WO2022013052A1

WO2022013052A1 - Compounds comprising voxelotor and 2,5-dihydroxybenzoic acid and crystal forms

Info

Publication number: WO2022013052A1
Application number: PCT/EP2021/068981
Authority: WO
Inventors: Nolwenn Martin; Marijan STEFINOVIC; Ulrich Griesser; Kristina VILUSIC; Dennis Dimo ENKELMANN; Doris Braun
Original assignee: Sandoz Ag
Priority date: 2020-07-15
Filing date: 2021-07-08
Publication date: 2022-01-20

Abstract

The present invention relates to compounds comprising 2-hydroxy-6-((2-(1-isopropyl-1H- pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (INN: voxelotor) and 2,5-dihydroxybenzoic acid and to crystalline forms thereof. Also provided are processes of producing said compounds and their crystalline forms. Furthermore, the invention relates to a pharmaceutical composition comprising the compounds of the present invention, preferably crystalline forms thereof, 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 sickle cell disease.

Description

COMPOUNDS COMPRISING VOXELOTOR AND 2,5- DIHYDROXYBENZOIC ACID AND CRYSTAL FORMS

FIELD OF THE INVENTION

The present invention relates to compounds comprising 2-hydroxy-6-((2-(l -isopropyl- \H- pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (INN: voxelotor) and 2,5-dihydroxybenzoic acid and to crystalline forms thereof. Also provided are processes of producing said compounds and their crystalline forms. Furthermore, the invention relates to a pharmaceutical composition comprising the compounds of the present invention, preferably crystalline forms thereof, 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 sickle cell disease.

BACKGROUND OF THE INVENTION

Voxelotor is an orally bioavailable modulator and stabilizer of sickle cell hemoglobin (HbS), useful in the treatment of sickle cell disease (SCD). Upon administration, voxelotor targets and covalently binds to the L -ter inal valine of the alpha chain of HbS. This stabilizes HbS, thereby improving oxygen binding affinity. The binding of voxelotor to HbS prevents HbS polymerization, reduces sickling, decreases red blood cell (RBC) damage and increases the half-life of RBCs. This improves blood flow and decreases hemolytic anemia.

Voxelotor is chemically designated as 2-hydroxy-6-((2-( l -isopropyl- l//-pyrazol-5-yl)pyridin- 3-yl)methoxy)benzaldehyde and can be represented by the chemical structure as depicted in Formula (I)

WO 2013/102142 A1 discloses substituted benzaldehyde compounds used for increasing tissues oxygenation, including voxelotor (compound 43). Examples 17 and 18 describe the synthesis of voxelotor, which is isolated after chromatographic purification as a pale yellow oil or a pale yellow solid, respectively, and is characterized by NMR spectroscopy and mass spectrometry. No further data regarding solid state are given.

WO 2015/120133 A1 discloses crystalline forms of voxelotor (free base) and more particularly the crystalline free base ansolvate forms designated as Form I, Form II and Material N, as well as the crystalline free base solvates designated as Material E, Material F, Material G, Material H, Material J, Material K, Material L, Material M, Material O and Material P.

WO 2015/031285 A1 discloses voxelotor hydrochloride salt forms I, II and III.

Different solid-state forms of an active pharmaceutical ingredient (API) often possess different physical and chemical properties such as but not limited to dissolution rate, solubility, chemical stability, physical stability, hygroscopicity, melting point, morphology, flowability, bulk density and compressibility. 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 API. Also processing or handling of an API during the formulation process may be improved. New solid-state forms of an API 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-state forms.

Apart from conventional polymorphs, multi-component crystals such as hydrates, solvates, salts and co-crystals open up further opportunities for customizing the physicochemical properties of APIs with a process or clinical need. For example, they can be tailored to enhance drug product bioavailability and stability and to enhance the processability of APIs during drug product manufacture.

However, the solvates disclosed in WO 2015/120133 A1 (i.e. Material E, Material F, Material G, Material H, Material J, Material K, Material L, Material M, Material O and Material P) are highly unstable and already desolvate to the crystalline free base ansolvate forms when subjected to vacuum conditions as indicated in WO 2015/120133 Al, paragraph [0032] Hence, while the solvates of WO 2015/120133 Al may be used e.g. as intermediates for the preparation of the free base ansolvate forms of voxelotor, they are not appropriate for the preparation of an oral solid dosage form, since changes in the solid-state of the active pharmaceutical ingredient during pharmaceutical processing or storage can have severe consequences with regard to safety and efficacy of the drug product.

WO 2015/031285 A1 mentions on page 19, paragraph [0075] that voxelotor hydrochloride Form II and III are unstable and convert to either voxelotor hydrochloride Form I or a mixture of Form I and voxelotor free base already at ambient conditions. In addition, the inventors of the present invention have found that also Form I of voxelotor HC1 is unstable when subjected to moisture and/or temperature stress. For example, Form I of voxelotor HC1 is unstable when subjected to accelerated stress conditions of 40°C/75% relative humidity and partially disproportionates to the free base (see Comparative Example 1 of the present invention). Similar disproportionation was observed when Form 1 of the HC1 salt was subjected to humidity during a gravimetric moisture sorption experiment.

It is thus an objective of the present invention to provide improved solid-state forms of voxelotor, in particular stable forms which can be reliably formulated into an oral solid dosage form and which preserve their crystal structure and thus their physicochemical properties over the whole shelf-life of the drug product.

SUMMARY OF THE INVENTION

The inventors of the present invention have surprisingly found that under very specific conditions and when applying a particular coformer, voxelotor can form multi -component compounds, which have improved properties relevant for pharmaceutical purposes. In particular the inventors of the present invention have identified multi -component compounds comprising voxelotor and 2,5-dihydroxybenzoic acid in different stoichiometric ratios of about 2: 1 and 1: 1 (voxelotor: 2,5-dihydroxybenzoic acid), respectively. In particular, the invention relates to a crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid at a stoichiometric ratio of about 2: 1 (voxelotor: 2,5-dihydroxybenzoic acid), which is hereinafter also designated as “form 1”. Moreover, the present invention relates to a crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid at a stoichiometric ratio of about 1: 1 (voxelotor: 2,5-dihydroxybenzoic acid), which is hereinafter also designated as “form 2”.

The compounds and crystalline forms of the present invention possess one or more unexpected improved physicochemical properties selected from the group consisting of dissolution rate, solubility, chemical stability, physical stability, chemical purity, residual solvent content, hygroscopicity, melting point, morphology, flowability, wettability, bulk density and compressibility.

In particular, the compounds of the present invention and their crystalline forms 1 and 2 possess high melting points with onset temperatures of about 125°C and 119°C (see Example 4, Figure 2 and Figure 7), show low residual solvent contents (see Example 5, Figure 3 and Figure 8) exhibit high crystallinity (see Example 3, Figure 1 and Figure 6), are non-hygroscopic or at maximum slightly hygroscopic and show no hysteresis between their sorption and desorption curves during a gravimetric moisture sorption experiment (see Example 6, Figure 4). In addition, they show improved stability and preserve their crystal structures even when subjected to conditions such as temperature and moisture stress (see Comparative Example 1 and Comparative Example 2).

Abbreviations

PXRD powder X-ray diffractogram

DSC differential scanning calorimetry

TGA thermogravimetric analysis

GMS gravimetric moisture sorption

NMR nuclear magnetic resonance

RT room temperature

RH relative humidity

API active pharmaceutical ingredient 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.

The term “voxelotor” as used herein refers to the compound having the chemical name 2- hydroxy-6-((2-( 1 -isopropyl- l//-pyrazol-5-yl )pyri din-3 -yl)methoxy)benzaldehyde and the chemical structure as depicted in Formula (I) disclosed herein above. The term “co-crystal” as used herein refers to crystalline materials composed of two or more different molecular and/or ionic compounds in the same crystal lattice that are associated by nonionic and noncovalent bonds, wherein at least two of the individual molecular and/or ionic compounds are solids at room temperature. Unlike salts, the components of co-crystals are in a neutral state and interact nonionically.

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 20-50% relative humidity.

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 9.2° 2-Theta for example can appear between 9.0° and 9.4° 2-Theta, preferably between 9.1 and 9.3° 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 term “solid-state form” as used herein refers to any crystalline and/or amorphous phase of a compound. Crystalline phases may include anhydrous/non-solvated forms, hydrates, solvates, salts and co-crystals of a compound as well as any mixtures thereof.

The term “anhydrous” as used herein refers 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 “non-solvated” as used herein, when talking about a crystalline solid indicates that no organic solvent is cooperated in or accommodated by the crystal structure. Non-solvated forms may still contain residual organic solvents, which are not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

The term “non-hygroscopic” as used herein refers to a compound showing a water uptake of at most 0.2 w-% in the sorption cycle when measured with GMS at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1) °C, based on the weight of the compound.

The term “slightly hygroscopic” as used herein refers to a compound showing a water uptake in the range of from 0.3 to 2.0 w-% in the sorption cycle when measured with GMS at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1) °C, based on the weight of the compound.

The crystalline forms comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1 and form 2) of the present invention may be referred 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 positions and 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.

As used herein, the term “mother liquor” refers to the solution remaining after crystallization of a solid from said solution. The term “anti -solvents” as used herein refers to liquids which reduce the solubility of a compound in a solvent.

A “predetermined amount” as used herein with regard to the voxelotor compounds and their crystalline forms of the present invention refers to the initial amount of the voxelotor compounds and their crystalline forms used for the preparation of a pharmaceutical composition having a desired dosage strength of voxelotor.

As used herein, the term “effective amount” in conjunction with the voxelotor compounds and their crystalline forms of the present invention encompasses an amount of the voxelotor compounds and their crystalline forms of the present invention which causes the desired therapeutic 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.

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. Excipients may take the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, wetting agent, stabilizer or a manufacturing aid among others.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: illustrates a representative PXRD of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) according to 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 DSC curve of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 3: illustrates a representative TGA curve of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) according to 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 4: illustrates representative GMS isotherms of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention in the range of from 0 to 90% 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 weight percent (w-%). The sorption cycles are marked by triangles, whereas the desorption cycles are marked by squares. The sample weight at 0% relative humidity at the end of the desorption cycle was set as reference weight.

Figure 5: illustrates the single crystal structure of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention.

Figure 6: illustrates a representative PXRD of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) according to 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 7: illustrates a representative DSC curve of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 8: illustrates a representative TGA curve of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) according to 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-%).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds comprising voxelotor and 2,5-dihydroxybenzoic acid having different stoichiometric ratios of 2: 1 and 1: 1 (voxelotor: 2,5-dihydroxybenzoic acid) and to crystalline forms thereof, hereinafter also designated as “form 1” and “form 2”.

Compound comprising voxelotor and 2,5-dihydroxybenzoic acid at a stoichiometric ratio of about 2: 1, a crystalline form 1 thereof, compositions comprising the same and a method for its preparation In a first aspect, the present invention relates to a compound comprising voxelotor and 2,5- dihydroxybenzoic acid characterized by having the chemical structure as depicted in Formula (P)

Formula (II), wherein n is in the range of from 0.3 to 0.7, preferably in the range of from 0.4 to 0.6, more preferably in the range of from 0.45 to 0.55 and most preferably n is about 0.5. For example, n is selected from the group consisting of about 0.3, 0.4, 0.45, 0.5, 0.55, 0.6 and 0.7.

In a preferred embodiment, the compound of the present invention as defined above is crystalline. More preferably, the compound is a co-crystal, a salt or a mixture of a co-crystal and a salt and most preferably the compound is a co-crystal.

In one embodiment the present invention relates to a crystalline form of a compound comprising 2-hydroxy-6-((2-( 1 -isopropyl- l//-pyrazol-5-yl )pyri din-3 -yl)methoxy)benzaldehyde (voxelotor) and 2,5-dihydroxybenzoic acid as defined in the above described aspect and its corresponding embodiments hereinafter also designated as “form 1”.

The crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing crystalline solids. Such methods comprise but are not limited to powder X-ray diffraction, single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and gravimetric moisture sorption. The crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (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, the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) 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 a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) characterized by having a PXRD comprising reflections at 2- Theta angles of:

(9.2 ± 0.2)°, (11.0 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ±

0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (22.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (18.6 ± 0.2)°, (22.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (18.6 ± 0.2)°, (19.4 ± 0.2)°, (22.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (18.6 ± 0.2)°, (19.4 ± 0.2)°, (19.9 ± 0.2)°, (22.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 0.2)°; or

(9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (18.6 ± 0.2)°, (19.4 ± 0.2)°, (19.9 ± 0.2)°, (20.4 ± 0.2)°, (22.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 0.2)°; or (9.2 ± 0.2)°, (11.0 ± 0.2)°, (11.8 ± 0.2)°, (13.0 ± 0.2)°, (13.3 ± 0.2)°, (18.6 ± 0.2)°, (19.4 ± 0.2)°, (19.9 ± 0.2)°, (20.4 ± 0.2)°, (21.1 ± 0.2)°, (22.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 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 a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) characterized by having a PXRD comprising reflections at 2- Theta angles of:

(9.2 ± 0.1)°, (11.0 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (13.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ±

0.1)°; or (9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (13.3 ± 0.1)°, (22.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (13.3 ± 0.1)°, (18.6 ± 0.1)°, (22.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (13.3 ± 0.1)°, (18.6 ± 0.1)°, (19.4 ± 0.1)°, (22.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (13.3 ± 0.1)°, (18.6 ± 0.1)°, (19.4 ± 0.1)°, (19.9 ± 0.1)°, (22.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 0.1)°; or

(9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (13.3 ± 0.1)°, (18.6 ± 0.1)°, (19.4 ± 0.1)°, (19.9 ± 0.1)°, (20.4 ± 0.1)°, (22.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 0.1)°; or (9.2 ± 0.1)°, (11.0 ± 0.1)°, (11.8 ± 0.1)°, (13.0 ± 0.1)°, (13.3 ± 0.1)°, (18.6 ± 0.1)°, (19.4 ± 0.1)°, (19.9 ± 0.1)°, (20.4 ± 0.1)°, (21.1 ± 0.1)°, (22.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 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 a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) characterized by having a PXRD comprising reflections at 2- Theta angles of (9.2 ± 0.2)°, (11.0 ± 0.2)°, (13.0 ± 0.2)°, (14.9 ± 0.2)°, (15.0 ± 0.2)°, (17.9 ±

0.2)°, (18.6 ± 0.2)°, (22.3 ± 0.2)°, (26.1 ± 0.2)° and (26.5 ± 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 a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) characterized by having a PXRD comprising reflections at 2- Theta angles of (9.2 ± 0.1)°, (11.0 ± 0.1)°, (13.0 ± 0.1)°, (14.9 ± 0.1)°, (15.0 ± 0.1)°, (17.9 ±

0.1)°, (18.6 ± 0.1)°, (22.3 ± 0.1)°, (26.1 ± 0.1)° and (26.5 ± 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 a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) 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. Furthermore, the present invention relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (125 ± 5)°C, preferably of (125 ± 3)°C, even more preferably of (125 ± 2)°C and most preferably of (125 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (126 ± 5)°C, preferably of (126 ± 3)°C, even more preferably of (126 ± 2)°C and most preferably of (126 ± 1)°C, when measured a heating rate of 10 K/min.

In still another embodiment, the invention relates to a crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1), characterized by having a melting point onset at a temperature of (125 ± 5) °C, preferably of (125 ± 3) °C, more preferably of (125 ± 2)°C, even more preferably of (125 ± 1)°C, for example having a melting point onset at a temperature of about 125 °C, when measured with DSC at a heating rate of 10 K/min.

In another embodiment, the present invention relates to a crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1), characterized by having a TGA curve showing a mass loss of not more than 0.5 w-%, preferably of not more than 0.4 w-%, more preferably of not more than 0.3 w-%, 0.2 w-% or 0.1 w-%, based on the weight of the crystalline form, when heated from 25 to 130°C at a rate of 10 K/min.

Preferably, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention as defined in any one of the above described embodiments is anhydrous.

Even more preferably, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention as defined in any one of the above defined embodiments is non-solvated.

In one embodiment, the present invention relates to a crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) characterized by showing a mass change of not more than 0.2 w-%, preferably of not more than 0.1 w-%, based on the weight of the crystalline form, when measured with GMS at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 0.1)°C. Preferably, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention as defined in any one of the above described embodiments is non- hygroscopic.

Moreover, the present invention relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) characterized by exhibiting a tri clinic unit cell having space group RΪ. Preferably, the unit cell has the following parameters: a = 12.0868 Angstrom b = 13.3385 Angstrom c = 15.5423 Angstrom alpha = 68.426° beta = 67.355° gamma = 65.159 ° when measured with single crystal X-ray diffraction at 193 K with Mo radiation having a wavelength of 0.71073 Angstrom.

In another aspect, the present invention relates to a composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention as defined in any one of the above described embodiments, said composition being essentially free of any other solid-state form of voxelotor. For example, a composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5 w- %, 4 w-%, 3 w-%, 2 w-% or 1 w-% of any other solid-state form of voxelotor, based on the weight of the composition. Preferably, the any other solid-state form of voxelotor is selected from the group consisting of voxelotor free base Form I, Form II and Material N of WO 2015/120133 Al. Form I, Form II and Material N of voxelotor free base have PXRDs comprising amongst others characteristic reflections at 2-Theta angles of (5.5 ± 0.2)° (Form I) and (5.6 ± 0.2)° (Form II and Material N), respectively. Therefore, the absence of reflections at 2-Theta angles of (5.5 ± 0.2)° and (5.6 ± 0.2)° in the PXRD confirms the absence of voxelotor Form I, Form II and Material N in the composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention. Even more preferably, the any other solid-state form of voxelotor is the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention. Form 2 of the present invention has a PXRD comprising amongst others a characteristic reflection at a 2- Theta angle of (6.0 ± 0.2)°. Therefore, the absence of reflections at a 2-Theta angle of (6.0 ± 0.2)° in the PXRD confirms the absence of the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) of the present invention in the composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention.

Hence, in a preferred embodiment, the present invention relates to a composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention as defined in any one of the above described embodiments, said composition having a PXRD comprising no reflections at 2-Theta angles of (5.5 ± 0.2)°, (5.6 ± 0.2)° and (6.0 ± 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 further aspect, the present invention relates to a process for the preparation of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid, in particular of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) or the composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) as defined in any one of the above described aspects and their corresponding embodiments comprising:

(a) providing a solution comprising voxelotor, 2,5-dihydroxybenzoic acid and a solvent selected from «-butanol and/or «-butyl acetate;

(b) optionally filtering the solution obtained in (a) in order to remove any undissolved solid;

(c) optionally adding seed crystals comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention;

(d) crystallizing the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention from the solution obtained in (a) or (b) or from the mixture obtained in (c);

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

(f) optionally washing the isolated crystals in (e); and

(g) drying the crystals obtained in any one of steps (d) to (f).

Voxelotor free base can for example be prepared according to the procedures provided in Examples 17 and 18 of WO 2013/102142 A1 or according to the procedures disclosed in WO 2015/120133 Al, all of these douments are being herewith incorporated by reference. Voxelotor, which is used as starting material in step (a) of the above described process, may be applied as crystalline and/or amorphous material. Crystalline forms, which may be applied are, e.g. selected from the group consisting of Form I, Form II and Material N of WO 2015/120133 A1 or any mixtures thereof. Voxelotor may also be provided as any one of the crystalline solvates reported in WO 2015/120133 A1 or any mixtures thereof.

In a first step of the above described process a solution comprising voxelotor free base, 2,5- dihydroxybenzoic acid and a solvent comprising «-butanol or «-butyl acetate is provided. The applied voxelotor concentration in step (a) of the above described process may be in the range of from about 50 to 500 g/L, preferably of from about 100 to 400 g/L. The molar ratio of voxelotor and 2,5-dihydroxybenzoic acid is preferably in the range of from about 3.0: 1.0 to 1.0: 3.0, more preferably in the range of from about 1.0: 0.5 to 1.0: 1.5 (voxelotor: 2,5- dihydroxybenzoic acid). Dissolution may optionally be accelerated by increasing the temperature of the mixture provided in step (a) to a range of from about 40 to 90°C, more preferably of from 50 to 80°C. Optionally, sonication may be applied to facilitate dissolution.

In order to initiate crystallization the solution is stirred, e.g. at a temperature in the range of from 15 to 70°C, preferably in the range of from 20 to 50°C, typically for a period in the range of from 0.5 to 24 hours. Optionally, seed crystals comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) are added in order to promote crystallization and/or to control particle size distribution. The amount of seed crystals employed may be in the range of from about 1 to 20 w-%, preferably of from about 1 to 10 w-% and most preferably of from about 1 to 5 w-%, based on the weight of the applied voxelotor starting material. Seed crystals may be prepared according to any one of Examples 1-1 to 1-7 hereinafter.

After crystallization, the mixture can optionally be cooled to a temperature in the range from 0 to 20°C, preferably in the range of from 5 to 15°C and/or one or more anti-solvents can be added to the mixture to increase the process yield. Regarding anti -solvents, no specific restrictions exist, provided that the solubility of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention is decreased by the addition of the antisolvent and that form 1 is stable.

Once the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) is obtained or preferably obtained in essentially pure form, at least a part of the crystals is separated from the mother liquor. Preferably, the crystals are separated 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. Optionally, in a further step the isolated crystals are washed with a suitable solvent. Suitable solvents may comprise but are not limited to «-butanol, «-butyl acetate, «-heptane, diethyl ether or any mixtures thereof.

In a final step, the obtained crystals are dried. Drying may be performed at a temperature in the range of from about 20 to 80°C, preferably in the range of from about 20 to 60°C and most preferably in the range of from 20 to 40°C. Drying may be performed for a period in the range of from about 1 to 72 hours, preferably of from about 2 to 48 hours, more preferably of from about 2 to 30 hours and most preferably of from about 3 to 24 hours. Drying may be performed at ambient pressure and/ or under reduced pressure. Preferably, drying is performed at a pressure of about 100 mbar or less, more preferably of about 50 mbar or less, for example a vacuum in the range of from about 10 to 30 mbar is applied.

Compound comprising voxelotor and 2,5-dihydroxybenzoic acid at a stoichiometric ratio of about 1: 1, a crystalline form 2 thereof and compositions comprising the same

In a further aspect, the present invention relates to a compound comprising voxelotor and 2,5- dihydroxybenzoic acid characterized by having the chemical structure as depicted in Formula (P)

Formula (II). wherein n is in the range of from 0.8 to 1.2, preferably in the range of from 0.9 to 1.1, 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 0.8, 0.9, 0.95, 1.0, 1.05, 1.1 and 1.2.

In a preferred embodiment, the compound of the present invention as defined above is crystalline. More preferably, the compound is a co-crystal, a salt or a mixture of a co-crystal and a salt and most preferably the compound is a co-crystal. In one embodiment the present invention relates to a crystalline form of a compound comprising 2-hydroxy-6-((2-( 1 -isopropyl - l//-pyrazol-5-yl )pyri din-3 -yl)methoxy)benzaldehyde (voxelotor) and 2,5-dihydroxybenzoic acid as defined in the above described aspect and its corresponding embodiments hereinafter also designated as “form 2”.

The crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing crystalline solids. Such methods comprise but are not limited to powder X-ray diffraction, single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and gravimetric moisture sorption. The crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) 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 a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) characterized by having a PXRD comprising reflections at 2- Theta angles of:

(6.0 ± 0.2)°, (7.9 ± 0.2)° and (12.1 ± 0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)° and (14.8 ± 0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)° and (14.8 ± 0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)°, (14.0 ± 0.2)° and (14.8 ± 0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)°, (14.0 ± 0.2)°, (14.8 ± 0.2)° and (15.9 ±

0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)°, (14.0 ± 0.2)°, (14.8 ± 0.2)°, (15.9 ± 0.2)° and (25.1 ± 0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)°, (14.0 ± 0.2)°, (14.8 ± 0.2)°, (15.9 ± 0.2)°, (23.0 ± 0.2)° and (25.1 ± 0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)°, (14.0 ± 0.2)°, (14.8 ± 0.2)°, (15.9 ± 0.2)°, (18.1 ± 0.2)°, (23.0 ± 0.2)° and (25.1 ± 0.2)°; or

(6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)°, (14.0 ± 0.2)°, (14.8 ± 0.2)°, (15.9 ± 0.2)°, (17.6 ± 0.2)°, (18.1 ± 0.2)°, (23.0 ± 0.2)° and (25.1 ± 0.2)°; or (6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (13.4 ± 0.2)°, (14.0 ± 0.2)°, (14.8 ± 0.2)°, (15.9 ± 0.2)°, (17.6 ± 0.2)°, (18.1 ± 0.2)°, (18.7 ± 0.2)°, (23.0 ± 0.2)° and (25.1 ± 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.

Alternatively, the present invention relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) characterized by having a PXRD comprising reflections at 2- Theta angles of:

(6.0 ± 0.1)°, (7.9 ± 0.1)° and (12.1 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)° and (14.8 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)° and (14.8 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)°, (14.0 ± 0.1)° and (14.8 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)°, (14.0 ± 0.1)°, (14.8 ± 0.1)° and (15.9 ±

0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)°, (14.0 ± 0.1)°, (14.8 ± 0.1)°, (15.9 ± 0.1)° and (25.1 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)°, (14.0 ± 0.1)°, (14.8 ± 0.1)°, (15.9 ± 0.1)°, (23.0 ± 0.1)° and (25.1 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)°, (14.0 ± 0.1)°, (14.8 ± 0.1)°, (15.9 ± 0.1)°, (18.1 ± 0.1)°, (23.0 ± 0.1)° and (25.1 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)°, (14.0 ± 0.1)°, (14.8 ± 0.1)°, (15.9 ± 0.1)°, (17.6 ± 0.1)°, (18.1 ± 0.1)°, (23.0 ± 0.1)° and (25.1 ± 0.1)°; or

(6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (13.4 ± 0.1)°, (14.0 ± 0.1)°, (14.8 ± 0.1)°, (15.9 ± 0.1)°, (17.6 ± 0.1)°, (18.1 ± 0.1)°, (18.7 ± 0.1)°, (23.0 ± 0.1)° and (25.1 ± 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 a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) characterized by having a PXRD comprising reflections at 2- Theta angles of (6.0 ± 0.2)°, (7.9 ± 0.2)°, (12.1 ± 0.2)°, (14.0 ± 0.2)°, (14.8 ± 0.2)°, (15.9 ± 0.2)°, (18.1 ± 0.2)°, (24.4 ± 0.2)°, (25.1 ± 0.2)° and (27.2 ± 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. Alternatively, the present invention relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) characterized by having a PXRD comprising reflections at 2- Theta angles of (6.0 ± 0.1)°, (7.9 ± 0.1)°, (12.1 ± 0.1)°, (14.0 ± 0.1)°, (14.8 ± 0.1)°, (15.9 ± 0.1)°, (18.1 ± 0.1)°, (24.4 ± 0.1)°, (25.1 ± 0.1)° and (27.2 ± 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 present invention also relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) characterized by having a PXRD essentially the same as shown in Figure 6 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.

Furthermore, the present invention relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) characterized by having a DSC curve comprising an endothermic peak having an onset at a temperature of (119 ± 5)°C, preferably of (119 ± 3)°C, even more preferably of (119 ± 2)°C and most preferably of (119 ± 1)°C, when measured at a heating rate of 10 K/min.

The present invention also relates to a crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) characterized by having a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (121 ± 5)°C, preferably of (121 ± 3)°C, even more preferably of (121 ± 2)°C and most preferably of (121 ± 1)°C, when measured a heating rate of 10 K/min.

In still another embodiment, the invention relates to a crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2), characterized by having a melting point onset at a temperature of (119 ± 5) °C, preferably of (119 ± 3) °C, more preferably of (119 ± 2)°C, even more preferably of (119 ± 1)°C, for example having a melting point onset at a temperature of about 119 °C, when measured with DSC at a heating rate of 10 K/min.

In another embodiment, the present invention relates to a crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2), characterized by having a TGA curve showing a mass loss of not more than 0.5 w-%, preferably of not more than 0.4 w-%, more preferably of not more than 0.3 w-%, 0.2 w-% or 0.1 w-%, based on the weight of the crystalline form, when heated from 25 to 130°C at a rate of 10 K/min. Preferably, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention is anhydrous.

Even more preferably, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention is non-solvated.

In another aspect, the present invention relates to a composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention as defined in any of the above described embodiments, said composition being essentially free of any other solid-state form of voxelotor. For example, a composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5 w-%, 4 w-%, 3 w-%, 2 w-% or 1 w-% of any other solid-state form of voxelotor, based on the weight of the composition. Preferably, the any other solid-state form of voxelotor is selected from the group consisting of voxelotor free base Form I, Form II and Material N of WO 2015/120133 Al. Even more preferably, the any other solid-state form of voxelotor is the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention. Form 1 has a PXRD comprising amongst others characteristic reflections at a 2-Theta angle of (9.2 ± 0.2)°. Therefore, the absence of reflections at a 2-Theta angles of (9.2 ± 0.2)° in the PXRD confirms the absence of the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention in the composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention.

Hence, in a preferred embodiment, the present invention relates to a composition comprising the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention as defined in any of the above described embodiments, said composition having a PXRD comprising no reflections at a 2-Theta angle of (9.2 ± 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.

Pharmaceutical compositions and medical use

In addition, the present invention relates to the use of the compounds comprising voxelotor and 2,5-dihydroxybenzoic acid, in particular the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) of the present invention, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention or the composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition.

Furthermore, the present invention relates to a pharmaceutical composition comprising the compounds comprising voxelotor and 2,5-dihydroxybenzoic acid, in particular the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention or the composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments, preferably in a predetermined and/or an effective amount, and at least one pharmaceutically acceptable excipient. Preferably, the predetermined and/or effective amount is in the range of from about 300 mg to about 1500 mg, more preferably of from about 300 to 900 mg and most preferably of from about 300 to 500 mg calculated as voxelotor free base. For example, the predetermined and/or effective amount is selected from the group consisting of 300 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg and 1500 mg calculated as voxelotor free base. Preferably, the predetermined and/or effective amount is selected from the group consisting of 300 mg, 450 mg, 500 mg, 900 mg and 1500 mg calculated as voxelotor free base. Most preferably, the predetermined and/or effective amount is 300 mg or 500 mg calculated as voxelotor free base.

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 (or diluents), disintegrants, lubricants, glidants, and combinations thereof. Most preferably, all of these pharmaceutically acceptable excipients are comprised by the pharmaceutical composition of the present invention. Optionally, the at least one pharmaceutically acceptable excipient may also comprise wetting agents and/or binders. 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 or an oral dispersible tablet. Most preferably, the pharmaceutical composition of the present invention is an immediate-release film-coated tablet. In a particular embodiment, the pharmaceutical composition of the present invention as describe above is a tablet, preferably a film-coated tablet, more preferably an immediate-release film- coated tablet comprising a tablet core and a coating.

The tablet or tablet core may be prepared by mixing the compounds comprising voxelotor and 2,5-dihydroxybenzoic acid of the present invention, in particular the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention or the composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments with at least one excipient selected from the group consisting of fillers, disintegrants, lubricants, glidants, or combinations thereof and optionally with at least one wetting agent and/or binder followed by compressing the mixture. Optionally, a dry granulation step is performed before compression. Preferably, the tablet core is subsequently coated with a film-coat, whereat non-limiting examples of coatings include polyvinylalcohol-based, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium polyethylene glycol 4000 and cellulose acetate phthalate coatings. Methods of preparing such tablets, tablet cores and film-coated tablets are well known in the pharmaceutical arts.

In another particular embodiment, the pharmaceutical composition of the present invention as describe above is a capsule. In a further embodiment, the capsule shell is a gelatin shell or a hydroxypropylmethylcellulose (HPMC) shell. The capsule may be prepared by mixing the compounds comprising voxelotor and 2,5-dihydroxybenzoic of the present invention, in particular the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention or the composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments with at least one excipient selected from the group consisting of fillers, disintegrants, lubricants, glidants, wetting agents or combinations thereof and optionally with at least one wetting agent and/or binder followed by filling the blend into the capsule. Optionally, a dry granulation step is performed before capsule filling. Alternatively, the capsule may be prepared by filling the neat compounds comprising voxelotor and 2,5-dihydroxybenzoic acid of the present invention, in particular the neat crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention, the neat crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) of the present invention or the neat composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments into the capsule.

In a further aspect, the present invention relates to the compounds comprising voxelotor and 2,5-dihydroxybenzoic acid of the present invention, in particular the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention or the composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.

In yet another aspect, the present invention relates to the compounds comprising voxelotor and 2,5-dihydroxybenzoic of the present invention, in particular the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention or the composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of sickle cell disease.

In another preferred embodiment, the invention concerns a method of treating sickle cell disease, said method comprising administering an effective amount of the compounds comprising voxelotor and 2,5-dihydroxybenzoic of the present invention, in particular the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 1) of the present invention, the crystalline form comprising voxelotor and 2,5-dihydroxybenzoic acid (form 2) of the present invention or the composition comprising form 1 or form 2 as defined in any one of the above described aspects and their corresponding embodiments 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 the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1

Example 1-1: To voxelotor free base (99.95 g, 0.30 mol) and 2,5-dihydroxybenzoic acid (41.30 g, 0.27 mol) warm (45-50°C) «-butanol (360 mL) was added. The mixture was stirred at a temperature of 55-60°C. Before all solids dissolved crystallization took place. The thus obtained suspension was further stirred at 55°C for 5 min, then cooled in 15 min to 25 °C, kept for 5 min at 25 °C and further cooled to 10°C in 90 min. The solid material was collected by filtration, washed with a mixture of //-butanol///-heptane (1.3: 1 volume/volume) and dried under vacuum (10 mbar, 40°C, 22 hours) to obtain 106.50 g (yield: 87% of theory) of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1.

Example 1-2:

To voxelotor free base (10.02 g, 29.7 mmol) and 2,5-dihydroxybenzoic acid (4.17 g, 27 mmol) warm (45-50°C) «-butanol (40 mL) was added. The mixture was stirred at a temperature of 55- 60°C leading to a clear solution. The thus obtained solution was cooled in 10-15 min to 25°C, whereupon a suspension was obtained. The suspension was further cooled to 10°C in 90 min. The solid material was collected by filtration, washed with cold «-butanol and dried under vacuum (10 mbar, 40°C, 15 hours) to obtain 10.83 g (yield: 88% of theory) of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1.

Example 1-3:

To voxelotor free base (276.4 mg, 0.82 mmol, mixture of Form I and Material N, e.g. prepared according to the procedure disclosed in WO 2015/120133 A1 in Example 8) and 2,5- dihydroxybenzoic acid (72.1 mg, 0.47 mmol) «-butanol (750 pL) was added. The mixture was heated to 60-80°C yielding a pale yellow solution. The solution was then allowed to cool to room temperature leading to the formation of a slurry within a few minutes of stirring. The mixture was further stirred for 3-4 hours and solvent was allowed to partially evaporate until a volume of about 200-300 mΐ remained. Afterwards, the solid material was collected by filtration, washed with a small amount of «-butanol and dried at room temperature under vacuum (about 10 mbar, 13 hours) to obtain 242.0 mg (yield: 71% of theory) of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1.

Example 1-4:

To voxelotor free base (185.2 mg, 0.55 mmol, Form II, e.g. prepared according to the procedure disclosed in WO 2015/120133 A1 in Example 17) and 2,5-dihydroxybenzoic acid (95.9 mg, 0.62 mmol) «-butanol (600 pL) was added. The mixture was heated to 60-80°C yielding a pale yellow solution. Warm «-heptane (300 pL) was added before the solution was allowed to cool to room temperature leading to the formation of a slurry within a few minutes of stirring. The mixture was further stirred for 3-4 hours at room temperature. Afterwards, the solid material was collected by filtration, washed with a small amount of an //-butanol///-heptane (3:2 volume/volume) mixture and dried at room temperature under vacuum (about 10 mbar, 15 hours) to obtain 196.6 mg (yield: 86% of theory) of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1.

Example 1-5:

To voxelotor free base (1002 mg, 2.97 mmol, Form I, e.g. prepared according to the procedure disclosed in WO 2015/120133 A1 in Example 8) and 2,5-dihydroxybenzoic acid (149 mg, 2.72 mmol) «-butanol (4 mL) was added. The mixture was heated to 70-75°C yielding a pale yellow solution. The solution was allowed to cool to room temperature and further stirred at room temperature leading to the formation of a slurry. Afterwards, the solid material was collected by filtration, washed with a small amount of an //-butanol///-heptane (1 :1 volume/volume) mixture and dried at room temperature under vacuum (about 10 mbar, 15 hours) followed by drying at a temperature of 40°C under vacuum (about 10 mbar, 40 minutes) to obtain 1025 mg (yield: 83% of theory) of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1.

Example 1-6:

To voxelotor free base (184.5 mg, 0.55 mmol, Form I, e.g. prepared according to the procedure disclosed in WO 2015/120133 A1 in Example 8) and 2,5-dihydroxybenzoic acid (49.3 mg, 0.32 mmol) «-butyl acetate (600 pL) was added. The mixture was heated to 60-80°C yielding a pale yellow solution. The solution was allowed to cool to room temperature and further stirred at room temperature leading to the formation of a slurry within a few minutes, which was further stirred for about 20 minutes. Afterwards, the solid material was collected by filtration, washed with a small amount of an «-butyl acetate and dried at a temperature of 40°C under vacuum (about 10 mbar, 14 hours) to obtain 175.0 mg (yield: 77% of theory) of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1.

Example 1-7:

To voxelotor free base (184.4 mg, 0.55 mmol, Form II, e.g. prepared according to the procedure disclosed in WO 2015/120133 A1 in Example 17) and 2,5-dihydroxybenzoic acid (48.3 mg, 0.31 mmol) «-butanol (600 pL) was added. The suspension was stirred at room temperature for 15 hours leading to the formation of a dense slurry. Afterwards, a mixture of «-butanol/«- heptane (1:1 volume/volume, 0.3 mL) was added. The suspension was further stirred for a few seconds before the solid material was collected by filtration, washed with a small amount of an //-butanol///-heptane (1:1 volume/volume) mixture and dried at a temperature of 40°C under vacuum (about 10 mbar, 4 hours) to obtain 171.0 mg (yield: 75% of theory) of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 1.

Example 2: Preparation of the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 2

Example 2-1:

To voxelotor (30 mg, 0.09 mmol, mixture of Form I and Material N, e.g. prepared according to the procedure disclosed in WO 2015/120133 A1 in Example 8) and 2,5-dihydroxybenzoic acid (13.7 mg, 0.09 mmol) diisopropyl ether (85 pL) was added. The obtained suspension was stirred under the following temperature conditions: 10 min at 10°C, 20 minutes heating to 25°C, 10 min at 25°C, 20 min cooling down to 10°C and repeating these heating and cooling steps for 43 hours. After about 2 hours, additional diisopropyl ether (2 x 85 pL) was added. After 43 hours, the solid material was collected by filtration, washed with a little amount of diisopropyl ether and dried at room temperature under vacuum (about 10 mbar) to yield the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 2.

Example 2-2:

To voxelotor free base (184.6 mg, 0.55 mmol, Form I, e.g. prepared according to the procedure disclosed in WO 2015/120133 A1 in Example 8) and 2,5-dihydroxybenzoic acid (93.22 mg, 0.60 mmol) «-butyl acetate (600 pL) was added. The mixture was heated to 60-80°C yielding a pale yellow solution. The solution was allowed to cool to room temperature and let stand at room temperature without stirring. After five days, no solid formation was observed. The sample was slightly open to allow solvent evaporation, yielding - after two days - a highly viscous solution. The sample was then closed again and further kept at room temperature. After several days, solid material was formed on the vial bottom. Afterwards, the solid material was collected by filtration, washed (first with a small amount of «-butyl acetate and then twice with a small amount of diethyl ether) and dried at a temperature of 40°C under vacuum (about 10 mbar, 5 hours) to yield the compound comprising voxelotor and 2,5-dihydroxybenzoic acid in crystalline form 2.

Example 3: 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.

A representative diffractogram of the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) according to the present invention is displayed in Figure 1 and the corresponding reflection list (peak list) from 2 to 30° 2-Theta is provided in Table 1 below.

Table 1: Reflection (peak) positions of the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 1) according to the present invention 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.

A representative diffractogram of the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) according to the present invention is displayed in Figure 6 and the corresponding reflection list (peak list) from 2 to 30° 2-Theta is provided in Table 2 below.

Table 2: Reflection (peak) positions of the crystalline form comprising voxelotor and 2,5- dihydroxybenzoic acid (form 2) according to the present invention 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 4: Differential scanning calorimetry DSC was performed on a Mettler Polymer DSC R instrument. The samples (4.80 mg form 1, 3.79 mg form 2) were each heated in a 40 microliter aluminium pan with a pierced aluminium lid from 25 to 250 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.

The DSC curves of form 1 (see Figure 2) and form 2 (see Figure 7) of the present invention both show no thermal events until a single sharp endothermic peak appears, which is due to melting of the samples. An overview of the DSC data is displayed in Table 3 below.

Table 3: Thermal events of form 1 and form 2 of the present invention in the DSC curves

Example 5: Thermogravimetric analysis

TGA was performed on a Mettler TGA/DSC 1 instrument. The samples (9.30 mg form 1, 10.00 mg form 2) were each weighed in a 100 microliter aluminum pan closed with an aluminum lid. The lid was automatically pierced at the beginning of the measurement. The samples were heated from 25 to 150 °C or 250 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas. The TGA curves of form 1 (see Figure 3) and form 2 (see Figure 8) of the present invention both show almost no weight loss until they melt. A summary of the TGA data is displayed in Table 4 below.

Example 6: Gravimetric moisture sorption

Moisture sorption isotherms were recorded with an SPSx-Im moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at ambient relative humidity (RH) of 30%. RH was then decreased to 5% in 5% steps, followed by a further decrease to 3% and to 0%. Afterwards RH was increased from 0% to 90% in a sorption cycle and subsequently decreased to 0 % in a desorption cycle each in 5% steps. Finally, RH was increased to ambient relative humidity of 30% in 5% steps. The time per step was set to a minimum of 2 hours and a maximum of 6 hours. If an equilibrium condition with a constant mass of ± 0.01% within 1 hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of 6 hours. If no equilibrium was achieved the consecutive humidity step was applied after the maximum time of 6 hours. The temperature was 25 ± 0.1 °C.

As can be seen from Figure 4 of the present invention the water uptake of form 1 in the sorption cycle between 0 and 90% is only about 0.1 w-%. Hence, form 1 of the present invention can be assigned as being non-hygroscopic. The sample still shows the same PXRD after the experiment.

Example 7: Single crystal X-ray diffraction

Intensity data were collected at 193 K, using Mo radiation (lambda = 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 F² 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 anisotropically. Hydrogen atoms bonded to C atoms were fixed in idealized positions and the thermal displacement parameters of the former were set to 1.2U_eq or 1.5U_eq (for methyl H atoms) of the parent C atom. H atoms bonded to O atoms were located in difference maps and refined using distance restraints, O-H = 0.84(2) A, and their thermal displacement parameters were refined freely.

The investigated form 1 crystal shows no intermolecular proton transfers and can be assigned as a co-crystal of voxelotor and 2,5-dihydroxybenzoic acid in a stoichiometric ratio of 2: 1 (voxelotor: 2,5-dihydroxybenzoic acid).

Comparative Example 1: Accelerated stress test

Form 1 of the present invention and voxelotor hydrochloride Form I of WO 2015/031285 A1 were open stored at accelerated stress conditions of 40°C and 75% RH for 1, 3 and 8 weeks, respectively. The PXRDs of the stressed samples have been compared with the initial PXRDs. The results are summarized in Table 5 below.

Table 5: Result of accelerated stress test

As can be seen from Table 5, form 1 of the present invention remained stable throughout the whole stress test, which was confirmed by the unchanged powder X-ray diffractogram.

In contrast, voxelotor hydrochloride Form I was not stable. It partially disproportionated or lost hydrochloric acid, leading to the formation of voxelotor free base (Form I). This result confirms the stability issues encountered with voxelotor hydrochloride at relevant stress conditions.

Comparative Example 2: Physical stability

The solvates disclosed in WO 2015/120133 A1 (i.e. Material E, Material F, Material G, Material H, Material J, Material K, Material L, Material M, Material O and Material P) are highly unstable and already desolvate to the crystalline free base ansolvate forms when subjected to vacuum conditions as indicated in WO 2015/120133 Al, paragraph [0032] Also, said ansolvate forms e.g. Form I (melting point onset ~ 97°C, see Figure 14 of WO 2015/120133 Al), Form II (melting point onset ~ 96°C, see Figure 13 of WO 2015/120133 Al) and Material N (mp onset ~ 94°C, see Figure 12 of WO 2015/120133 Al) disclosed in WO 2015/120133 Al are not very stable but all have melting points below 100°C and are therefore sensitive against temperature stress. In stark contrast the co-crystals of the present invention only melt at about 125°C (form 1, see Table 3 herein) and 119°C (form 2, see Table 3 herein), respectively and remain stable when dried under vacuum and 40°C (see Examples 1 and 2 herein). Therefore, both co-crystal forms of the present invention are significantly more stable upon temperature and/or vacuum stress compared to the solvated and unsolvated free base forms of WO 2015/120133 Al. Reference Example 1: Preparation of voxel otor hydrochloride Form I

Voxelotor (200.0 mg, crystalline mixture of Form I and Material N) was dissolved in a solution containing ethanol (2 mL) and hydrochloric acid fuming (37 w-% aqueous solution, 147 microliters) under sonication at a temperature of about 40°C. The obtained solution was stirred at room temperature for about 2 hours, leading to the formation of a slurry. Afterwards, the solid material was collected by filtration, washed with ethanol and dried at a temperature between 25 and 40°C under vacuum (about 30 mbar) to yield 177 mg of crystalline voxelotor hydrochloride Form I. The PXRD of the obtained material is in accordance with the PXRD provided in Figure 1 of WO 2015/031285 Al, confirming the presence of the same crystalline form.

Claims

1) A compound comprising 2-hydroxy-6-((2-( 1 -isopropyl - l//-pyrazol-5-y l)pyri din-3 - yl)methoxy)benzaldehyde (voxelotor) and 2,5-dihydroxybenzoic acid characterized by having the chemical structure according to Formula (II)

Formula (II), wherein n is in the range of from 0.3 to 0.7.

2) The compound of claim 1, characterized in that the compound is crystalline.

3) The crystalline compound of claim 2, characterized in that the crystalline compound is a co-crystal, a salt or a mixture of a co-crystal and a salt.

4) The compound as defined in any one of the preceding claims, characterized in that the compound is a co-crystal.

5) A crystalline form (form 1) of the compound as defined in any one of the preceding claims, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.2 ± 0.2)°, (11.0 ± 0.2)° and (26.5 ± 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.

6) The crystalline form according to claim 5 characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (11.8 ± 0.2)° and/or (26.1 ± 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.

7) A composition comprising the crystalline form as defined in claim 5 or 6 characterized by having a powder X-ray diffractogram comprising no reflections at 2-Theta angles of (5.5 ± 0.2)°, (5.6 ± 0.2)° and/or (6.0 ± 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. 8) A compound comprising 2-hydroxy-6-((2-(l -isopropyl-l//-pyrazol-5-yl)pyridin-3- yl)methoxy)benzaldehyde (voxel otor) and 2,5-dihydroxybenzoic acid characterized by having the chemical structure according to Formula (II)

Formula (II), wherein n is in the range of from 0.8 to 1.2.

9) The compound of claim 8, characterized in that the compound is crystalline.

10) The crystalline compound of claim 9, characterized in that the crystalline compound is a co-crystal, a salt or a mixture of a co-crystal and a salt.

11) The compound as defined in any one of claims 8 to 10, characterized in that the compound is a co-crystal.

12) A crystalline form (form 2) of a compound as defined in any one of claims 8 to 11, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.0 ± 0.2)°, (7.9 ± 0.2)° and (12.1 ± 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.

13) The crystalline form according to claim 12 characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (13.4 ± 0.2)° and/or (14.8 ± 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.

14) A composition comprising the crystalline form as defined in claim 12 or 13 characterized by having a powder X-ray diffractogram comprising no reflections at 2- Theta angles of (9.2 ± 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. 15) Use of the compound as defined in any one of claims 1 to 4 or 8 to 11 or the crystalline form as defined in any one of claims 5 to 6 or 12 to 13 or the composition as defined in claim 7 or 14 for the preparation of a pharmaceutical composition.

16) A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 4 or 8 to 11 or the crystalline form as defined in any one of claims 5 to 6 or 12 to 13 or the composition as defined in claim 7 or 14 and at least one pharmaceutically acceptable excipient.

17) The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is an oral solid dosage form.

18) The pharmaceutical composition of claim 17, wherein the oral solid dosage form is a tablet or a capsule.

19) The compound as defined in any one of claims 1 to 4 or 8 to 11 or the crystalline form as defined in any one of claims 5 to 6 or 12 to 13 or the composition as defined in claim 7 or 14 or the pharmaceutical composition as defined in any one of claims 16 to 18 for use as a medicament.

20) The compound as defined in any one of claims 1 to 4 or 8 to 11 or the crystalline form as defined in any one of claims 5 to 6 or 12 to 13 or the composition as defined in claim 7 or 14 or the pharmaceutical composition as defined in any one of claims 16 to 18 for use in the treatment of sickle cell disease.