FIELD OF THE INVENTION

The present invention relates to a crystalline form of risdiplam and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline form of risdiplam of the present invention 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 of spinal muscular atrophy (SMA).

BACKGROUND OF THE INVENTION

Risdiplam is a survival of motor neuron 2 (SMN2) gene splicing modifier indicated for the treatment of spinal muscular atrophy (SMA). The chemical name of risdiplam is 7-(4,7- diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[l,2-Z>] pyridazin-6-yl)pyrido-4Z7-[l,2- a]pyrimidin-4-one. Risdiplam can be represented by the following chemical structure according to Formula (A)

Formula (A).

Risdiplam and its preparation are disclosed in WO 2015/173181 Al. In Example 20 the product is obtained as light yellow solid after purification by column chromatography.

In Examples 14 and 15 of WO 2019/057740 Al risdiplam is obtained as yellow crystals, respectively.

WO 2020/079203 Al mentions various crystalline forms of risdiplam free base including Form A (anhydrous), Form B (metastable polymorph), Form C (monohydrate), Form D (trihydrate), Form E (trihydrate), Form F (hydrate) and Form G (metastable polymorph). Several anhydrous and hydrated forms of risdiplam are also mentioned in WO 2021/021775 Al, which are therein denominated as Form 1, Form 2, Form 3, Form 4 and Form 5.

Different solid-state forms of an active pharmaceutical ingredient often possess different properties. Differences in physicochemical properties of solid-state forms can play a crucial role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile and bioavailability or with improved stability or shelf-life can become accessible due to an improved solid-state form of an active pharmaceutical ingredient. Also processing or handling of the active pharmaceutical ingredient during the formulation process may be improved. New solid-state forms of an active pharmaceutical ingredient can thus have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid forms.

There is thus a need for the provision of solid-state forms of risdiplam having improved physicochemical properties.

SUMMARY OF THE INVENTION

The present invention provides a crystalline form of risdiplam, which is hereinafter also designated as “Form 1”.

Risdiplam Form 1 of the present invention posesses one or more advantageous properties selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.

It is noteworthy, that the crystalline Form 1 of the present invention was only accessible by applying very specific crystallization conditions. In contrast to the teaching of the prior art (e.g. WO 2020/079203 Al and WO 2021/021775 Al), which uses ridsiplam free base as starting material for the preparation of the various forms, the inventors of the present invention followed a different approach by treating risdiplam dihydrochloride salt with an amine base such as tri ethylamine in the presence of methanol, which unexpectedly yielded the novel Form 1 of risdiplam of the present invention.

Abbreviations

PXRD powder X-ray diffractogram FTIR Fourier transform infrared

DSC differential scanning calorimetry

TGA thermogravimetric analysis

GMS gravimetric moisture sorption

Boc tert-butyloxycarbonyl

RH relative humidity

EDTA ethylenediaminetetraacetic acid

PEG polyethylne glycol

Definitions

In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:

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 20-60% RH, preferably 30-50% RH, more preferably 40% RH and most preferably 20 - 30% RH.

The term “reflection” with regard 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 7.5° 2-Theta for example can appear between 7.3° and 7.7° 2-Theta, preferably between 7.4° and 7.6° 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, particle size, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.

Crystalline Form 1 of risdiplam of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, powder X-ray diffraction. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact reflection positions and intensities. However, a comparison of the graphical data in the figure herein with the graphical data generated for another or an unknown solid 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.

As used herein, the term “amorphous” refers to a solid-state form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern with reflections.

The terms “anhydrous form” or “anhydrate” as used herein refer to a crystalline solid where no water is cooperated in or accommodated by the crystal structure. Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

The term “hydrate” as used herein, refers to a crystalline solid where either water is cooperated in or accommodated by the crystal structure e.g. is part of the crystal structure or entrapped into the crystal (water inclusions). Thereby, water can be present in a stoichiometric or non- stoichiometric amount. When water is present in stoichiometric amount, the hydrate may be referred to by adding greek numeral prefixes. For example, a hydrate may be referred to as a hemihydrate or as a monohydrate depending on the water/compound stoichiometry. The water content can be measured, for example, by Karl-Fischer-Coulometry. As used herein, the term “mother liquor” refers to the solution remaining after crystallization of a solid from said solution.

The term “pharmaceutically acceptable excipient” as used herein refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient.

BRIEF DESCRIPTION OF THE FIGURE

Figure 1: illustrates a representative PXRD of Form 1 of risdiplam 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a crystalline form of risdiplam, herein also designated as “Form 1”.

Crystalline Form 1 of risdiplam of the present invention 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, FTIR spectroscopy, DSC; TGA and GMS. Risdiplam Form 1 of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, Form 1 of risdiplam of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

In one embodiment the invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of:

(7.5 ± 0.2)°, (13.1 ± 0.2)° and (26.2 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)° and (26.2 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)° and (26.2 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ±

0.2)°; or

(7.5 ± 0.2)°, (12.3± 0.2)°, (13.1 ± 0.2)°, (13.7 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ± 0.2)°; or

(7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (13.7 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (19.4 ± 0.2)°, (21.5 ± 0.2)° and (26.2 ± 0.2)°; or (7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (13.7 ± 0.2)°, (14.5 ± 0.2)°, (15.1 ± 0.2)°, (16.4 ± 0.2)°, (19.4 ± 0.2)°, (21.5± 0.2)° and (26.2 ± 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.

In another embodiment, the invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of (7.5 ± 0.2)°, (12.3 ± 0.2)°, (13.1 ± 0.2)°, (14.5 ± 0.2)°, (16.4 ± 0.2)°, (17.0 ± 0.2)°, (18.5 ± 0.2)°, (19.4 ± 0.2)°, (19.8 ± 0.2)° and (26.2 ± 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.

In a further embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of: (7.5 ± 0.1)°, (13.1 ± 0.1)° and (26.2 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)° and (26.2 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)° and (26.2 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ±

0.1)°; or

(7.5 ± 0.1)°, (12.3± 0.1)°, (13.1 ± 0.1)°, (13.7 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (13.7 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (19.4 ± 0.1)°, (21.5 ± 0.1)° and (26.2 ± 0.1)°; or

(7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (13.7 ± 0.1)°, (14.5 ± 0.1)°, (15.1 ± 0.1)°, (16.4 ± 0.1)°, (19.4 ± 0.1)°, (21.5± 0.1)° and (26.2 ± 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 yet another embodiment, the invention relates to a crystalline form (Form 1) of risdiplam characterized by having a PXRD comprising reflections at 2-Theta angles of (7.5 ± 0.1)°, (12.3 ± 0.1)°, (13.1 ± 0.1)°, (14.5 ± 0.1)°, (16.4 ± 0.1)°, (17.0 ± 0.1)°, (18.5 ± 0.1)°, (19.4 ± 0.1)°, (19.8 ± 0.1)° and (26.2 ± 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 PXRD of risdiplam Form 1 of the present invention can be readily distinguished from the PXRDs of risdiplam Form A, Form B, Form C, Form D, Form E, Form F and Form G of WO 2019/075108 Al, since in contrast to Forms A to G, the PXRD of Form 1 shows no reflections at or below (7.0 ± 0.2)° 2-Theta.

Hence, in one embodiment the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (7.0 ± 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.

For example, the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (6.9 ± 0.2)°, (6.8 ± 0.2)°, (6.7 ± 0.2)°, (6.6 ± 0.2)°, (6.5 ± 0.2)°, (6.4 ± 0.2)°, (6.3 ± 0.2)°, (6.2 ± 0.2)°, (6.1 ± 0.2)°, (6.0 ± 0.2)°, (5.9 ± 0.2)°, (5.8 ± 0.2)°, (5.7 ± 0.2)°, (5.6 ± 0.2)°, (5.5 ± 0.2)°, (5.4 ± 0.2)°, (5.3 ± 0.2)°, (5.2 ± 0.2)°, (5.1 ± 0.2)° and (5.0 ± 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.

In a particular preferred embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.5 ± 0.2)°, (13.1 ± 0.2)° and (26.2 ± 0.2)°, but comprising no reflection at 2-Theta angles of or below (7.0 ± 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.

In another embodiment the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (7.0 ± 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.

For example, the present invention relates to a crystalline form (Form 1) of risdiplam as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflection at 2-Theta angles of or below (6.9 ± 0.1)°, (6.8 ± 0.1)°, (6.7 ± 0.1)°, (6.6 ± 0.1)°, (6.5 ± 0.1)°, (6.4 ± 0.1)°, (6.3 ± 0.1)°, (6.2 ± 0.1)°, (6.1 ± 0.1)°, (6.0 ± 0.1)°, (5.9 ± 0.1)°, (5.8 ± 0.1)°, (5.7 ± 0.1)°, (5.6 ± 0.1)°, (5.5 ± 0.1)°, (5.4 ± 0.1)°, (5.3 ± 0.1)°, (5.2 ± 0.1)°, (5.1 ± 0.1)° and (5.0 ± 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 a preferred embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam characterized by having a powder X-ray diffractogram comprising reflections at 2- Theta angles of (7.5 ± 0.1)°, (13.1 ± 0.1)° and (26.2 ± 0.1)°, but comprising no reflection at 2- Theta angles of or below (7.0 ± 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 yet another embodiment, the present invention relates to a crystalline form (Form 1) of risdiplam 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.

In another aspect, the present invention relates to a process for the preparation of the crystalline form of risdiplam (Form 1) of the present invention as defined in the above described aspect and its corresponding embodiments comprising:

(a) providing risdiplam dihydrochloride;

(b) treating the risdiplam dihydrochloride provided in (a) with an amine base in the presence of a solvent comprising methanol;

(c) crystallizing risdiplam from the mixture obtained in (b);

(d) separating at least a part of the crystals obtained in (c) from the mother liquor;

(e) optionally, washing the isolated crystals obtained in (d); and

(f) drying the crystals obtained in (d) or (e);

In one embodiment, the amine base in step (b) is selected from the group consisting of ammonia, benethamine, benzathine, tert-butylamine, diethanolamine, diethylamine, epolamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, glucamine, hydrabamine, imidazole, meglumine, morpholine, piperazine, pyrrolidine, triethanolamine, triethylamine and tromethamine. In a preferred embodiment the amine base is selected from the group consisting of tert-butylamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, triethanolamine, triethylamine and tromethamine, most preferably the amine base is triethylamine. In another embodiment, the amine base is used in an amount of from 1.5 to 5.0 mol equivalent, preferably of from 1.8 to 2.2 mol equivalent such as 2.0 mol equivalent, based on the amount of risdiplam dihydrochloride.

In a further embodiment, the crystals are separated in step (d) from their 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. In still another embodiment, the crystals are dried in step (f) at a temperature of about 60°C or less, preferably of about 40°C or less.

In a further aspect, the present invention relates to the use of the crystalline form of risdiplam (Form 1) of the present invention as defined in the above described aspect and its corresponding embodiments for the preparation of a pharmaceutical composition.

Furthermore, the present invention relates to a pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention and at least one pharmaceutically acceptable excipient.

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 one or more diluent, acidifyer, preservative, antioxidant, stabilizer, lubricant, sweetener, flavoring agent and combinations thereof.

In one embodiment, the diluent is mannitol and/or isomalt. In another embodiment, the acidifyer is tartaric acid. In still another embodiment, the preservative is sodium benzoate. In a further embodiment the antioxidant is ascorbic acid. In an additional embodiment, the lubricant is polyethylene glycol. In another embodiment, the sweetener is sucralose. In a further embodiment the flavoring agent is a strawberry flavour.

Preferably, the pharmaceutical composition of the present invention as defined in any one of the above described embodiments is an oral solid dosage form, more preferably a powder for oral solution.

In a further aspect, the present invention relates to the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention for use as a medicament.

In still a further aspect, the present invention relates to the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention for use in the treatment of spinal muscular atrophy (SMA).

In another aspect, the present invention relates to a method of treating spinal muscular atrophy (SMA) said method comprising administering an effective amount of the crystalline form of risdiplam (Form 1) of the present invention or the pharmaceutical composition comprising the crystalline form of risdiplam (Form 1) of the present invention to a patient in need of such a treatment.

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.

Example 1: Preparation of risdiplam Form 1

Risdiplam dihydrochloride (5.00 g, prepared by treating either risdiplam free base or a Boc- protected precursor as described in Example 11 of WO 2019/057740 Al with hydrochloric acid in a solvent or solvent mixture) was suspended in methanol (70 mL) at room temperature. Triethylamine (4.3 mL, 3 mol eqivalents) was added and the suspension was stirred at room temperature for 4 hours. Subsequently, the crystals were collected by filtration and dried for 17 hours at 40°C under vacuum (5 mbar).

Yield: 3.86 g (91% of theory)

Example 2: Powder X-ray diffraction

Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-theta with 40s per step (255 channels) in the angular range of 2° to 40° 2-Theta at ambient conditions. A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta.

The reflection list of crystalline Form 1 of risdiplam of the present invention is provided in Table 1 below. Table 1: Reflection positions of crystalline Form 1 of risdiplam 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.

Example 3: Powder blend for the preparation of an oral solution of risdiplam at a concentration of 0.75 mg/mL in a bottle containing 80 mL solution The formulation process comprises dry granulation by roller compaction. The composition of

Table 2 is used to constitute oral solutions with water to obtain 80 mL solution.

Table 2: Powder blend comprising risdiplam Form 1 of the present invention

Example 4: Powder blend for the preparation of an oral solution of risdiplam at a concentration of 0.75 mg/mL in a bottle containing 80 mL solution The formulation process comprises dry granulation by roller compaction. The composition of Table 3 is used to constitute oral solutions with water to obtain 80 mL solution.

Table 3: Powder blend comprising risdiplam Form 1 of the present invention