New solid forms of (3R)-n-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide

Abstract

The present invention provides solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, salts and solvates thereof, as well as therapeutic uses thereof and pharmaceutical compostion comprising them.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P38902

[0003] New solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy- phenyl]-3-fluoro-pyrrolidine-l-sulfonamide

[0004] Field of the invention

[0005] The present invention provides new solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4- oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide, as well as therapeutic uses thereof and pharmaceutical compositions comprising said forms.

[0006] Background Art

[0007] The Rapidly Accelerated Fibrosarcoma (RAF) class of serine-threonine kinases comprise three members (ARAF, BRAF, RAFI) that compose the first node of the MAP kinase signalling pathway. Despite the apparent redundancy of the three RAF isoforms in signalling propagation through phosphorylation of MEK1 and 2, frequent oncogenic activating mutations are commonly found only for BRAF. In particular, substitution of V600 with glutamic acid or lysine renders the kinase highly activated with consequent hyper-stimulation of the MAPK pathway, independently from external stimulations (Cell. 2015 Jun 18; 161(7): 1681-1696).

[0008] Mutant BRAF is a targetable oncogenic driver and three BRAF inhibitors (vemurafenib, dabrafenib and encorafenib) reached the market up to now showing efficacy in BRAFV600E- positive melanoma. However rapid acquisition of drug resistance is almost universally observed and the duration of the therapeutic benefits for the targeted therapy remains limited.

[0009] Moreover, the developed BRAF inhibitors revealed an unexpected and “paradoxical” ability to repress MAPK signalling in BRAFV600E-driven tumours while the same inhibitors presented MAPK stimulatory activities in BRAF wild type (WT) models (N Engl J Med 2012; 366:271-273; and British Journal of Cancer volume 111, pages640-645(2014)).

[0010] Mechanistic studies on the RAF paradox then clarified that oncogenic BRAFV600E phosphorylates MEK 1 / 2 in its monomeric cytosolic form while WT BRAF and RAFI activation requires a complex step of events including cell membrane translocation and homo and / or heterodimerization promoted by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer volume 14, pages455-467(2014)).

[0011] The binding of inhibitors like vemurafenib, dabrafenib or encorafenib to a WT BRAF or RAFI protomer, quickly induces RAF homo and / or hetero dimerization and membrane association of the newly formed RAF dimer. In the dimeric conformation, one RAF protomer allosterically induces conformational changes of the second resulting in a kinase active status and, importantly, in a conformation unfavourable for the binding of the inhibitor. The dimer induced by drug treatment, as a result, promotes MEK phosphorylation by the catalysis operated by the unbound protomer with hyperactivation of the pathway.

[0012] The RAF paradox results in two clinically relevant consequences: 1) accelerated growth of secondary tumours upon BRAFi monotherapy (mainly keratochantoma and squamous-cell carcinomas) (N Engl J Med 2012; 366:271-273) and 2) the acquisition of drug resistance in the setting of BRAFi monotherapy as well as in combinations of BRAFi+MEKi presents activation of dimer-mediated RAF signalling by genetically driven events including RAS mutations, BRAF amplifications, expression of dimeric-acting BRAF splice variants (Nature Reviews Cancer volume 14, pages 455-467(2014)). There is thus the need for RAF inhibitors capable of breaking that paradox.

[0013] Furthermore, the currently approved classical BRAF inhibitors Vemurafenib (Mol. Pharmaceutics 2012, 9, 11, 3236-3245), Dabrafenib (J Pharmacol Ex Ther 2013, 344 (3) 655- 664) and Encorafenib (Pharmacol Res. 2018;129:414-423) all have very poor brain permerability. This is major limitation for the use of those classical BRAF inhibitors for the treatment of brain cancer or brain metastases. There is thus the need for BRAF inhibitors having improved brain permeability.

[0014] There is accordingly a need for compounds that are efficient BRAF inhibitors showing considerably less paradoxial activation of the MAPK signaling pathway while retaining high potency. Such compounds can be referred to as a paradox breaker or RAF paradox breaker, in contrast to compounds inducing the RAF paradox (and which could be referred to as paradox inducers or RAF paradox inducers). (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6- yl)oxy-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide satisfies these needs, and is a paradox breaking BRAF inhibitor with favourable brain penetration properties. Multicomponent crystals encompass two or more distinct compounds in a single crystal. Such multi component crystals may provide novel solid forms with favourable physicochemical properties and are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the solid form is not held constant during clinical studies, the exact dosage form used or studie may not be comparable form one lot to another. It is also desirable to have processes for producing a compound with the selected solid form in high purity when the compound is used in clinical studies or commercial products since any impurities may produce undesired effects (e.g. toxicity). Certain solid forms may display enhanced stability or may be more readily manufactured in high purity in large quantities, and certain solid forms may be more suitable for inclusion in pharmaceutical formulations. Certain solid forms may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.

[0015] (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro- pyrrolidine-l-sulfonamide is a pardox breaking BRAF inhibitor with favourable brain penetration properties and useful in the therapy of cancer, in particular melanoma, lung cancer, colorectal cancer and brain metastatic cancer. Accordingly, for pharmaccuetical development and commercialization, there is a need to identify solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3- methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide having desirable properties such as high crystallinity, high purity, and favourable physical stability, chemical stability, dissolution and mechanical properties. WO2022 / 258584 described procedures to isolate the polymorphic solid form A, as well as amorphous (3R)-N-[2-cyano-4-fluoro-3-(3- methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide. The present invention provides (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3- fluoro-pyrrolidine-1 -sulfonamide in novel solid forms, namely sodium salts, potassium salts and multicomponent crystals further comprising L-tartaric acid or gentisic acid.

[0016] Detailed description of the invention

[0017] The present invention relates to a solid form comprising a pharmaceutically acceptable sodium salt of the compound of formula (I)

[0018]

[0019] One embodiment relates to a solid form comprising a pharmaceutically acceptable sodium salt of the compound of formula (I) wherein the pharmaceutically acceptable sodium salt is of formula (la)

[0020] One embodiment relates to a solid form comprising a pharmaceutically acceptable sodium salt of the compound of formula (I) wherein the pharmaceutically acceptable sodium salt is sodium;[2-cyano-4-fluoro-3-(3- methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1 : 1).

[0021] One embodiment relates to a solid form comprising sodium; [2-cyano-4-fluoro-3 -(3- methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1 : 1).

[0022] One embodiment relates to a solid form comprising a pharmaceutically acceptable sodium salt of the compound of formula (I) wherein the pharmaceutically acceptable sodium salt is ethanol;hydrate;sodium;[2-cyano- 4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l- yl]sulfonyl-azanide (1 : 1 : 1 : 1).

[0023] One embodiment relates to a solid form comprising ethanol;hydrate;sodium;[2-cyano-4- fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l- yl]sulfonyl-azanide (1 : 1 : 1 : 1).

[0024] One embodiment relates to a solid form comprising a pharmaceutically acceptable sodium salt of the compound of formula (I) wherein the pharmaceutically acceptable sodium salt is ethanol;hydrate;sodium;[2-cyano- 4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l- yl]sulfonyl-azanide (1 : 1 : 1 : 1).

[0025] One embodiment relates to a solid form comprising a pharmaceutically acceptable potassium salt of the compound of formula (I) wherein the pharmaceutically acceptable potassium salt is of formula (lb)

[0026] One embodiment relates to a solid form comprising a pharmaceutically acceptable potassium salt of the compound of formula (I) wherein the pharmaceutically acceptable potassium salt is potassium;[2-cyano-4-fluoro-3- (3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l-yl]sulfonyl- azanide (1 : 1).

[0027]

[0028] One embodiment relates to a solid form comprising potassium;[2-cyano-4-fluoro-3-(3- methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1:1). One embodiment relates to a solid form comprising a compound of formula (I) and a second compound selected from gentisic acid and tartaric acid.

[0029] One embodiment relates to a solid form comprising a compound of formula (I)

[0030] (I), and a compound of formula (II) One embodiment relates to a solid form comprising a compound of formula (I)

[0031] (I), and a compound of formula (III)

[0032] The compound of formula (I) is also referred to as (3R)-N-[2-cyano-4-fluoro-3-(3-methyl- 4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide.

[0033] The compound of formula (II) is also referred to as (2>,3 ’)-(+)-Tartaric acid or commonly known as L-(+)-Tartaric acid.

[0034] The compound of formula (III) is also referred to as 2,5-dihydroxybenzoic acid or commonly known as gentisic acid.

[0035] The solid forms Na_A and Na-B are characterized by favourable dissolution properties compared with the amorphous form, Form A and Form B of the free form. Notably, the unfavourable dissolution properties of free forms A and B can be addressed by addition of pH- modifying excipients, such as e.g. magnesium oxide. However the use of such excipients comes with additional challenges such as for example a costly price and dose-limiting toxicity of the excipient. At the same time, the Na-salts of the present invention have further beneficial physico-chemical properties thus making these forms suitable for large-scale manufacturing, as well as ultimately safe and efficient administration to patients in need thereof. Notably, the dissolution properties of free Forms A and Form B are comparably low which in consequence leads to a high pill burden for the patients. By virtue of their improved dissolution properties, the new solid forms identified herein as Form Na_A and Na_B provide improved dissolution properties and accordingly may benefit patients by allowing for a significantly reduction in daily dosage and overall pill burden. Furthermore, the dose-limiting toxicity of pH-modifying excipients such as magnesium oxide can be avoided since the present forms Na_A and Na_B do not require such an excipient.

[0036] The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

[0037] The term “BRAF associated cancer” refers to cancers that are associated and / or caused by activating BRAF mutations. Non-limiting examples of such such a mutation include for instance BRAF V600E and V600K mutations.

[0038] The term “room temperature” refers to 18-30°C, in particular 20-25°C, more particular to 20°C.

[0039] The terms “about” and “approximately” are interchangeably and refer to a range of values that fall within 5%, greater or less than the stated reference value. More particularly “about” or “approximately” refers to ±0.2° degrees 2-theta or ±0.5 °C.

[0040] The terms “substantial amounts” as used herein, can mean at least 50%, in particular at least 60%, and more particular at least 70% of the initially present amount of a specific substance in a defined fraction. For instance after a purification step, the fraction comprising a substantial amount of a specific substance will comprise at least 50%, in particular at least 60%, more particularly at least 70% of the specific substance of the initially present amount of that specific substance prior to the purification step.

[0041] “crystallization” and “recrystallization” may be used interchangeably; referring to a process that leads to a stable polymorph or crystalline form of a particular chemical compound wherein the chemical compound prior to the process can be in amorphous form, or dissolved or suspended in a solvent system. For example, the crystallization steps can be done by forming a crystal with a solvent and an anti-solvent.

[0042] „XRPD” refers the analytical method of X-Ray Powder Diffraction. The repeatability of the angular values is in the range of 2-theta ±0.2°. The term “approximately” given in combination with an angular value denotes the repeatability which is in the range of 2-theta The relative XRPD peak intensity is dependent upon many factors such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. Relative intensities may vary considerably from one measurement to another due to preferred orientation effects. According to USP 941 (US Pharmacopoeia, 37th Edition, General Chapter 941), relative intensities between two samples of the same material may vary considerably due to “preferred orientation” effects. Anisotropic materials adopting preferred orientation will lead to anisotropic distribution of properties such as modulus, strength, ductility, toughness, electrical conductivity, thermal expansion, etc., as described e. g. in Kocks U.F. et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In XRPD but also Raman spectroscopy, preferred orientations cause a change in the intensity distribution. Preferred orientation effects are particularly pronounced with crystalline APIs of relatively large particle size.

[0043] "characteristic peak" refers to the presence of the powder X-ray diffraction peak which, alone or in combination with other characteristic peaks, definitively identifies the (3R)-N-[2- cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide or salt thereof as the referenced crystalline form. Typically, the powder X-ray diffraction analysis is conducted at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu Kai radiation, primary monochromator, silicon strip detector, angular range 3 to 42 degrees two-theta, approximately 30 minutes total measurement time). The samples (approximately 10 to 50 mg) are prepared between thin polymer films and are analyzed without further processing (e. g. grinding or sieving) of the substance.

[0044] "Polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions forming the crystal. In general, reference throughout this specification will be to a polymorphic form of (3R)-N-[2- cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide or salts thereof. The term “polymorphic form” as used herein may or may not include other crystalline solid state molecular forms including hydrates (e.g. bound water present in the crystalline structure) of the same compound. Polymorphs typically have a different crystal structure due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and / or unit cell parameters which directly influences its physical properties such as the X-ray diffraction characteristics of crystals or powder.

[0045] “Amorphous” refers to solid materials that lack the long-range order that is characteristic of a crystalline solid. The term “solvate” refers herein to a molecular complex comprising a compound of formula (I) and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e. g., ethanol). “Hydrate” refers herein to a solvate comprising a compound of formula (I) and a stoichiometric or non-stoichiometric amount of water.

[0046] The term “solid form” as used herein, denotes a material in the solid state as understood by the skilled person, and comprises in particular the amorphous solid state and the crystalline solid state. When reference to solid forms of the compound of formula (I) is made, then it is understood that salts, such as sodium salts and potassium salts are also encompassed.

[0047] The term “multicomponent crystal” refers to a molecular complex in a crystalline state in a fixed stoichiometric ratio held together by non-covalent interactions (i.e. hydrogen bonds, ionic bonds, van der Waals and dipole interactions).

[0048] The terms “pharmaceutically acceptable excipient”, pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.

[0049] The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

[0050] The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

[0051] “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. The term “substantially pure” when used in reference to a solid form (3R)-N-[2-cyano-4- fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide or a salt thereof, refers to said polymorph being > 90% pure. The solid form of (3R)-N-[2-cyano-4- fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide or a salt thereof, does not contain more than 10% of any other compound, in particular does not contain more than 10% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide or a salt thereof.

[0052] More particular, the term “substantially pure” when used in reference to a solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine- 1 -sulfonamide or a salt thereof, refers to said solid being > 95% pure. The solid form of (3R)-N- [2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide or salt thereof does not contain more than 5% of any other compound, in particular does not contain more than 5% of any other solid form (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4- oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide or a salt thereof.

[0053] Even more particular, the term “substantially pure” when used in reference to a solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro- pyrrolidine-l-sulfonamide or a salt thereof refers to said solid form being > 97% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3 -(3 -methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3 -fluoro- pyrrolidine-l-sulfonamide or a salt thereof does not contain more than 3% of any other compound, in particular does not contain more than 3% of any other solid form of (3R)-N-[2- cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide or a salt thereof.

[0054] Most particular, the term “substantially pure” when used in reference to a solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine- 1 -sulfonamide or a salt thereof refers to said polymorph being > 99% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine- 1 -sulfonamide or a salt thereof, does not contain more than 1% of any other compound, in particular does not contain more than 1% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3- (3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide or a salt thereof. Most particular, the term “substantially pure” when used in reference to a solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine- 1-sulfonamide or a salt thereof refers to said polymorph being > 99.5% pure. The solid form of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine- 1-sulfonamide or a salt thereof does not contain more than 1% of any other compound, in particular does not contain more than 1% of any other solid form of (3R)-N-[2-cyano-4-fluoro-3- (3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide or a salt thereof.

[0055] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes can be made and equivalents can be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. All separate embodiments can be combined.

[0056] Specific numbered aspects of the invention are:

[0057] 1. A solid form comprising a pharmaceutically acceptable sodium salt of the compound of formula (I)

[0058] 2. The solid form according to aspect 1, wherein the pharmaceutically acceptable sodium salt is of formula (la)

[0059] 3. The solid form according to aspect 1 or 2, wherein the molar ration of the compound of formula (I) and sodium is around 0.8 to around 1.2, preferably around 0.9 to around 1.1, most preferably around 1.0.

[0060] 4. The solid form according to any one of aspects 1 to 3, characterized by a X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.9 degrees 2- theta and at least one additional peak expressed in values of degrees 2-theta at about 9.0,

[0061] 10.2, 14.3, 14.5 or 19.4.

[0062] 5. The solid form according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.9 degrees 2- theta and a peak at about 9.0 degrees 2-theta.

[0063] 6. The solid form according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.9 degrees 2- theta and a peak at about 9.0 degrees 2-theta; wherein the pattern is further comprising at least one additional peak expressed in values of degrees 2-theta at about 10.2, 14.3, 14.5 or 19.4.

[0064] 7. The solid form according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern comprising at least three of the peaks at an angle of diffraction at about 9.0, 10.2, 12.9, 14.3, 14.5 or 19.4 degrees 2-theta.

[0065] 8. The solid form according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern comprising peaks at an angle of diffraction at about 9.0, 10.2, 12.9,

[0066] 14.3, 14.5 and 19.4 degrees 2-theta.

[0067] 9. The solid form according to any one of aspects 1 to 8, characterized by an X-ray powder diffraction pattern as shown in Figure 1.

[0068] 10. A solid form of a compound of formula (la) wherein the solid form is crystalline polymorphic Form B characterized by an IRspectrum comprising at least one peak at one of the positions 774 (±2) cm’1, 791 (±2) cm’1, 1089 (±2) cm’1, 1108 (±2) cm’1or 1401 (±2) cm’1, in particular comprising at least two peaks at positions 774 (±2) cm’1, 791 (±2) cm’1, 1089 (±2) cm’1, 1108 (±2) cm’1or 1401 (±2) cm’1, more particularly comprising the peaks at positions 774 (±2) cm’1, 791 (±2) cm’1, 1089 (±2) cm’1, 1108 (±2) cm’1or 1401 (±2) cm’1. . A solid form of a compound of formula (la) wherein the solid form is crystalline polymorphic Form B characterized by a Raman spectrum comprising at least one peak at one of the positions 98 (±2) cm’1, 439 (±2) cm’1, 1013 (±2) cm’1, 1233 (±2) cm’1and 3061 (±2) cm’1, in particular comprising at least two peaks at positions 98 (±2) cm’1, 439 (±2) cm’1, 1013 (±2) cm’1, 1233 (±2) cm’1and 3061 (±2) cm’1, more particularly comprising the peaks at positions 98 (±2) cm’1, 439 (±2) cm’1, 1013 (±2) cm’1, 1233 (±2) cm’1and 3061 (±2) cm’1. . The solid form according to any one of aspects 1 to 3 further comprising ethanol and hydrate each individually in a ratio of about 0.8 to 1.2 relative to the compound of formula (I), preferably each individually in a ratio of about 0.9 to 1.1, more preferably each individually in a ratio of about 1.0 relative to the compound of formula (I), characterized by a X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.5 degrees 2-theta and at least one additional peak expressed in values of degrees 2-theta at about 9.4, 11.1, 13.3, 13.9, 15.1, 16.9, 17.8, 22.1, 22.3 and 23.8 degrees 2-theta. The solid form according to any one of aspects 1 to 3 further comprising ethanol and hydrate each individually in a ratio of about 0.8 to 1.2 relative to the compound of formula (I), preferably each individually in a ratio of about 0.9 to 1.1, more preferably each individually in a ratio of about 1.0 relative to the compound of formula (I), characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.5 degrees 2-theta and a peak at about 15.1 degrees 2-theta. The solid form according to any one of aspects 1 to 3 further comprising ethanol and hydrate each individually in a ratio of about 0.8 to 1.2 relative to the compound of formula (I), preferably each individually in a ratio of about 0.9 to 1.1, more preferably each individually in a ratio of about 1.0 relative to the compound of formula (I), characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.5 degrees 2-theta and a peak at about 15.1 degrees 2-theta; wherein the pattern is further comprising at least one additional peak expressed in values of degrees 2-theta at about 9.4, 11.1, 13.3, 13.9, 16.9, 17.8, 22.1, 22.3 or 23.8 degrees 2- theta The solid form according to any one of aspects 1 to 3 further comprising ethanol and hydrate each individually in a ratio of about 0.8 to 1.2 relative to the compound of formula (I), preferably each individually in a ratio of about 0.9 to 1.1, more preferably each individually in a ratio of about 1.0 relative to the compound of formula (I), characterized by an X-ray powder diffraction pattern comprising at least three of the peaks at an angle of diffraction at about 9.4, 11.1, 12.5, 13.3, 13.9, 15.1, 16.9, 17.8, 22.1, 22.3 or 23.8 degrees 2-theta. The solid form according to any one of aspects 1 to 3 further comprising ethanol and hydrate each individually in a ratio of about 0.8 to 1.2 relative to the compound of formula (I), preferably each individually in a ratio of about 0.9 to 1.1, more preferably each individually in a ratio of about 1.0 relative to the compound of formula (I), characterized by an X-ray powder diffraction pattern comprising peaks at an angle of diffraction at about 9.4, 11.1, 12.5, 13.3, 13.9, 15.1, 16.9, 17.8, 22.1, 22.3 and 23.8 degrees 2-theta. . The solid form according to any one of aspects 1 to 3 or 10 to 14, characterized by an X- ray powder diffraction pattern as shown in Figure 2. . A solid form of a compound of formula (la) further comprising ethanol and hydrate, preferably each individually in a ratio of about 0.9 to 1.1, more preferably each individually in a ratio of about 1.0 relative to the compound of formula (la), wherein the solid form is crystalline polymorphic Form B characterized by an IRspectrum comprising at least one peak at one of the positions 677 (±2) cm’1, 927 (±2) cm’1, 1046 (±2) cm’1, 1204 (±2) cm’1or 1395 (±2) cm’1, in particular comprising at least two peaks at positions 677 (±2) cm’1, 927 (±2) cm’1, 1046 (±2) cm’1, 1204 (±2) cm’1or 1395 (±2) cm’1, more particularly comprising the peaks at positions 677 (±2) cm’1, 927 (±2) cm’1, 1046 (±2) cm’1, 1204 (±2) cm’1or 1395 (±2) cm’1. . A solid form of a compound of formula (la) further comprising ethanol and hydrate, preferably each individually in a ratio of about 0.9 to 1.1, more preferably each individually in a ratio of about 1.0 relative to the compound of formula (la), wherein the solid form is crystalline polymorphic Form B characterized by a Raman spectrum comprising at least one peak at one of the positions 75 (±2) cm’1, 1007 (±2) cm’1, 1256 (±2) cm’1, 2981 (±2) cm’1and 3086 (±2) cm’1, in particular comprising at least two peaks at positions 75 (±2) cm’1, 1007 (±2) cm’1, 1256 (±2) cm’1, 2981 (±2) cm’1and 3086 (±2) cm’1, more particularly comprising the peaks at positions 75 (±2) cm’1, 1007 (±2) cm’1, 1256 (±2) cm’1, 2981 (±2) cm’1and 3086 (±2) cm’1. 20. A solid form comprising a compound of formula (I) and a second compound selected from gentisic acid and (L)-(+)-tartaric acid.

[0069] 21. The solid form according to claim 20, wherein the solid form is a multicomponent crystalline system.

[0070] 22. The solid form according to claim 20 or 21, wherein the molar ration of the compound of formula (I) and the second component is around 0.8 to around 1.2, preferably around 0.9 to around 1.1, most preferably around 1.0.

[0071] 23. The solid form according to any one of claims 20 to 22, wherein the second component is tartaric acid.

[0072] 24. The solid form according to any one of claims 20 to 22, wherein the second component is gentisic acid.

[0073] 25. The solid form according to claim 23, characterized by a X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 7.3 degrees 2-theta and at least one additional peak expressed in values of degrees 2-theta at about 10.8, 11.3, 12.7, 14.6 or 15.0 or 15.3.

[0074] 26. The solid form according to claim 23, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 7.3 degrees 2-theta and a peak at about 15.3 degrees 2-theta.

[0075] 27. The solid form according to claim 23, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 7.3 degrees 2-theta and a peak at about 15.3 degrees 2-theta; wherein the pattern is further comprising at least one additional peak expressed in values of degrees 2-theta at about 10.8, 11.3, 12.7, 14.6 or 15.0. A solid form according to claim 23, characterized by an X-ray powder diffraction pattern comprising at least three of the peaks at an angle of diffraction at about 7.3, 10.8, 11.3, 12.7, 14.6, 15.0 or 15.3 degrees 2-theta. A solid form according to claim 23, characterized by an X-ray powder diffraction pattern comprising peaks at an angle of diffraction at about 7.3, 10.8, 11.3, 12.7, 14.6, 15.0 and 15.3. degrees 2-theta. A solid form according to any one of claims 23 or 25 to 29, characterized by an X-ray powder diffraction pattern as shown in Figure 4. A solid form according to claim 24, characterized by a X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 11.0 degrees 2-theta and at least one additional peak expressed in values of degrees 2-theta at about 6.0, 7.7, 11.9, 12.0, 13.3, 15.1 or 15.7. The solid form according to claim 24, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 11.0 degrees 2-theta and a peak at about 15.1 degrees 2-theta; wherein the pattern is further comprising at least one additional peak expressed in values of degrees 2-theta at about 6.0, 7.7, 11.9, 12.0, 13.3 or 15.7. A solid form according to claim 24, characterized by an X-ray powder diffraction pattern comprising at least three of the peaks at an angle of diffraction at about 6.0, 7.7, 11.0, 11.9, 12.0, 13.3, 15.1 or 15.7 degrees 2-theta. A solid form according to claim 24, characterized by an X-ray powder diffraction pattern comprising peaks at an angle of diffraction at about 6.0, 7.7, 11.0, 11.9, 12.0, 13.3, 15.1 and 15.7 degrees 2-theta. A solid form according to any one of claims 24 or 31 to 35, characterized by an X-ray powder diffraction pattern as shown in Figure 5. A substantially pure solid form according to any one of claims 1 to 35. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 36 and one or more pharmaceutically acceptable auxiliary substances. 38. A solid form or a pharmaceutical composition according to any one of claims 1 to 37 for use as a medicament.

[0076] 39. A solid form or a pharmaceutical composition according to any one of claims 1 to 37 for the treatment of cancer, in particular BRAF associated cancer.

[0077] 40. A solid form or a pharmaceutical composition according to any one of claims 1 to 37 for the treatment of melanoma, colorectal cancer or non-small cell lung cancer, in particular melanoma or colorectal cancer.

[0078] 41. A solid form or a pharmaceutical composition according to any one of claims 1 to 37 for the treatment of cancer, in particular BRAF associated cancer.

[0079] 42. Use of a solid form or a pharmaceutical composition according to any one of claims 1 to 37 for the preparation of a medicament for the treatment of cancer, in particular BRAF associated cancer.

[0080] 43. A method for therapeutic or prophylactic treatment of cancer, in particular BRAF associated cancer, said method comprising administering an effective amount of a solid form or a pharmaceutical composition according to any one of claims 1 to 37 to a patient in need thereof.

[0081] In one embodiment, the solid form comprising compound of formula (I) is anhydrous, .i.e. free of water bound in the crystal lattice, and non-hygroscopic (< 0.2% water uptake according to European Pharmacopeia).

[0082] The invention also relates to a compound according to the invention when manufactured according to a process of the invention.

[0083] Pharmaceutical Compositions

[0084] The compound of formula (I) in its various solid forms can be used as therapeutically active substance, e.g. in the form of a pharmaceutical composition. The pharmaceutical composition can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compound of formula (I) can be processed with a pharmaceutically inert, inorganic or organic carriers for the production of a pharmaceutical composition. Lactose, com starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[0085] The pharmaceutical composition can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0086] Pharmaceutical compositions comprising a compound of formula (I) alone or in combination, can be prepared for storage by mixing the active ingredient having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. (ed.) (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3 -pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEENTM, PLLTRONICSTM or polyethylene glycol (PEG).

[0087] Medicaments containing the a solid form of the compound of formula (I) as described herein and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of formula (I) and / or pharmaceutically acceptable solvates thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

[0088] Pharmaceutical compositions of a BRAF inhibitor include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration.

[0089] The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 200 mg to about 4000 mg per day of a compound of general formula (I) or of the corresponding amount of a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

[0090] The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 5-800 mg, particularly 200-500 mg, of a solid form comprising the compound of formula (I) and sodium, potassium, L-tartaric acid or gentisic acid. Examples of compositions according to the invention are:

[0091] Example A

[0092] Tablets of the following composition are manufactured in the usual manner:

[0093]

[0094] Table 1 : possible tablet composition

[0095] Manufacturing Procedure

[0096] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[0097] 2. Dry the granules at 50°C. 3. Pass the granules through suitable milling equipment.

[0098] 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

[0099] Example B-l

[0100] Capsules of the following composition are manufactured:

[0101]

[0102] Table 2: possible capsule ingredient composition

[0103] Manufacturing Procedure

[0104] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[0105] 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule.

[0106] The solid form comprising the compound of formula (I) and sodium, potassium, L-tartaric acid or gentisic acid, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules. Example B-2

[0107] Soft Gelatin Capsules of the following composition are manufactured:

[0108] Table 3: possible soft gelatin capsule ingredient composition

[0109] Table 4: possible soft gelatin capsule composition

[0110] Manufacturing Procedure

[0111] The solid form comprising the compound of formula (I) and sodium, potassium, L-tartaric acid or gentisic acid, is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

[0112] Brief description of the drawings Figure 1 illustrates a X-ray powder diffraction pattern of sodium;[2-cyano-4-fluoro-3-(3-methyl- 4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(3R)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1 : 1), wherein the form is termed Form Na_A.

[0113] Figure 2 illustrates a X-ray powder diffraction pattern of ethanol;hydrate;sodium;[2-cyano-4- fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(3A)-3-fluoropyrrolidin-l- yl]sulfonyl-azanide (1 : 1 : 1 : 1), wherein the form is termed Form Na_B.

[0114] Figure 3 illustrates a X-ray powder diffraction pattern of a multicomponent crystal of (3R)-N-[2- cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide, L-tartaric acid and acetone.

[0115] Figure 4 illustrates a X-ray powder diffraction pattern of a multicomponent crystal of (3R)-N-[2- cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide and L-tartaric acid.

[0116] Figure 5 illustrates a X-ray powder diffraction pattern of a multicomponent crystal of (3R)-N-[2- cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide and gentisic acid.

[0117] Figure 6 is an IR spectrum of sodium; [2-cyano-4-fluoro-3 -(3 -methyl-4-oxo-quinazolin-6-yl)oxy- phenyl]-[rac-(3R)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1:1), wherein the form is termed Form Na_A.

[0118] Figure 7 is an IR spectrum of ethanol;hydrate;sodium;[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-[rac-(3A)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1 : 1 : 1 : 1), wherein the form is termed Form Na_B.

[0119] Figure 8 is a raman spectrum of sodium; [2-cyano-4-fluoro-3 -(3 -methyl-4-oxo-quinazolin-6- yl)oxy-phenyl]-[rac-(3R)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1:1), wherein the form is termed Form Na_A.

[0120] Figure 9 is a raman spectrum of ethanol;hydrate;sodium;[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-[rac-(3A)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1 : 1 : 1 : 1), wherein the form is termed Form Na_B. Figure 10 illustrates the dissolution curves of Sodium salt forms Na_A (Fig.10 (a), top) and Na_B (Fig.10 (b), bottom) in FASSIF at pH 6.5. Each form was dissolved at two relevant concentrations: 1200 mg / 250 mL and 400 mg / mL. Forms Na_A and Na_B show drastically enhanced dissolution over time compared with the known free forms A and B (not shown here).

[0121] Experimental Part

[0122] The following experiments are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

[0123] Abbreviations:

[0124] ATR = attenuated total reflection; DCM = dichloromethane; DIPEA = N,N- diisopropylethylamine; DMF = dimethylformamide; DMSO dimethyl sulfoxide; DSC = differential scanning calorimetry; DVS = dynamic vapour sorption; ESI = electrospray ionization; EtOAc = ethyl acetate; FASSIF = fasted stated simulated interstinal fluid; FT = fourier transform; FTIR = fourier-transform infrared; IR = infrared; LC-MS / MS = liquid chromatography -MS / MS; MeOH = methanol; MS = mass spectrometry; PTFE = polyfluoroethylene; RH = relative humidity; rt = room temperature; SFC = supercritical fluid chromatography; TGA = thermogravimetry.

[0125] High Resolution X-Ray Powder Diffraction

[0126] High resolution X-ray powder diffraction (XRPD) patterns are recorded either in transmission or reflection geometry. Whereas transmission mode XRPD is less prone to effects of preferred orientation and less sample amount is needed, reflection mode XRPD is in most cases the preferred choice for quantification of crystalline or partly crystalline mixtures. In transmission geometry X-ray diffraction patterns are recorded on a STOE STADI P diffractometer with CuKal radiation (1.5406 A) and a Mythen position sensitive detector. The samples (approximately 10 to 50 mg) are prepared between thin polymer films and are usually analyzed without further processing (e.g., grinding or sieving) of the substance. The reflection mode diffractometers (Bruker D8 Advance) use CuKa radiation. The D8 Advance uses a Nickel filter and a LynxEye position sensitive detector. The sample amount needed for an analysis in reflection geometry ranges from 50 to 200 mg.

[0127] For the solid form comprising sodium; [2-cyano-4-fluoro-3 -(3 -methyl-4-oxo-quinazolin-6- yl)oxy-phenyl]-[rac-(3A)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide (1 : 1) and termed Form Na_A, the following peaks have been found by XRPD (expressed in values of degrees 2-theta) at approximately: 6.4, 9.0, 10.2, 12.9, 14.3, 14.5, 16.4, 16.5, 17.2, 18.1, 18.4, 18.7, 18.9, 19.4, 20.3, 20.6, 21.0, 21.1, 21.6, 23.0, 23.1, 23.6, 24.7, 24.9, 25.2, 25.9, 26.1, 26.7, 26.9, 27.7, 28.0, 28.2, 28.6, 28.9, 29.4, 30.6. The following peaks can be considered as characteristic peaks for this solid form (expressed in values of degrees 2-theta) at approximately: 9.0, 10.2, 12.9, 14.3,

[0128] 14.5, 19.4.

[0129] For the solid form comprising ethanol;hydrate;sodium;[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-[rac-(37?)-3-fluoropyrrolidin-l-yl]sulfonyl-azanide(l : 1 : 1 : 1) and termed Form Na_B, the following peaks have been found by XRPD (expressed in values of degrees 2-theta) at approximately: 6.2, 8.9, 9.4, 11.1, 12.5, 13.3, 13.9, 14.0, 14.8, 15.1, 15.8,

[0130] 16.9, 17.3, 17.8, 18.5, 18.7, 19.0, 20.5, 21.2, 21.8, 22.0, 22.1, 22.3, 22.5. The following peaks can be considered as characteristic peaks for this solid form (expressed in values of degrees 2- theta) at approximately: 9.4, 11.1, 12.5, 13.3, 13.9, 15.1, 16.9, 17.8, 22.1, 22.3, 23.8.

[0131] For the multicomoponent crystal comprising (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide, L-(+)-tartaric acid and acetone, the following peaks have been found by XRPD (expressed in values of degrees 2-theta) at approximately: 3,8, 6,2, 6,8, 7,7, 9,3, 10,5, 11,4, 12,4, 12,8, 13,4, 13,8, 14,2, 14,4, 15,0, 15,4,

[0132] 15.6, 15,9, 16,5, 17,5, 17,6, 18,0, 18,6, 18,9, 19,3, 19,5, 19,6, 20,5, 21,0, 21,5, 21,7, 22,1, 22,7, 23,0, 23,2, 23,3, 23,6, 23,7, 24,1, 24,3, 24,9. Characteristic peaks for this solid form are (expressed in values of degrees 2-theta) at approximately: 3.8, 6.2, 6.8, 9.3, 13.4, 14.2, 15.6,

[0133] 15.9, 16.5, 18.6.

[0134] For the multicomoponent crystal comprising (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide and L-(+)-tartaric acid, the following peaks have been found by XRPD (expressed in values of degrees 2-theta) at approximately: 7,3, 9,4, 10,8, 11,3, 12,4, 12,7, 12,9, 14,1, 14,4, 14,6, 15,0, 15,3, 17,4, 17,6, 17,9, 19,0, 19,5, 20,2, 20,6, 20,7, 21,1, 21,7, 21,9, 22,5, 23,0, 23,4, 23,6, 23,8, 23,9, 24,5, 24,9, 25,0. Characteristic peaks for this solid form are (expressed in values of degrees 2-theta) at approximately: 7.3, 10.8, 11.3, 12.7, 14.6, 15.0, 15.3.

[0135] For the multicomoponent crystal comprising (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide and gentisic acid, the following peaks have been found by XRPD (expressed in values of degrees 2-theta) at approximately: 6,0, 7,7, 10,4, 11,0, 11,9, 12,0, 13,3, 13,6, 14,5, 15,1, 15,7, 15,9, 16,5, 17,3, 18,1, 18,2, 19,0, 19,2, 19,5, 19,9, 20,6, 20,7, 20,8, 21,2, 22,1, 22,2, 22,4, 22,8, 23,2, 23,3, 23,5, 23,7, 23,9, 24,2, 24,6, 24,8. Characteristic peaks for this solid form are (expressed in values of degrees 2-theta) at approximately: 6.0, 7.7, 11.0, 11.9, 12.0, 13.3, 15.1, 15.7. IR Spectroscopy

[0136] The ATR FTIR spectra were recorded without any sample preparation using a ThermoNicolet i S 5 FTIR spectrometer with ATR accessory. The spectral range was between 4000 cm'1and 650 cm' resolution 2 cm'1, and at least 50 co-added scans were collected. Happ-Genzel apodization was applied. Using ATR FTIR will cause the relative intensities of infrared bands to differ from those seen in a transmission FTIR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FTIR, the bands at lower wavenumber are more intense than those at higher wavenumber.

[0137] Peakpicking was performed using Thermo Scientific Omnic 8.3 software using the automated ‘Find Peaks’ function. The ‘threshold’ and ‘sensitivity’ were manually adjusted to get a representative number of peaks.

[0138] Table 5: list of peaks identified by infrared spectroscopy of Form Na_A.

[0139] Table 6: list of peaks identified by infrared spectroscopy of Form Na_B.

[0140] Raman Spectroscopy

[0141] The FT-Raman spectra were recorded without any sample preparation in the spectral range of 4000-50 cm’1with a Bruker MultiRam FT-Raman spectrometer, equipped with a NdYAG 1064 nm laser and a liquid nitrogen cooled Germanium detector. The laser power at the sample was about 300 mW, 2 cm’1resolution was used, and 2048 scans were co-added. The Blackman-Harris 4-term apodization function was used. About 5 mg of sample (powder in a glass vial) were needed. Peakpicking was performed using Thermo Scientific Omnic 8.3 software using the automated ‘Find Peaks’ function. The ‘threshold’ and ‘sensitivity’ were manually adjusted to get a representative number of peaks.

[0142] Table 7: list of peaks identified by Raman spectroscopy of Form Na_A

[0143] Table 8: list of peaks identified by Raman spectroscopy of Form Na_B

[0144] Materials

[0145] Gentisic acid (98%) was purchased by Sigma Aldrich (Ref 149357-25G; Lot: WXBC6863V).

[0146] L-(+)-Tartaric acid (99%) was purchased by Alfa Aesar (Ref A13668; Lot: 10207372).

[0147] Synthesis and Crysatallization Protocol

[0148] The synthesis of the active pharmaceutical ingredient (API) (3R)-N-[2-cyano-4-fluoro-3-(3- methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide was previously disclosed in WO2021 / 116055 and WO2022 / 258584. Importantly, WO2022 / 258584 also described a procedure to isolate polymorphic solid form A and the amorphous form of (3R)-N- [2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l- sulfonamide of the free form.

[0149] Preparation of Form Na_A (mono sodium salt anhydrate)

[0150] 125mg of the mono ethanol solvate mono hydrate of the sodium salt Form Na_B have been weighed into an HPLC glass vial and 500 pL ethanol have been added together with five ZrCh beads. The suspension was ground in a planetary mill at 600 rpm for 30 min without temperature control.

[0151] The obtained white slurry was filtered through a 0.22 pm PTFE centrifuge filter unit and analyzed with XRPD without further drying. Physically pure Form Na_A was observed as a result and subsequently characterized as anhydrate by TGA showing a mass loss of 0,22% over the temperature range from 25 °C to 220 °C. The substance showed a melting with decomposition with an onset temperature of 273,9 °C and was analyzed with XRPD as Form Na_A (Figure 1).

[0152] Preparation of Form Na_B (mono ethanol solvate mono hydrate of the sodium salt)

[0153] In a 200 ml reactor, 15.01 g of BRAFi free base and 120.2 g of EtOH were added. The white suspension was heated to 30 °C. Then, 4.49 g of 32% NaOHaqsolution was added, resulting in a thin suspension with a pH of approximately 10-11. An additional 0.4 g of 32% NaOH solution was added, still resulting in a thin suspension. The temperature was then increased to 40 °C and briefly stirred. At this point, only very few undissolved particles remained. The solution was then clarified by filtration using a glass funnel with a paper filter into a second reactor. The reactor and filter were washed with 3 g of EtOH / H2O 95:5. The now clear solution was then tempered to 30 °C.

[0154] The solution spontaneously started to crystallize, forming a thick white suspension. The well- stirrable white suspension was further stirred at 30°C. It was then cooled gradually to 0°C over a period of 180 minutes. A sample was taken from the suspension and analyzed with XRPD as Form Na_B (Figure 2).

[0155] Preparation of multicomponent crystal comprising (3R)-N-[2-cyano-4-fluoro-3-(3-methyl- 4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide and L-tartaric acid:

[0156] 1001,5 mg (3R)-N-[2-cyano-4-fluoro-3 -(3 -methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3 -fluoro- pyrrolidine-l-sulfonamide (polymorphic form A) and 648,0 mg L-tartaric acid were suspended in 5 mL acetone. The slurry was stirred for seven days with a magnetic stirrer bar at 100 rpm while temperature cycling (2h 20°C, 2h heating 5°C / h, 2h 30°C, 2h cooling 5°C / h ). The white solid was filtered and analyzed by XRPD (Figure 3) as solid form comprising (3R)-N-[2-cyano- 4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide, L- tartaric acid and acetone.

[0157] The material was further dried at 129°C within 15 minutes to obtain the desolvated multicomponent solid form comprising (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo- quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide and L-tartaric acid. The white solid was analyzed by XRPD (Figure 4). Preparation of multicomponent crystal comprising (3R)-N-[2-cyano-4-fluoro-3-(3-methyl- 4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide and gentisic acid:

[0158] 90,6mg (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro- pyrrolidine-l-sulfonamide (polymorphic form A) and 62,lmg gentisic acid (2,5 dihydroxybenzoic acid) were suspended in 1 mL acetonitrile. The slurry was stirred for seven days with a magnetic stirrer bar at 100 rpm while temperature cycling (2 hours at 20 °C, 2 hours slope up, 2 hours at 30 °C, 2 hours slope down) . The off-white solid was filtered and analyzed by XRPD (Figure 5) as multicomponent solid form comprising (3R)-N-[2-cyano-4-fluoro-3-(3- methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l -sulfonamide and gentisic acid.

[0159] Dissolution assay

[0160] Preparation of FaSSIF pH 6,5, 250 ml:

[0161] ■ Prepare 1 1 buffer:

[0162] ■ Dissolve 6.19 g NaCl: 6195.60 mg (Fisher Scientific UK, Lot: 1563173)

[0163] ■ Dissolve 3.95 g NaH2PO4xH2O: 3964.48 mg (Merck KGaa, AM1457046928)

[0164] ■ Dissolve 0.42 g NaOH: 416.69 mg (52BG3360, Sigma-Aldrich)

[0165] ■ Adjust to pH 6.5 with NaOH or HC1

[0166] ■ Make up to volume 11 at room temperature

[0167] ■ Add 0.56 g of FaSSIF powder to 125 ml of buffer and stir until it is completely dissolved: 566.55 mg

[0168] ■ Make up to volume of 250 ml at room temperature

[0169] ■ Put in warming cabinet, and let stand for 2 hours Dissolution test:

[0170] • Pre-heat dissolution media at 37°C

[0171] • Weigh the defined amount of active into 20 mL screw cap glass vials (n=3 per experiment). Drug solubility was 0.098 mg / mL in fasted state simulating intestinal media. The corresponding nominal concentrations (80% of solubility concentration) is 0.078 mg / mL.

[0172] • At t=0, measure the pH and add 20 mL FaSSIF pH 6.5 into the vials and put the vials on an end-over-end stirrer at 37°C and 5 rpm.

[0173] • After 5, 10, 15, 20, 30, 60, 120 min remove 200 pl samples from each vial into an Eppendorf cap, centrifuge at 13000 rpm for 90 seconds and dilute 100 pL clear supernatant in 900 pL diluent (Methanol) Measure the pH in each vial after 120 min

[0174] • Analyze the samples via UPLC (2 mL UPLC vial)

Claims

- 36 -Claims1. A solid form comprising a pharmaceutically acceptable sodium salt of the compound of formula (I)2. The solid form according to claim 1, wherein the pharmaceutically acceptable sodium salt is of formula (la)(la).

3. The solid form according to claim 1 or 2, wherein the molar ration of the compound of formula (I) and sodium is around 0.8 to around 1.2, preferably around 0.9 to around 1.1, most preferably around 1.0.

4. The solid form according to any one of claims 1 to 3, characterized by a X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.9 degrees 2- theta and at least one additional peak expressed in values of degrees 2-theta at about 9.0, 10.2, 14.3, 14.5 or 19.4.

5. The solid form according to any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.9 degrees 2- theta and a peak at about 9.0 degrees 2-theta.

6. The solid form according to any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.9 degrees 2- theta and a peak at about 9.0 degrees 2-theta; wherein the pattern is further comprising at- 37 - least one additional peak expressed in values of degrees 2-theta at about 10.2, 14.3, 14.5 or 19.4.

7. The solid form according to any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising at least three of the peaks at an angle of diffraction at about 9.0, 10.2, 12.9, 14.3, 14.5 or 19.4 degrees 2-theta.

8. The solid form according to any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising peaks at an angle of diffraction at about 9.0, 10.2, 12.9, 14.3, 14.5 and 19.4 degrees 2-theta.

9. The solid form according to any one of claims 1 to 8, characterized by an X-ray powder diffraction pattern as shown in Figure 1.

10. A solid form of a compound of formula (la)wherein the solid form is crystalline polymorphic Form B characterized by an IRspectrum comprising at least one peak at one of the positions 774 (±2) cm’1, 791 (±2) cm’1, 1089 (±2) cm’1, 1108 (±2) cm’1or 1401 (±2) cm’1, in particular comprising at least two peaks at positions 774 (±2) cm’1, 791 (±2) cm’1, 1089 (±2) cm’1, 1108 (±2) cm’1or 1401 (±2) cm’1, more particularly comprising the peaks at positions 774 (±2) cm’1, 791 (±2) cm’1, 1089 (±2) cm’1, 1108 (±2) cm’1or 1401 (±2) cm’1.

11. A solid form of a compound of formula (la)wherein the solid form is crystalline polymorphic Form B characterized by a Raman spectrum comprising at least one peak at one of the positions 98 (±2) cm’1, 439 (±2) cm’1, 1013 (±2) cm’1, 1233 (±2) cm’1and 3061 (±2) cm’1, in particular comprising at least two peaks at positions 98 (±2) cm’1, 439 (±2) cm’1, 1013 (±2) cm’1, 1233 (±2) cm’1and 3061 (±2) cm’1, more particularly comprising the peaks at positions 98 (±2) cm’1, 439 (±2) cm’1, 1013 (±2) cm’1, 1233 (±2) cm’1and 3061 (±2) cm’1.

12. The solid form according to any one of claims 1 to 3 further comprising ethanol and hydrate, characterized by a X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.5 degrees 2-theta and at least one additional peak expressed in values of degrees 2-theta at about 9.4, 11.1, 13.3, 13.9, 15.1, 16.9, 17.8, 22.1, 22.3 or 23.8 degrees 2-theta.

13. The solid form according to any one of claims 1 to 3 further comprising ethanol and hydrate, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.5 degrees 2-theta and a peak at about 15.1 degrees 2- theta.

14. The solid form according to any one of claims 1 to 3 further comprising ethanol and hydrate, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.5 degrees 2-theta and a peak at about 15.1 degrees 2- theta; wherein the pattern is further comprising at least one additional peak expressed in values of degrees 2-theta at about 9.4, 11.1, 13.3, 13.9, 16.9, 17.8, 22.1, 22.3 or 23.8.

15. The solid form according to any one of claims 1 to 3 further comprising ethanol and hydrate, characterized by an X-ray powder diffraction pattern comprising at least three of the peaks at an angle of diffraction at about 9.4, 11.1, 12.5, 13.3, 13.9, 15.1, 16.9, 17.8, 22.1, 22.3 or 23.8 degrees 2-theta.

16. The solid form according to any one of claims 1 to 3 further comprising ethanol and hydrate, characterized by an X-ray powder diffraction pattern comprising peaks at an angle of diffraction at about 9.4, 11.1, 12.5, 13.3, 13.9, 15.1, 16.9, 17.8, 22.1, 22.3 and 23.8 degrees 2-theta.

17. The solid form according to any one of claims 1 to 3 or 10 to 14, characterized by an X- ray powder diffraction pattern as shown in Figure 2.

18. A solid form of a compound of formula (la) further comprising ethanol and hydratewherein the solid form is crystalline polymorphic Form B characterized by an IRspectrum comprising at least one peak at one of the positions 677 (±2) cm’1, 927 (±2) cm’1, 1046 (±2) cm’1, 1204 (±2) cm’1or 1395 (±2) cm’1, in particular comprising at least two peaks at positions 677 (±2) cm’1, 927 (±2) cm’1, 1046 (±2) cm’1, 1204 (±2) cm’1or 1395 (±2) cm’1, more particularly comprising the peaks at positions 677 (±2) cm’1, 927 (±2) cm’1, 1046 (±2) cm’1, 1204 (±2) cm’1or 1395 (±2) cm’1.

19. A solid form of a compound of formula (la) further comprising ethanol and hydratewherein the solid form is crystalline polymorphic Form B characterized by a Raman spectrum comprising at least one peak at one of the positions 75 (±2) cm’1, 1007 (±2) cm’1, 1256 (±2) cm’1, 2981 (±2) cm’1and 3086 (±2) cm’1, in particular comprising at least two peaks at positions 75 (±2) cm’1, 1007 (±2) cm’1, 1256 (±2) cm’1, 2981 (±2) cm’1and 3086 (±2) cm’1, more particularly comprising the peaks at positions 75 (±2) cm’1, 1007 (±2) cm’1, 1256 (±2) cm’1, 2981 (±2) cm’1and 3086 (±2) cm’1.

20. A substantially pure solid form according to any one of claims 1 to 19.

21. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 20 and one or more pharmaceutically acceptable auxiliary substances.

22. A solid form or a pharmaceutical composition according to any one of claims 1 to 20 for use as a medicament.

23. A solid form or a pharmaceutical composition according to any one of claims 1 to 20 for the treatment of cancer, in particular BRAF associated cancer.

24. A solid form or a pharmaceutical composition according to any one of claims 1 to 20 for the treatment of melanoma, colorectal cancer or non-small cell lung cancer, in particular melanoma or colorectal cancer.

25. A solid form or a pharmaceutical composition according to any one of claims 1 to 20 for the treatment of cancer, in particular BRAF associated cancer.

26. Use of a solid form or a pharmaceutical composition according to any one of claims 1 to 20 for the preparation of a medicament for the treatment of cancer, in particular BRAF associated cancer.

27. A method for therapeutic or prophylactic treatment of cancer, in particular BRAF associated cancer, said method comprising administering an effective amount of a solid form or a pharmaceutical composition according to any one of claims 1 to 20 to a patient in need thereof.

28. The invention as described herein.* * *

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