Crystalline form of camlipixant

Abstract

This invention relates to a crystalline form of camlipixant and its use in pharmaceutical compositions as well as in therapy, in particular use in the treatment of refractory chronic cough. (I)

Description

[0001] CRYSTALLINE FORM OF CAMLIPIXANT

[0002] FIELD OF THE INVENTION

[0003] This invention relates to a crystalline form of camlipixant and its use in pharmaceutical compositions as well as in therapy, in particular use in the treatment of refractory chronic cough.

[0004] BACKGROUND TO THE INVENTION

[0005] P2X3 antagonists are useful in the treatment of various diseases, particularly in the treatment of refractory chronic cough. One particular P2X3 antagonist in development is known as camlipixant.

[0006] There exists a need to provide crystalline forms of camlipixant, which are suitable for the development of camlipixant for the treatment of refractory chronic cough. WO 2020 / 099923 describes certain crystalline forms of camlipixant, in particular those characterised by the Type A* family.

[0007] There is a need to provide further crystalline forms of camlipixant, capable of development.

[0008] SUMMARY OF THE INVENTION

[0009] According to a first aspect of the invention, there is provided a crystalline form of camlipixant (Type V), which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4 and 13.3 ± 0.2° 29.

[0010] According to a second aspect of the invention, there is provided a crystalline form of camlipixant (Type T), which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of 5.5, 6.5 and 10.3 ± 0.2° 29.

[0011] According to a third aspect of the invention, there is provided a pharmaceutical composition comprising a crystalline form of camlipixant according to the first or second aspect.

[0012] According to a fourth aspect of the invention, there is provided a crystalline form according to the first or second aspect, for use in the treatment of cough, in particular refractory chronic cough.

[0013] According to a fifth aspect of the invention, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of the crystalline form according to the first aspect or second aspect or comprising administering a pharmaceutical composition according to the third aspect. BRIEF DECEPTION OF THE FIGURES

[0014] Figure 1 shows an X-ray powder diffraction pattern (XRPD) of crystalline form Type of camlipixant.

[0015] Figure 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline form Type of camlipixant.

[0016] Figure 3 shows a thermogravimetric analysis (TGA) trace of crystalline form Type of camlipixant.

[0017] Figure 4 shows a gravimetric vapour sorption (GVS) of crystalline form Type of camlipixant.

[0018] Figure 5 shows X-ray (single crystal) structure of crystalline form Type of camlipixant.

[0019] Figure 6 shows a variable temperature XRPD of crystalline form Type of camlipixant.

[0020] Figure 7 shows a variable humidity XRPD of crystalline form Type of camlipixant.

[0021] Figure 8 shows solid state NMR of crystalline form Type of camlipixant.

[0022] Figure 9 shows an X-ray powder diffraction pattern (XRPD) of crystalline form Type T of camlipixant.

[0023] Figure 10 shows a differential scanning calorimetry (DSC) thermogram of crystalline form Type T of camlipixant.

[0024] Figure 11 shows a thermogravimetric analysis (TGA) trace of crystalline form Type T of camlipixant.

[0025] Figure 12 shows a gravimetric vapour sorption (GVS) of crystalline form Type T of camlipixant.

[0026] Figure 13 shows a variable humidity XRPD of crystalline form Type T of camlipixant.

[0027] Figure 14 shows solid state NMR of crystalline form Type T of camlipixant.

[0028] Figure 15 shows solid state NMR of crystalline form Type A, versus Type V, versus Type T.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] Definitions

[0031] As used herein, the term “treatment” refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject. A reference to “camlipixant” is a reference to methyl (2S)-2-({2-[2,6-difluoro-4- (methylcarbamoyl)phenyl]-7-methylimidazo[1 ,2-a]pyridin-3-yl}methyl)morpholine-4-carboxylate, i.e. a compound having the following structure, or a pharmaceutically acceptable salt thereof:

[0032] As used herein, the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0033] The term “therapeutically effective amount” refers to the quantity of a compound of the invention, which will elicit the desired biological response in a human body. It may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.

[0034] Description of the Embodiments

[0035] In a first aspect of the invention, there is provided a crystalline form of camlipixant (Type V), which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4 and 13.3 ± 0.2° 29.

[0036] In one embodiment, the crystalline form of camlipixant (Type V) is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4, 13.3, 14.5 and 19.7 ± 0.2° 29.

[0037] In one embodiment, the crystalline form of camlipixant (Type V) is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of those set out in Table 1a. Peaks shown in bold are considered to be characterising peaks.

[0038] Table 1a

[0039] In one embodiment, the crystalline form of camlipixant (Type V) is characterised by an X-ray powder diffraction (XRPD) substantially in accordance with Figure 1 .

[0040] In one embodiment, the crystalline form Type of camlipixant is characterised by a DSC trace with a single endotherm with an onset temperature of about 164 °C.

[0041] In one embodiment, the crystalline form Type of camlipixant is characterised by a DSC trace substantially in accordance with Figure 2.

[0042] In one embodiment, the crystalline form Type is characterised by a TGA trace substantially in accordance with Figure 3.

[0043] In an embodiment, the crystalline form Type is characterised by a solid state NMR having peaks at about 21 .8, 52.1 , 71 .2, 129.2, 141 .6, 165.6 and 167.1 ppm.

[0044] In an embodiment, the crystalline form Type is characterised by a solid state NMR comprising at least one peak at about 21 .8, 52.1 , 71 .2, 129.2, 141 .6, 165.6 and 167.1 ppm.

[0045] In an embodiment, the crystalline form Type is characterised by a solid state NMR comprising at least two peaks at about 21.8, 52.1 , 71.2, 129.2, 141.6, 165.6 and 167.1 ppm.

[0046] In an embodiment, the crystalline form Type is characterised by a solid state NMR comprising peaks at about 21 .8, 52.1 , 71 .2, 129.2, 141 .6, 165.6 and 167.1 ppm. In an embodiment, the crystalline form Type is characterised by a solid state NMR having peaks in accordance with those shown in Table 1 b. Peaks shown in bold are considered to be characterising peaks.

[0047] Table 1b

[0048] In an embodiment, the crystalline form Type is characterised by a solid state NMR substantially in accordance with that shown in Figure 8.

[0049] In an embodiment, crystalline form Type is characterised by XRPD pattern having peaks at a 26 angle of about 5.7, 7.4 and 13.3 ± 0.2° 26 and a DSC trace with a single endotherm with an onset temperature of about 164 °C.

[0050] In an embodiment, crystalline form Type is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 26 angle of about 5.7, 7.4, 13.3, 14.5 and 19.7 ± 0.2° 26 and a DSC trace with a single endotherm with an onset temperature of about 164 °C. In an embodiment, crystalline form Type is characterised an X-ray powder diffraction (XRPD) substantially in accordance with Figure 1 and a DSC trace substantially in accordance with Figure 2.

[0051] In an embodiment, crystalline form Type is characterised by a solid state NMR having peaks at about 21.8, 52.1 , 71.2, 129.2, 141.6, 165.6 and 167.1 ppm, and a DSC trace with a single endotherm with an onset temperature of about 164 °C.

[0052] In an embodiment, the crystalline form Type is characterised by a solid state NMR comprising at least one peak at about 21 .8, 52.1 , 71 .2, 129.2, 141 .6, 165.6 and 167.1 ppm, and a DSC trace with a single endotherm with an onset temperature of about 164 °C.

[0053] In an embodiment, the crystalline form Type is characterised by a solid state NMR comprising peaks at about 21.8, 52.1 , 71.2, 129.2, 141.6, 165.6 and 167.1 ppm, and a DSC trace with a single endotherm with an onset temperature of about 164 °C.

[0054] In an embodiment, the crystalline form Type is characterised by a solid state NMR substantially in accordance with Figure 8 and a DSC trace substantially in accordance with Figure 2.

[0055] In an embodiment, crystalline form Type is characterised by having at least two of the following properties:

[0056] (a) an XRPD pattern substantially in accordance with Figure 1 ;

[0057] (b) an XRPD pattern having peaks at a 29 angle of about 5.7, 7.4 and 13.3 ± 0.2° 29;

[0058] (c) a DSC trace substantially in accordance with Figure 2;

[0059] (d) a DSC trace with a single endotherm with an onset temperature of about 164 °C; or

[0060] (e) a TGA trace substantially in accordance with Figure 3;

[0061] (f) a GVS trace substantially in accordance with Figure 4;

[0062] (g) a solid state NMR comprising at least one peak at about 21 .8, 52.1 , 71 .2, 129.2, 141 .6, 165.6 and 167.1 ppm; or

[0063] (h) a solid state NMR substantially in accordance with Figure 8.

[0064] In an embodiment, crystalline form Type is characterised by having at least two of the following properties:

[0065] (i) an XRPD pattern substantially in accordance with Figure 1 ;

[0066] (j) an XRPD pattern having peaks at a 29 angle of about 5.7, 7.4 and 13.3 ± 0.2° 29;

[0067] (k) a DSC trace substantially in accordance with Figure 2;

[0068] (l) a DSC trace with a single endotherm with an onset temperature of about 164 °C; or

[0069] (m) a TGA trace substantially in accordance with Figure 3. It should be noted that all XRPD peaks stated as characterising peaks for Type of camlipixant (i.e. 5.7, 7.4, 13.3, 14.5 and 19.7 ± 0.2° 29) are not present in the XRPD of previously disclosed Type A of camlipixant.

[0070] It should be noted that at least the Type characterising peak at 7.4 ± 0.2° 29 is not present in the XRPD of previously disclosed Type A, Type K, Type N, Type O or Type B.

[0071] In an embodiment, Type of camlipixant is a variable hydrate.

[0072] In an embodiment, Type has a water content of about 0.9% at 20% RH and 25 °C, or a water content of about 1 .2% at 40% RH and 25 °C, or a water content of about 1 .4% at a water content of about 60% RH and 25 °C, or a water content of about 1 .5% at 90% RH and 25 °C.

[0073] In an embodiment, Type has a water content of about 0.9% to about 1 .5% at 20-90% RH and 25 °C.

[0074] In an embodiment, Type has a water content of about 0.9% to about 1 .4% at 20-60% RH and 25 °C.

[0075] In an embodiment, Type has a water content of about 0.9% to about 1 .2% at 20-40% RH and 25 °C.

[0076] In a second aspect of the invention, there is provided a crystalline form of camlipixant (Type T), which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5 and 10.3 ± 0.2° 29.

[0077] In one embodiment, the crystalline form of camlipixant (Type T) is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5, 7.9, 10.3, 13.0, 15.6 and 20.4 ± 0.2° 29.

[0078] In one embodiment, the crystalline form of camlipixant (Type T) is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of those set out in the Table 2a. Peaks shown in bold are considered to be characterising peaks.

[0079] Table 2a

[0080] In one embodiment, the crystalline form of camlipixant (Type T) is characterised by an X-ray powder diffraction (XRPD) substantially in accordance with Figure 9.

[0081] In one embodiment, the crystalline form Type T of camlipixant is characterised by a DSC trace with a single endotherm with an onset temperature of about 103 °C.

[0082] In one embodiment, the crystalline form Type T of camlipixant is characterised by a DSC trace substantially in accordance with Figure 10. In one embodiment, the crystalline form Type T is characterised by a TGA trace substantially in accordance with Figure 11.

[0083] According to the TGA trace shown in Figure 11 , it can be seen that Type T undergoes loss of water upon heating. Therefore, it is believed that Type T is a hydrate.

[0084] In an embodiment, the crystalline form Type T is characterised by a solid state NMR having peaks at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm.

[0085] In an embodiment, the crystalline form Type T is characterised by a solid state NMR comprising at least one peak at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm.

[0086] In an embodiment, the crystalline form Type T is characterised by a solid state NMR comprising at least two peaks at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm.

[0087] In an embodiment, the crystalline form Type T is characterised by a solid state NMR comprising peaks at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm.

[0088] In an embodiment, the crystalline form Type T is characterised by a solid state NMR having peaks in accordance with those shown in Table 2b. Peaks shown in bold are considered to be characterising peaks.

[0089] Table 2b

[0090] In an embodiment, the crystalline form Type T is characterised by a solid state NMR substantially in accordance with that shown in Figure 14.

[0091] In an embodiment, crystalline form Type T is characterised by XRPD pattern having peaks at a 29 angle of about 5.5, 6.5 and 10.3 ± 0.2° 29 and a DSC trace with a single endotherm with an onset temperature of about 103 °C.

[0092] In an embodiment, crystalline form Type T is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5, 7.9, 10.3, 13.0, 15.6 and 20.4 ± 0.2° 29_and a DSC trace with a single endotherm with an onset temperature of about 103 °C.

[0093] In an embodiment, crystalline form Type T is characterised an X-ray powder diffraction (XRPD) substantially in accordance with Figure 9 and a DSC trace substantially in accordance with Figure 10.

[0094] In an embodiment, crystalline form Type T is characterised by a solid state NMR having peaks at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm, and a DSC trace with a single endotherm with an onset temperature of about 103 °C.

[0095] In an embodiment, crystalline form Type T is characterised by a solid state NMR comprising at least one peak at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm, and a DSC trace with a single endotherm with an onset temperature of about 103 °C.

[0096] In an embodiment, crystalline form Type T is characterised by a solid state NMR comprising at least two peaks at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm, and a DSC trace with a single endotherm with an onset temperature of about 103 °C.

[0097] In an embodiment, crystalline form Type T is characterised by a solid state NMR comprising peaks at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm, and a DSC trace with a single endotherm with an onset temperature of about 103 °C.

[0098] In an embodiment, crystalline form Type T is characterised by a solid state NMR substantially in accordance with Figure 14 and a DSC trace substantially in accordance with Figure 10.

[0099] In an embodiment, crystalline form Type T is characterised by having at least two of the following properties:

[0100] (a) an XRPD pattern substantially in accordance with Figure 9;

[0101] (b) an XRPD pattern having peaks at a 29 angle of about 5.5, 6.5 and 10.3 ± 0.2° 29; (c) a DSC trace substantially in accordance with Figure 10;

[0102] (d) a DSC trace with a single endotherm with an onset temperature of about 103 °C;

[0103] (e) a TGA trace substantially in accordance with Figure 11 ;

[0104] (f) a TGA trace substantially in accordance with Figure 3;

[0105] (g) a GVS trace substantially in accordance with Figure 12;

[0106] (h) a solid state NMR comprising at least one peak at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm; or

[0107] (i) a solid state NMR substantially in accordance with Figure 14.

[0108] In an embodiment, crystalline form Type T is characterised by having at least two of the following properties:

[0109] (j) an XRPD pattern substantially in accordance with Figure 9;

[0110] (k) an XRPD pattern having peaks at a 29 angle of about 5.5, 6.5 and 10.3 ± 0.2° 29;

[0111] (l) a DSC trace substantially in accordance with Figure 10;

[0112] (m) a DSC trace with a single endotherm with an onset temperature of about 103 °C; or

[0113] (n) a TGA trace substantially in accordance with Figure 11.

[0114] It should be noted that all XRPD peaks stated as characterising peaks for Type T of camlipixant (i.e. 5.5, 6.5, 7.9, 10.3, 13.0, 15.6 and 20.4 ± 0.2° 29) are not present in the XRPD of previously disclosed Type A of camlipixant.

[0115] It should be noted that at least the Type T characterising peak at 7.9 ± 0.2° 29 is not present in the XRPD of previously disclosed Type A, Type K, Type N, Type O or Type B.

[0116] An XRPD pattern will be understood to comprise a diffraction angle (expressed in degrees 2 9) of “about” a value specified herein when the XRPD pattern comprises a diffraction angle within ± 0.2 degrees 29 of the specified value. Further, it is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an X-ray powder diffraction (XRPD) pattern may cause some variability in the appearance, intensities, and positions of the lines / peaks in the diffraction pattern. An X-ray powder diffraction pattern that is “substantially in accordance” with that of Figure 1 provided herein is an XRPD pattern that would be considered by one skilled in the art to represent a compound possessing the same crystalline form as the compound that provided the XRPD pattern of Figure 1 . That is, the XRPD pattern may be identical to that of Figure 1 or it may be somewhat different. Such an XRPD pattern may not necessarily show each of the lines / peaks of the diffraction pattern presented herein, and / or may show a slight change in appearance, intensity, or a shift in position of said lines / peaks resulting from differences in the conditions involved in obtaining the data. A person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, the form disclosed herein by comparison of their XRPD patterns. For example, one skilled in the art can overlay an XRPD pattern of a sample of a different form or group of camlipixant with Figure 1 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample is substantially in accordance with the XRPD pattern of Type of camlipixant. If the XRPD pattern is substantially in accordance with Figure 1 , the sample form can be readily and accurately identified as being Type of camlipixant. The same is true for Figure 9 in relation to Type T of camlipixant.

[0117] In an embodiment, Type is characterised by an XRPD pattern having peaks at 29 angles when measured using Cu Ka radiation at 1 .54 Angstroms. As discussed above, an XRPD pattern of Type is shown in Figure 1 . The corresponding reflections and heights are provided in Table 1 a above.

[0118] In an embodiment, Type T is characterised by an XRPD pattern having peaks at 29 angles when measured using Cu Ka radiation at 1 .54 Angstroms. As discussed above, an XRPD pattern of Type T is shown in Figure 9. The corresponding reflections and heights are provided in Table 2a above.

[0119] Methods of Treatment

[0120] In a fourth aspect of the invention, there is provided a crystalline form of camlipixant according to the first or second aspect, for use in the treatment of cough, in particular refractory chronic cough.

[0121] In particular, there is provided a crystalline form of camlipixant (Type V), which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4 and 13.3 ± 0.2° 29, for use in the treatment of cough, in particular refractory chronic cough.

[0122] In one embodiment, there is provided a crystalline form of camlipixant (Type V) which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4, 13.3, 14.5 and 19.7 ± 0.2° 29, for use in the treatment of cough, in particular refractory chronic cough.

[0123] In one embodiment, the crystalline form of camlipixant (Type V) is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of those set out in the Table 1a above.

[0124] In one embodiment, there is provided a crystalline form of camlipixant is characterised by an X- ray powder diffraction (XRPD) substantially in accordance with Figure 1 , for use in the treatment of cough, in particular refractory chronic cough. Alternatively, there is provided a crystalline form of camlipixant (Type T), which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5 and 10.3 ± 0.2° 29, for use in the treatment of cough, in particular refractory chronic cough.

[0125] In one embodiment, there is provided a crystalline form of camlipixant (Type T) which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5, 7.9, 10.3, 13.0, 15.6 and 20.4 ± 0.2° 29, for use in the treatment of cough, in particular refractory chronic cough.

[0126] In one embodiment, the crystalline form of camlipixant (Type T) is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of those set out in the Table 2a above

[0127] In one embodiment, there is provided a crystalline form of camlipixant is characterised by an X- ray powder diffraction (XRPD) substantially in accordance with Figure 9, for use in the treatment of cough, in particular refractory chronic cough.

[0128] In a fifth aspect of the invention, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of the crystalline form according to the first aspect or second aspect or comprising administering a pharmaceutical composition according to the third aspect.

[0129] In particular, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of a crystalline form of camlipixant (Type V), which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4 and 13.3 ± 0.2° 29.

[0130] In one embodiment, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of a crystalline form of a crystalline form of camlipixant (Type V) which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4, 13.3, 14.5 and 19.7 ± 0.2° 29.

[0131] In one embodiment, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of a crystalline form of a crystalline form of camlipixant (Type V) characterised by an X-ray powder diffraction (XRPD) substantially in accordance with Figure 1 .

[0132] In one embodiment, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of a crystalline form of a crystalline form of camlipixant (Type T) which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5 and 10.3 ± 0.2° 29. In one embodiment, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of a crystalline form of a crystalline form of camlipixant (Type T) is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5, 7.9, 10.3, 13.0, 15.6 and 20.4 ± 0.2° 29.

[0133] In one embodiment, there is provided a method of treatment of cough, particularly refractory chronic cough, comprising administering to said human a therapeutically effective amount of a crystalline form of a crystalline form of camlipixant (Type T) characterised by an X-ray powder diffraction (XRPD) substantially in accordance with Figure 9.

[0134] For the avoidance of doubt, refractory chronic cough may be defined as a disease manifesting as a cough that persists for > 8 weeks despite adequate treatment of other cough-associated diseases or for which no cause can be identified.

[0135] The following non-limiting examples illustrate the present invention.

[0136] EXAMPLES

[0137] Compound 1 = methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1 ,2- a]pyridin-3-yl)methyl)morpholine-4-carboxylate having the following structure

[0138] Type V

[0139] Preparation

[0140] Compound 1 (2g) was slurried in water (100ml_) with magnetic stirring (300rpm). The slurry was then heated to 80 °C for 7 days. The temperature was cooled to room temperature over 1 h and the solid isolated using vacuum filtration and washed with water (50 mL) before drying at 50 °C under vacuum to isolate camlipixant Type V.

[0141] Compound 1 input material was crystalline form Type A. Type A of camlipixant can be prepared in accordance with the disclosure in WO 2020 / 099923 and WO 2021 / 161109. For example, Example 2E in WO 2020 / 099923 relating to preparation of Type A*. Alternatively, Type A could be obtained according to Example 2A in WO 2020 / 099923, followed by drying at 50 °C under vacuum.

[0142] Alternatively, the input material for generation of Type according to the above method may be amorphous compound 1.

[0143] Alternative preparation of Type

[0144] Compound 1 was slurried in methanol (8.99 vol) and water (10 vol) and heated to 55 °C to achieve dissolution. The mixture was then cooled to 50 °C and before charging with water (0.5vol). The solution was seeded with Type Compound 1 (2wt%) held for 1 h before charging more water (2.7vol) and cooling to 40 °C. The final slurry was held for two days and Type was isolated in by vacuum filtration (39 % w / w yield).

[0145] Compound 1 input material may be prepared in accordance with the procedure set out in the previous section.

[0146] Type see material may be prepared according to the previous slurry experiment.

[0147] Alternative preparation of Type

[0148] Amorphous compound 1 (20 mg) was suspended into 0.5 mL anisole at 50 °C and stirred for 13 days. The solids were then isolated and dried under vacuum to provide camlipixant Type V.

[0149] Compound 1 may be prepared by any suitable method, for example the method disclosed in WO 2014 / 117274, WO 2021 / 161109 or WO 2023 / 021328.

[0150] Characterising Data

[0151] XRPD of Type was carried out according to the following method.

[0152] X-ray powder diffraction (XRPD) patterns were collected in transmission configuration with the sample held in place using kapton film. The analysis parameters were as follows in Table 3:

[0153]

[0154] Table 3

[0155] The XRPD pattern for Type of camlipixant (Compound 1) can be seen in Figure 1.

[0156] Differential scanning calorimetry (DSC) was collected by heating a small amount of sample in an aluminium pan to 250 °C at 10 °C / min with N2purge gas. The trace obtained is shown in Figure

[0157] 2. Based on this, it was shown that the onset temperature of Type is about 164 °C.

[0158] Thermogravimetric analysis (TGA) was collected by heating a small amount of sample in an aluminium pan to 250 °C at 10 °C / min with N2purge gas. The trace obtained is shown in Figure

[0159] 3.

[0160] Gravimetric vapour sorption (GVS) was collected using a Surface Measurements Systems (SMS) Ltd DVS-Advantage instrument. The relative humidity was calibrated against deliquescence point of LiCI, MgCI2and NaCI at 25 °C.

[0161] The following parameters were used (Table 4):

[0162] Table 4 The trace obtained is shown in Figure 4.

[0163] The molecular structure of Type of camlipixant was determined from three-dimensional X-ray diffraction data and is shown in Figure 5. The study (details summarised in Table 5) confirmed the atomic connectivity of Type of camlipixant, with derived bond distances and angles being fully consistent with the proposed structure. The structure determination also allowed the unambiguous assignment of absolute configuration. Type of camlipixant contains one stereogenic centre and is the isomer with the S configuration.

[0164] Table 5

[0165] Crystal Data, Data Collection and Refinement Summary for the GSK5464714A Type V X- ray Diffraction Study

[0166] Variable temperature X-ray powder diffraction (VT-XRPD) patterns were collected in reflectance configuration. No change in the XRPD diffractogram was observed upon heating the material to temperatures of up to 150 °C with peak shift < 0.2 ° 2Theta, as shown in Figure 6. No change over varied temperature was observed.

[0167] The conditions used are as shown in Table 6.

[0168] Table 6

[0169] Variable humidity X-ray powder diffraction (VH-XRPD) patterns were collected in reflectance configuration. No change in the XRPD diffractogram was observed upon exposure of the material to relative humidities of up to 90% RH with peak shift < 0.2 ° 2Theta, as shown in Figure 7. No change over varied humidity was observed.

[0170] The conditions used are as shown in Table 7. Based on the results of the variable temperature and variable humidity experiments and data collected, it can be seen that the XRPD for Type does not vary substantially according to temperature or humidity, therefore providing an indication as to the stability of Type V, across the measured conditions.

[0171] Table 7

[0172] 13C Solid state NMR data were acquired using a Bruker Avance III NMR spectrometer with an operating1H frequency of 400.222 MHz. The spectrometer was equipped with a 4 mm double resonance magic-angle spinning probe operating at a rotation frequency of 8 kHz. Spectra were obtained using cross-polarisation, with a linear power ramp used on the1H channel to enhance cross-polarisation efficiency. Spinning sidebands were eliminated by a total sideband suppression sequence.1H decoupling was obtained using the SPINAL-64 sequence.13C chemical shifts are referenced to tetramethylsilane at 0 ppm (parts per million), using the carbonyl peak in a-glycine at 176.4 ppm as a secondary reference.

[0173] As a variable hydrate, it is known that differences in water content for Type will result in minor differences in peak shifts from the stated characteristic peak shifts for Type in Table 8 below. The spectra is shown in Figure 8.

[0174] Table 8

[0175] Biorelevant solubility data

[0176] To each vial with dispensed API (3mg) of crystalline form Type V, 3 mL of 10 mM Phosphate Buffer pH 6.8, 10mM Acetate Buffer pH 4.5, or 10 mM HCI Buffer pH 1.2 buffer was dispensed using an electronic pipette (BRAND, HandyStep Touch Multidispenser). Vials were placed on a bioshaker (BioShake iQ) set to 500 rpm and 37.5 °C. After 24h aliquots were removed from each vial, filtered through 0.45 urn PVDF filters and solubility quantified via HPLC UV. For HCL pH 1 .2 samples, a visual assessment only was conducted.

[0177] Stability data

[0178] The stability of Type solid was assessed at conditions of 40 °C and 75 % relative humidity (RH).

[0179] No change in the solid form or purity was observed over the 6 month time frame.

[0180] Results are show in Table 10.

[0181] Table 10

[0182] Water activity data

[0183] Water activity experiments were conducted at 25°C with methanol / water system to determine critical water activity between anhydrate and hydrate.

[0184] 1 :1 mass mixture of Type A and Type were studied in water activity experiments. About 5 mg of Type A and Type were equilibrated with 1 mL saturated solution of camlipixant at different water activities for 3 days at 25°C. The suspensions were filtered and dried for 10 min at ambient condition. The solid part was investigated by XRPD.

[0185] Results are shown in Table 11.

[0186] Table 11

[0187] As can be seen from the data in Table 11 , when a mixture of Type A and Type is subjected to solvent conditions where more water is present, Type formation is favoured. Contrary to this, when a mixture of Type A and Type is subjected to solvent conditions where less water is present, Type A formation is favoured. Therefore, it is hypothesised that when camlipixant is formulated in solid state (for example, tablet form), Type A is favoured, whereas when camlipixant is formulated in suspension form, i.e. in the presence of water, Type is favoured.

[0188] Type T

[0189] Preparation

[0190] To compound 1 (323 mg) was added water (2.1 mL) then methanol (4.9 mL) and then slurried at room temperature for at least 16 h. The solid was isolated by vacuum filtration before drying at 50 °C under vacuum overnight to isolate camlipixant Type T.

[0191] Compound 1 input material was crystalline form Type A. Type A of camlipixant can be prepared in accordance with the disclosure in WO 2020 / 099923 and WO 2021 / 161109. For example, Example 2E in WO 2020 / 099923 relating to preparation of Type A*. Alternatively, Type A could be obtained according to Example 2A in WO 2020 / 099923, followed by drying at 50 °C under vacuum.

[0192] Alternatively, the input material for generation of Type T according to the above method may be amorphous compound 1.

[0193] XRPD of Type T was carried out according to the following method.

[0194] X-ray powder diffraction (XRPD) patterns were collected in transmission configuration with the sample held in place using kapton film. The analysis parameters were as follows:

[0195]

[0196] Table 12

[0197] The XRPD pattern for Type T of camlipixant (Compound 1) can be seen in Figure 9.

[0198] Differential scanning calorimetry (DSC) was collected by heating a small amount of sample in an aluminium pan to 220 °C at 10 °C / min with N2purge gas. The trace obtained is shown in Figure

[0199] 10. Based on this, it was shown that the onset temperature of Type T is about 103 °C.

[0200] Thermogravimetric analysis (TGA) was collected by heating a small amount of sample in an aluminium pan to 300 °C at 10 °C / min with N2purge gas. The trace obtained is shown in Figure

[0201] 11.

[0202] Gravimetric vapour sorption (GVS) was collected using a Surface Measurements Systems (SMS) Ltd DVS-Advantage instrument. The relative humidity was calibrated against deliquescence point of LiCI, MgCI2and NaCI at 25 °C.

[0203] The following parameters were used (Table 13):

[0204] Table 13

[0205] The trace obtained is shown in Figure 12.

[0206] Variable humidity X-ray powder diffraction (VH-XRPD) patterns were collected in reflectance configuration. No change in the XRPD diffractogram was observed upon exposure of the material to relative humidities of up to 90% RH with peak shift < 0.2 ° 2Theta, as shown in Figure 13. No change over varied humidity was observed.

[0207] Based on the variable humidity XRPD results, it can be seen that the XRPD for Type T does not vary substantially according to different humidity conditions, therefore providing an indication as to the stability of Type T, across the measured conditions.

[0208] The conditions used are as shown in Table 14.

[0209] Table 14

[0210] Solid state NMR data were collected in accordance with the method set out above in relation to

[0211] Type V.

[0212] The peaks shifts are set out in Table 15 below and the spectra is provided in Figure 14.

[0213] Biorelevant solubility data

[0214] To each vial with dispensed API (3mg) of Type T form, 3 mL of 10 mM Phosphate Buffer pH 6.8, 10mM Acetate Buffer pH 4.5 or 10 mM HCI Buffer pH 1.2 buffer was dispensed using an electronic pipette (BRAND, HandyStep Touch Multidispenser). Vials were placed on a bioshaker (BioShake iQ) set to 500 rpm and 37.5 °C. After 24h aliquots were removed from each vial, filtered through 0.45 urn PVDF filters and solubility quantified via HPLC UV. For HCL pH 1 .2 samples, a visual assessment only was conducted.

[0215] Table 16

[0216] Stability data

[0217] The stability of Type T solid was assessed at 25 °C and 60 % relative humidity (RH). No change in the solid form or purity was observed over the 9 month time frame.

[0218] Results are shown in Table 17.

[0219] Table 17

[0220] Comparative data

[0221] Characterising data

[0222] A comparison of solid state NMR of Type A, and T was done.

[0223] 13C Solid state NMR data were acquired using a Bruker Avance III NMR spectrometer with an operating1H frequency of 400.222 MHz. The spectrometer was equipped with a 4 mm double resonance magic-angle spinning probe operating at a rotation frequency of 8 kHz. Spectra were obtained using cross-polarisation, with a linear power ramp used on the1H channel to enhance cross-polarisation efficiency. Spinning sidebands were eliminated by a total sideband suppression sequence.1H decoupling was obtained using the SPINAL-64 sequence.13C chemical shifts are referenced to tetramethylsilane at 0 ppm (parts per million), using the carbonyl peak in a-glycine at 176.4 ppm as a secondary reference.

[0224] As a variable hydrate, it is known that differences in water content for Type A will result in minor differences in peak shifts from the stated characteristic peak shifts for Type A in Table 18.

[0225] Table 18

[0226] A comparison of the solid state NMR spectra can be seen in Figure 15. Biorelevant Solubility

[0227] As mentioned above, Type A of camlipixant can be prepared in accordance with the disclosure in WO 2020 / 099923 and WO 2021 / 161109. The biorelevant solubility for Type A was assessed in accordance with the procedures set out above in relation to Type and Type T and the results are provided below in Table 19.

[0228] Table 19

[0229] By comparison of the biorelevant solubility of Type A and Type V, it can be seen that Type is less soluble than Type A. Therefore, Type is expected to be more stable in conditions where water may be present.

Claims

CLAIMS1 . A Type crystalline form of camlipixant, which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.7, 7.4 and 13.3 ± 0.2° 29.

2. The crystalline form of claim 1 , which is characterised by an XRPD pattern having peaks at a 29 angle of about 5.7, 7.4, 13.3, 14.5 and 19.7 ± 0.2° 29.

3. The crystalline form of claim 1 or 2, which is characterised by an XRPD pattern substantially in accordance with Figure 1.

4. The crystalline form of any one of claims 1 to 3, wherein the form is characterised by a DSC trace with a single endotherm with an onset temperature of about 164 °C.

5. The crystalline form of any one of claims 1 to 4, wherein the form is characterised by a DSC trace substantially in accordance with Figure 2.

6. The crystalline form of any one of claims 1 to 5, wherein the form is characterised by a solid state NMR having peaks at about 21.8, 52.1 , 71.2, 129.2, 141.6, 165.6 and 167.1 ppm.

7. The crystalline form of any one of claims 1 to 6, wherein the form is characterised by a solid state NMR substantially in accordance with Figure 15.

8. A Type T crystalline form of camlipixant, which is characterised by an X-ray powder diffraction (XRPD) pattern having peaks at a 29 angle of about 5.5, 6.5 and 10.3 ± 0.2° 29.

9. The crystalline form of claim 8, which is characterised by an XRPD pattern having peaks at a 29 angle of about 5.5, 6.5, 7.9, 10.3, 13.0, 15.6 and 20.4 ± 0.2° 29.

10. The crystalline form of claim 8 or 9, which is characterised by an XRPD pattern substantially in accordance with Figure 9.11 . The crystalline form of any one of claims 8 to 10, wherein the form is characterised by a DSC trace with a single endotherm with an onset temperature of about 103 °C.

12. The crystalline form of any one of claims 8 to 11 , wherein the form is characterised by a DSC trace substantially in accordance with Figure 10.

13. The crystalline form of any one of claims 8 to 12, wherein the form is characterised by a solid state NMR having peaks at about 20.4, 64.1 , 75.2, 132.2, 135.2, 162.1 and 163.6 ppm.

14. The crystalline form of any one of claims 8 to 13, wherein the form is characterised by a solid state NMR substantially in accordance with Figure 15.

15. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 14, and at least one inactive ingredient selected from pharmaceutically acceptable excipients, carriers of diluents.

16. The pharmaceutical composition according to claim 15, wherein the composition is formulated for oral administration.

17. The crystalline form according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 or 16, for use in the treatment of cough.

18. The crystalline form or pharmaceutical composition of claim 17, wherein the cough is chronic cough or acute cough.

19. The crystalline form or pharmaceutical composition of claim 17 or 18, wherein the cough is refractory chronic cough.

20. A method of treatment of cough in a human in need thereof comprising administering to said human a therapeutically effective amount of the crystalline form according to any one of claims 1 to 14 or pharmaceutical composition according to claims 15 or 16.21 . A method of treatment according to claim 20, where the cough is chronic cough or acute cough.

22. A method of treatment according to claim 20 or claim 21 , where the cough is refractory chronic cough.