 to 1.0: 1.3, preferably of from 1.0: 0.8 to 1.0: 1.2, more preferably of from 1.0: 0.9 to 1.0: 1.1, even more preferably of from 1.00: 0.95 to 1.00: 1.05 and most preferably the molar ratio is about 1.0 to 1.0.
The upadacitinib acetic acid solvate Form BHOA C of the present invention as defined in any one of the above described embodiments may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. It may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the upadacitinib acetic acid solvate Form BHOA C of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.
The present invention relates to upadacitinib acetic acid solvate (Form BHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of:
(11.3 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°; or
(9.8 ± 0.2)°, (11.3 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°; or
(9.8 ± 0.2)°, (11.3 ± 0.2)°, (13.1 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°; or
(9.8 ± 0.2)°, (11.3 ± 0.2)°, (12.1 ± 0.2)°, (13.1 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°; or
(9.8 ± 0.2)°, (11.3 ± 0.2)°, (12.1 ± 0.2)°, (13.1 ± 0.2)°, (14.3 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ±
0.2)°; or
(9.8 ± 0.2)°, (11.3 ± 0.2)°, (12.1 ± 0.2)°, (13.1 ± 0.2)°, (14.3 ± 0.2)°, (15.2 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°; or
(3.8 ± 0.2)°, (9.8 ± 0.2)°, (11.3 ± 0.2)°, (12.1 ± 0.2)°, (13.1 ± 0.2)°, (14.3 ± 0.2)°, (15.2 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°; or
(3.8 ± 0.2)°, (7.6 ± 0.2)°, (9.8 ± 0.2)°, (11.3 ± 0.2)°, (12.1 ± 0.2)°, (13.1 ± 0.2)°, (14.3 ± 0.2)°, (15.2 ± 0.2)°, (16.9 ± 0.2)° and (27.0 ± 0.2)°,
when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
Alternatively, the present invention relates to upadacitinib acetic acid solvate (Form BHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of:
(11.3 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ± 0.1)°; or
(9.8 ± 0.1)°, (11.3 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ± 0.1)°; or
(9.8 ± 0.1)°, (11.3 ± 0.1)°, (13.1 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ± 0.1)°; or
(9.8 ± 0.1)°, (11.3 ± 0.1)°, (12.1 ± 0.1)°, (13.1 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ± 0.1)°; or
(9.8 ± 0.1)°, (11.3 ± 0.1)°, (12.1 ± 0.1)°, (13.1 ± 0.1)°, (14.3 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ±
0.1)°; or
(9.8 ± 0.1)°, (11.3 ± 0.1)°, (12.1 ± 0.1)°, (13.1 ± 0.1)°, (14.3 ± 0.1)°, (15.2 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ± 0.1)°; or (3.8 ± 0.1)°, (9.8 ± 0.1)°, (11.3 ± 0.1)°, (12.1 ± 0.1)°, (13.1 ± 0.1)°, (14.3 ± 0.1)°, (15.2 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ± 0.1)°; or
(3.8 ± 0.1)°, (7.6 ± 0.1)°, (9.8 ± 0.1)°, (11.3 ± 0.1)°, (12.1 ± 0.1)°, (13.1 ± 0.1)°, (14.3 ± 0.1)°, (15.2 ± 0.1)°, (16.9 ± 0.1)° and (27.0 ± 0.1)°,
when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In addition, the present invention relates to upadacitinib acetic acid solvate (Form BHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of (11.3 ± 0.2)°, (13.1 ± 0.2)°, (16.9 ± 0.2)°, (18.0 ± 0.2)°, (18.6 ± 0.2)°, (19.1 ± 0.2)°, (19.6 ± 0.2)° (20.2 ± 0.2)°, (27.0 ± 0.2)° and (27.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm.
Alternatively, the present invention relates to upadacitinib acetic acid solvate (Form BHOA C ) characterized by having a PXRD comprising reflections at 2-Theta angles of (11.3 ± 0.1)°, (13.1 ± 0.1)°, (16.9 ± 0.1)°, (18.0 ± 0.1)°, (18.6 ± 0.1)°, (19.1 ± 0.1)°, (19.6 ± 0.1)° (20.2 ± 0.1)°, (27.0 ± 0.1)° and (27.4 ± 0.1)°, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai, 2 radiation having a wavelength of 0.15419 nm.
The present invention also relates to upadacitinib acetic acid solvate (Form BHOA C ) characterized by having a PXRD essentially the same as shown in Figure 4 of the present invention, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
The present invention also relates to upadacitinib acetic acid solvate (Form BHOA C ), characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (94 ± 5)°C, preferably of (94 ± 3)°C, even more preferably of (94 ± 2)°C and most preferably of (94 ± 1)°C, when measured with a pinholed pan at a heating rate of 5 K/min.
In addition, the present invention relates to upadacitinib acetic acid solvate (Form BHOA C ), characterized by having a TGA curve showing a mass loss of not more than 0.8 w-% based on the weight of the upadacitinib acetic acid solvate, when measured in range of from 25 to 75°C at a heating rate of 5 K/min.
In a further aspect, the present invention relates to a process for the preparation of the upadacitinib acetic acid solvate (Form BHOA C ) of the present invention comprising: (a) providing a solution comprising upadacitinib and acetic acid;
(b) adding at least one antisolvent to the solution provided in (a);
(c) adding upadacitinib acetic acid Form AHOA C seed crystals to the mixture of (b);
(d) subjecting the mixture provided in (c) to crystallization conditions leading to the formation of upadacitinib acetic acid solvate Form AHOA c ;
(e) separating at least a part of the crystals obtained in (d) from the mother liquor;
(f) optionally, washing the crystals isolated in (e); and
(g) subjecting upadacitinib acetic acid solvate Form AHOA C obtained in (e) or (f) to drying conditions allowing for the preparation of the upadacitinib acetic acid solvate Form BHOA C ;
Upadacitinib may be prepared according to the teachings of WO 2011/068881 A1 or WO 2017/066775 Al, in particular it may be prepared according to Example 3 or Example 4 of WO 2017/066775 Al . Acetic acid is commercially available and may be applied as concentrated acetic acid (e.g. from Sigma-Aldrich®, assay U 99.8%) or as aqueous acetic acid (e.g. acetic acid having an assay of 96%). Preferably, acetic acid is the only solvent present in the solution of step (a).
The upadacitinib concentration of the solution in step (a) is in the range of from 150 - 250 g/L, preferably of from 175 - 225g/L and most preferably the concentration is about 200 g/L. The solution is preferably prepared at room temperature.
The at least one antisolvent is selected from ethers and/or alkanes. For example, the ether may be selected from the group consisting of diethyl ether, /c/V-butyl methyl ether and diisopropyl ether and the alkane may be selected from the group consisting of «-hexane, «-heptane and «- octane. Preferably, the at least one antisolvent is diisopropyl ether and most preferably diisopropyl ether is the only antisolvent used. The at least one antisolvent may be added at room temperature and in such amount that the initial solution of step (a) becomes visually turbid. The exact amount of antisolvent required depends besides others on the type of antisolvent(s) used.
In the next step (c) upadacitinib acetic acid solvate Form AHOA C seed crystals are added. Seed crystals may be prepared according to the procedure for Form AHOA C preparation described hereinabove. The amount of seed crystals employed may range from about 0.1 to 20 weight%, preferably from about 0.1 to 10 weight% and most preferably from about 0.1 to 5 weight%, based on the weight of applied upadacitinib starting material. Upadacitinib acetic acid solvate Form AHOA C is thereafter allowed to crystallize from the mixture by keeping the mixture at room temperature and/or below, preferably under stirring.
Then, at least a part of the Form AHOA C crystals is separated from the mother liquor. Preferably, the crystals are separated from the mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.
Optionally, in a further step the isolated crystals are washed with the at least one antisolvent used in step (b) e.g. with diisopropyl ether.
The obtained upadacitinib acetic acid solvate Form AHOA C crystals are finally subjected to drying conditions allowing for the partial desolvation of acetic acid from Form AHOA C and the building of the upadacitinib acetic acid solvate Form BHOA C . The drying step may be performed by keeping Form AHOA C under a dry nitrogen purge at RT for a sufficient long time until Form AHOA C has transformed to Form BHOA C . The skilled person may monitor this conversion e.g. by PXRD. For example, the skilled person may monitor the evolution of one or more unique Form BHOA C reflections at 2-Theta angles selected from the group consisting of (3.8 ± 0.2)°, (7.6 ± 0.2)°, (12.0 ± 0.2)° and (15.2 ± 0.2)°, which indicate the presence of Form BHOA C . In addition, the skilled person may monitor the absence of the characteristic Form AHOA C reflection at (3.3 ± 0.2)° 2-Theta, which indicates the absence of Form AHOA C . The duration of the drying step may increase with increasing particle size of Form AHOA C . Hence, a size reduction step such as milling may optionally be applied before drying.
In a further aspect, the present invention relates to a process for the preparation of the upadacitinib acetic acid solvate (Form BHOA C ) of the present invention comprising the step of:
(a) converting upadacitinib acetic acid solvate Form AHOA C to upadacitinib acetic acid solvate Form BHOA c ;.
This conversion is typically achieved by drying Form AHOA C under conditions and for a time sufficient to achieve a partial desolvation of Form AHOA C , the form being transformed to Form BHOAC.
In another aspect, the present invention relates to a composition comprising the upadacitinib acetic acid solvate Form BHOA C of the present invention as defined in any one of the embodiments described above, said composition being essentially free of any other solid form of upadacitinib, in particular of the upadacitinib acetic acid solvate Form AHOA C of the present invention as defined in any one of the embodiments described above. For example, a composition comprising the upadacitinib acetic acid solvate Form BHOA C of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid form of upadacitinib, based on the weight of the composition. Preferably, the any other solid form of upadacitinib is upadacitinib acetic acid solvate Form AHOA C as defined in any one of the embodiments described hereinabove. Form AHOA C exhibits a PXRD comprising a characteristic reflection at (3.3 ± 0.2)° 2-Theta, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. Therefore, the absence of reflections at (3.3 ± 0.2)° 2-Theta in the PXRD confirms the absence of form AHOA C of upadacitinib in the composition.
Hence, in a preferred embodiment, the present invention also relates to a composition comprising the upadacitinib acetic acid solvate Form BHOA C of the present invention as defined in any one of the embodiments described above, said composition having a PXRD comprising no reflections at (3.3 ± 0.2)° 2-Theta, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.
In another embodiment, the invention relates to a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the upadacitinib acetic acid solvate Form BHOA C of the present invention as defined in any one of the embodiments described above, based on the total weight of the composition. The remaining material may comprise other solid form(s) of upadacitinib and/or reaction impurities and/or processing impurities arising from the preparation of the composition.
In a further aspect the present invention relates to the use of the upadacitinib acetic acid solvate of the present invention as defined in any one of the embodiments described above for the preparation of a pharmaceutical composition. For example, the present invention relates to the use of the upadacitinib acetic acid solvate Form AHOA C of the present invention, preferably to the use of the upadacitinib acetic acid solvate Form BHOA C of the present invention for the preparation of a pharmaceutical composition.
In another aspect, the present invention relates to a pharmaceutical composition comprising the upadacitinib acetic acid solvate of the present invention as defined in any one of the embodiments described above for example the upadacitinib acetic acid solvate Form AHOA C and/or preferably Form BHOA C of the present invention, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition of the present invention is an oral solid dosage form, such as a tablet or a capsule. More preferably, the pharmaceutical composition of the present invention is a tablet e.g. a film-coated tablet. Most preferably, the pharmaceutical composition of the present invention is an extended release film-coated tablet.
The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of fillers, pH-modifiers, release control polymers, lubricants, glidants, coating materials and combinations thereof. Preferably, all of these pharmaceutically acceptable excipients are comprised by the pharmaceutical composition of the present invention. More preferably, all of these pharmaceutically acceptable excipients except pH-modifiers are comprised by the pharmaceutical composition of the present invention.
Hence, the present invention also relates to a pharmaceutical composition comprising the upadacitinib acetic acid solvate of the present invention as defined in any one of the embodiments described above, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition does not comprise a pH-modifier. Preferably, the upadacitinib acetic acid solvate is upadacitinib acetic acid solvate Form BHOA C of the present invention.
In a preferred embodiment, the at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, mannitol, tartaric acid, hydroxyproyplmethyl cellulose, colloidal silicon dioxide, magnesium stearate and Opadry ® . More preferably, all of these pharmaceutically acceptable excipients are comprised by the pharmaceutical composition of the present invention. Most preferably, all of these pharmaceutically acceptable excipients except tartaric acid are comprised by the pharmaceutical composition of the present invention.
Furthermore, the present invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of upadacitinib acetic acid solvate is selected from the group consisting of 7.5 mg, 15 mg, 24 mg, 30 mg and 45 mg calculated as upadacitinib. Preferably, the invention relates to a pharmaceutical composition as described above, wherein the predetermined and/or effective amount of upadacitinib acetic acid solvate is 15 mg or 30 mg calculated as upadacitinib. Preferably, the upadacitinib acetic acid solvate is upadacitinib acetic acid solvate Form BHOA C of the present invention.
The present invention also relates to a pharmaceutical composition as defined in any one of the above described embodiments, wherein the pharmaceutical composition is to be administered once-daily. Preferably, the upadacitinib acetic acid solvate is upadacitinib acetic acid solvate Form BHOA C of the present invention.
In a further aspect, the present invention relates to the pharmaceutical composition as defined in any one of the above described embodiments for use as a medicament. Preferably, the upadacitinib acetic acid solvate is upadacitinib acetic acid solvate Form BHOA C of the present invention.
In yet another aspect, the present invention relates to the pharmaceutical composition as defined in any one of the above described embodiments for use in the treatment or prophylaxis of a condition selected from the group consisting of rheumatoid arthritis, psoriasis, hidrandenitis suppurativa, ulcerative colitis, psoriatic arthritis, atopic dermatitis, Crohn’s disease, giant cell arteritis and ankylosing spondylitis. Most preferably, the invention relates to the pharmaceutical composition as defined in any one of the above described embodiments for use in the treatment or prophylaxis of rheumatoid arthritis.
In another embodiment, the present invention is directed to a method of treating or prophylactically preventing a condition selected from the group consisting of rheumatoid arthritis, psoriasis, hidrandenitis suppurativa, ulcerative colitis, psoriatic arthritis, atopic dermatitis, Crohn’s disease, giant cell arteritis and ankylosing spondylitis by administering the pharmaceutical composition as defined in any one of the above described embodiments to a patient in need of such a treatment and/or prophylaxis. Preferably, the condition is rheumatoid arthritis.
EXAMPLES
The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention. Analytical Methods
Powder X-ray diffraction was performed in transmission geometry on an X’Pert PRO diffractometer (PANalytical, Almelo, NL) equipped with a theta/theta coupled goniometer, programmable XYZ stage with well plate holder, Cu-Kalphai,2 radiation source (wavelength 0.15419 nm) with a focussing mirror, a 0.5° divergence slit, a 0.02° sober slit collimator and a 1° anti -scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.04° sober slit collimator, a Ni-filter and a solid state PIXcel detector (255 channels) on the diffracted beam side. The diffractogram was recorded at a tube voltage of 40 kV, tube current of 40 mA, applying a step size of 20 = 0.013° with 40s per step in the 20 range between 2° and 40°. Data were analyzed with X’Pert Highscore Plus version 4.7 (PANalytical, Almelo, NL). A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.
Intensity data for a single crystal structure determination were collected at 173 K, using Mo radiation (l = 0.71073 A), on an Oxford Diffraction Gemini-R Ultra diffractometer operated by the CrysAlisPro software (Rigaku OD, 2015). The data were corrected for absorption effects by means of comparison of equivalent reflections. The structure was solved with the direct methods procedure implemented in SHELXT and refined by full-matrix least squares refinement on F 2 using SHELXL-2014 [Sheldrick, Acta Cryst. A71 (2015), 3-8 and C71 (2015), 3-8] Non-hydrogen atoms were located in difference maps and refined anisotropicaby. Hydrogen positions were located in difference maps. H atoms bonded to C atoms were refined using riding models, whilst those bonded to N and O atoms were refined with a distance restraint [(N-H 0.88(2) A and H-0 0.84(2) A]
TGA of Form AHOA C was performed using a TGA 7 instrument (PerkinElmer, Norwalk, Ct., USA) controlled by the Pyris 2.0 software. The sample (3.25 mg) was weighed into a platinum pan. A heating rate of 5 K/min was applied and dry nitrogen was used as the purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min).
DSC of Form AHOA C was performed on a Diamond DSC using the Pyris 7.0 software (PerkinElmer, Norwalk, Ct., USA). The sample (2.18 mg, using a UM3 ultramicrobalance, Mettler, Greifensee, CH) was heated in a closed aluminium pan (30 microlitre). The sample was scanned through the range of 25 to 130 °C using rates of 10 K/min with dry nitrogen as the purge gas (20 mL/min). The instrument was calibrated for temperature with pure benzophenone (mp 48.0 °C) and caffeine (mp 236.2 °C). The energy calibration was performed with pure indium (mp 156.6 °C; heat of fusion 28.45 J/g).
Example 1: Preparation of upadacitinib acetic acid solvate (Form AHOA C )
Upadacitinib (50 mg, 0.13 mmol, e.g. prepared according to Example 3 of WO 2017/066775 Al) was dissolved in acetic acid (0.3 mL, assay 96%) at RT. The obtained viscous solution was left at RT for about 2 weeks to allow for the evaporation of the solvent and to form a crystalline solid. Upadacitinib acetic acid solvate was obtained quantitatively.
Example 2: Solid-state characterization of upadacitinib acetic acid solvate Form AHOA C obtained in Example 1
Powder X-ray diffraction
A representative diffractogram of upadacitinib acetic acid solvate Form AHOA C is displayed in Figure 1 herein. The corresponding reflection list is provided in Table 1 below.
Table 1: PXRD reflections of upadacitinib acetic acid solvate Form AHOA C in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.
Thermoanalvsis of upadacitinib acetic acid solvate Form AHOA C obtained in Example 1 The TGA curve of upadacitinib acetic acid solvate (Form AHOA C ) shows a mass loss of only about 0.5 w-% from the start of the measurement until about 75 °C. Only at a temperature above about 75 °C, a significant weight loss can be observed (see Figure 2 herein), which corresponds well to the broad endothermic peak observed in the DSC curve (see Figure 3 herein). Single crystal X-ray diffraction
The unit cell parameters of upadacitinib acetic acid solvate Form AHOA C according to the present invention are provided in Table 2 below.
Table 2: Unit cell parameters of upadacitinib acetic acid solvate Form AHOA C According to single crystal X-ray diffraction no proton transfer from acetic acid to upadactinib took place proofing the presence of a solvate and excluding salt formation. In addition the upadacitinib acetic acid solvate Form of the present invention can be assigned as
<i/solvate.
Example 3: Preparation of upadacitinib acetic acid solvate Form BHOA C via Form AHOA C
Step A: Preparation of Form A HOAC
Upadacitinib (2.0 g, 5.26 mmol, e.g. prepared according to Example 3 of WO 2017/066775 Al) was dissolved in acetic acid (10 mL, 96%) at RT. To the solution diisopropyl ether (67 mL) was added until the solution became slighltly turbid. Thereafter, upadacitinib acetic acid solvate Form A HOAC seed crystals (10 mg, prepared according to Example 1 herein) were added and the mixture was stirred for 2 hours at RT. The obtained suspension was then stored overnight at 2- 8°C in the fridge. After adding additional diisopropyl ether (25 mL) the crystals were collected by filtration and washed with cold diisopropyl ether (8 mL).
Step B: Preparation of Form BHOA C
Form AHOA C obtained in Step A was kept under a dry nitrogen purge at 25°C for about 33 hours to obtain upadacitinib acetic acid solvate Form BHOA C .
Example 4: Solid state characterization of upadacitinib acetic acid solvate Form BHOA C
Powder X-ray diffraction
A representative diffractogram of upadacitinib acetic acid solvate Form BHOA C is displayed in Figure 4 herein. The corresponding reflection list is provided in Table 3 below.
Table 3: PXRD reflections of upadacitinib acetic acid solvate Form BHOA C in the range of from 2 to 30° 2-Theta; A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.
Differential Scanning Calorimetry
The DSC thermogram of Form BHOA C , which is also displayed in Figure 5 hereinafter, was recorded on a Hyper DSC using the Pyris 2.0 software (PerkinElmer, Norwalk, Ct., USA). Approximately 2.112 mg of an accurately weighed sample (using a UM3 ultramicrobalance, Mettler, Greifensee, CH) were heated in a five-pinholed aluminium pan (30 pL, 1 bar). The sample was scanned through the range of 25 to 130 °C using a rate of 5 K/min with dry nitrogen as the purge gas (20 mL/min). The instrument was calibrated for temperature with pure benzophenone (mp 48.0 °C) and caffeine (mp 236.2 °C). The energy calibration was performed with pure indium (mp 156.6 °C; heat of fusion 28.45 J/g). The DSC curve displays a single endotherm which is due to the melting of the sample. Under the applied measurement conditions an onset temperature of about 94.1 °C, a peak temperature of about 95.1 °C and a heat of fusion of about 28.5 J/g was determined.
Thermogravimetric analysis
TGA of Form BHOA C was performed using a TGA 7 instrument (PerkinElmer, Norwalk, Ct., USA) controlled by the Pyris 2.0 software. Approximately 2.655 mg of sample were weighed into a platinum pan. A heating rate of 5 °C between 20 - 270 °C was applied and dry nitrogen was used as the purge gas (sample purge: 20 mL/min, balance purge: 40 mL/min).
Form BHOA C shows a mass loss of about 12.3 w-% until 200°C, which corresponds to approximately 0.9 mol equivalent of acetic acid. Hence, Form BHOA C of the present invention can be assigned as /«o/wsolvate. The corresponding TGA curve is also displayed in Figure 6 herein.
Comparative Example 1: Thermal stability
Thermal stabilities of upadacitinib acetic acid solvate Form BHOA C of the present invention (prepared according to the procedure disclosed in Example 3 hereinabove) and upadacitinib tartrate hydrate of WO 2017/066775 A1 (prepared according to the procedure disclosed in WO 2017/066775 Al, Example 8, Method B) were investigated by DSC using a Mettler Polymer DSC R instrument. Upadacitinib acetic acid solvate Form BHOA C (4.77 mg) and upadacitinib tartrate hydrate (8.32 mg) were each heated in a 40 microliter aluminium pan with a pierced aluminium lid from 25 to 200 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.
The first endothermic signal indicating a phase change (e.g. due to melting) occurs more than 20 °C higher for Form BHOA C than for the upadacitinib tartrate hydrate. The respective onset and peak temperatures of both forms are displayed in Table 4 and an overlay of the DSC curves is provided in Figure 7.
Tonset Tpeak
Upadacitinib acetic acid
92.8 °C 94.1 °C
solvate Form BHOA C
Upadacitinib tartrate hydrate 70.4 °C 70.9 °C
Table 4: Comparison of onset temperatures (T onSet ) and peak temperatures (T peak ) Hence, it can be concluded from the comparative DSC experiments that Form BHOA C of the present invention is significantly more stable against temperature stress compared to the tartrate salt of WO 2017/066775 Al .
Comparative Example 2: Stability at dry conditions
Moisture sorption isotherms of upadacitinib acetic acid solvate Form BHOA C of the present invention (prepared according to the procedure disclosed in Example 3 hereinabove) and upadacitinib tartrate hydrate of WO 2017/066775 Al (prepared according to the procedure disclosed in WO 2017/066775 Al, Example 8, Method B) were recorded along with other samples with an SPSx-I m moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at ambient relative humidity (RH) of 25%. RH was then decreased to 5% in 5% steps, followed by a further decrease to 3% and to 0% RH. Samples were kept at every humidity step for approximately 6 hours and equilibrium sample weights were determined at the end of each humidity step. The equilibrium sample weight at 25% RH was used as reference weight.
As can be seen from Figure 8 herein the tartrate hydrate salt dehydrates at dry conditions below 10% RH, while the acetic acid solvate Form BHOA C of the present invention shows no significant mass loss. PXRD performed after the GMS experiments confirmed that Form BHOA C preserved its crystal structure in contrast to the tartrate salt which turned amorphous. Hence, it can be concluded from the GMS experiments that the upadacitinib acetic acid solvate Form BHOA C of the present invention is more stable at dry conditions compared to the upadacitinib tartrate hydrate of WO 2017/066775 Al .
Comparative Example 3:
Chemical stability of upadacitinib acetic acid solvate of the present invention and upadacitinib maleate was analyzed when exposed to 60°C/30% RH for 7 days or to 60°C/75% RH for 7 days. While upadacitinib acetic acid solvate was chemically stable, upadacitinib maleate showed major degradation at 60°C/75% RH (see Table 5).
Table 5: Chemical stability of upadacitinib maleate and upadacitinib acetic acid solvate when exposec to a temperature of 60°C at different humidity.
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