CRYSTALINE FORMS OF A CANNABIDIOL-LIKE CANNABINOID

RELATED APPLICATIONS

[0001] The present application is related to, and claims the benefit of, GB 2206506.4 filed on 04 May 2022 (04.05.2022), the contents of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to crystalline forms of 6-hydroxy cannabidivarin (6-OH CBDV), methods for their production, and their use in therapy.

BACKGROUND TO THE INVENTION

[0003] Alpha 6-hydroxy cannabidivarin (6-OH CBDV) is an oxidised cannabidiol-like (CBD-like) cannabinoid derivative having the formula:

[0004] International application PCT/GB2020/052944 provides data demonstrating the efficacy of 6-OH CBDV in two mouse models of seizure. Thus, 6-OH CBDV will be useful in the treatment of epilepsy.

[0005] PCT/GB2020/052944 describes the production of 6-OH CBDV by reduction of 6-oxo-CBDV diacetate. The 6-OH CBDV product was purified by column chromatography to provide glassy (amorphous) solid or semi-solid material.

[0006] The present invention has been devised in light of these considerations.

BRIEF SUMMARY OF THE INVENTION

[0007] At its most general, the present invention relates to 6-OH CBDV in crystalline form. The crystalline form is easier to handle than glassy, amorphous material.

[0008] In a first aspect of the invention there is provided 6-OH CBDV in crystalline form.

[0009] In a second aspect of the invention, there is provided crystalline Form A 6-OH CBDV. The inventors have found that Form A has excellent chemical stability. For example, Form A is particularly stable to various stress conditions including compression and milling, which aids processing and handling during formulation of a pharmaceutical product. Form A also has a high melting-point, further improving processability [0010] Form A 6-OH CBDV is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.83, 12.50, 13.01 , 14.64, 18.30, 20.79, 23.90, 24.60, 25.43, and 26.22 ±0.2 (°20).

[0011] Form A material may have a differential scanning calorimetry (DCS) thermogram comprising a peak with an onset temperature (T _onse t) of between 142 °C and 153 °C, such as about 151 °C. Form A material may comprise rod-like crystals. Form A material may have an XRPD pattern further comprising peaks at 9.26, 10.75, 11 .24, 12.03, 17.28, 18.52, 23.70, and 24.08 ±0.2 (°20). Further peaks may also occur at 17.52, 19.31 , and 19.94 ±0.2 (°20). Form A material may have an XRPD pattern substantial as shown in Figure 6. Form A material may be anhydrous.

[0012] In a third aspect of the invention, there is provided crystalline Form B 6-OH CBDV. Form B is highly ordered (low disorder).

[0013] Form B 6-OH CBDV is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.44, 10.10, 13.95, 15.89, 16.31 , 20.51 , 21.17, 21.76 and 26.21 ±0.2 (°20).

[0014] Form B material may have a thermogravimetric differential thermal analysis (TG/DTA) thermogram comprising a peak with a Tonset of about 78 ±2 °C. Form B may be a methyl ethyl ketone solvate.

[0015] In a fourth aspect of the invention, there is provided crystalline Form C 6-OH CBDV.

[0016] Form C 6-OH CBDV is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 9.59, 10.20, 13.96, 14.22, 15.85, 16.14, 16.51 , 20.53, 20.92, 21.40, 21.86, 24.39, and 24.65 ±0.2 (°20).

[0017] Form C material may have a TG/DTA thermogram comprising a peak with a Tonset of about 80 ±2 °C. Form C material may be an acetone solvate.

[0018] In a fifth aspect of the invention, there is provided crystalline Form D 6-OH CBDV.

[0019] Form D 6-OH CBDV is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.16, 12.46, 22.24, and 26.77 ±0.2 (°20).

[0020] Form D material may have a TG/DTA thermogram comprising a peak with a Tonset of about 94 °C.

[0021] In a sixth aspect of the invention, there is provided crystalline Form E 6-OH CBDV.

[0022] Form E 6-OH CBDV is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.73, 10.96, 12.62, 15.37, 17.52, 18.68, and 19.74 ±0.2 (°20).

[0023] Form E material may have a TG/DTA thermogram comprising a peak with a Tonset of about 117 °C. Form E material may be a dimethylacetamide solvate.

[0024] In a seventh aspect of the invention, there is provided a composition comprising 6-OH CBDV, wherein 5 wt% or more, such as 50 wt% or more, 90 wt% or more, or 95 wt% or more of the 6-OH CBDV is the crystalline form of the second, third, fourth, fifth, or sixth aspects.

[0025] In an eight aspect of the invention, there is provided a pharmaceutical composition comprising the crystalline form of any of the first, second, third, fourth, fifth, or sixth aspects, or the composition the seventh aspect, together with one or more ingredients selected from carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants, masking agents, colouring agents, flavouring agents, and sweetening agents.

[0026] Preferably, the pharmaceutical composition may be in a form selected from a tablet, a granule, a powder, a capsule, and a pill.

[0027] In a ninth aspect of the invention, there is provided the crystalline form of any of the first, second, third, fourth, fifth, or sixth aspects; the composition the seventh aspect; or the pharmaceutical composition of the eight aspect, for use in a method of treatment.

[0028] Preferably, the method of treatment of the ninth aspect is a method of treatment of epilepsy.

[0029] In a tenth aspect of the invention, there is provided a method for preparing a crystalline form of 6-OH CBDV, preferably Form A 6-OH CBDV, the method comprising the following steps:

(a) providing a composition comprising 6-OH CBDV and a solvent selected from water and a hydrocarbon solvent;

(b) heating the composition;

(c) cooling the composition; and

(d) isolating the solids.

[0030] These and other aspects and embodiments of the invention are described in further detail below.

BRIEF SUMMARY OF THE DRAWINGS

[0031] The present invention is described with reference to the figures listed below:

Figure 1 is an XRPD spectrum of amorphous 6-OH CBDV.

Figure 2 is a TG/DTA thermogram of amorphous 6-OH CBDV.

Figure 3 is a DSC thermogram of amorphous 6-OH CBDV.

Figure 4 is a hyper DSC thermogram of amorphous 6-OH CBDV.

Figure 5 is a photomicrographic image of amorphous 6-OH CBDV.

Figure 6 is an XRPD spectrum of Form A 6-OH CBDV. Figure 7 is a TG/DTA thermogram of Form A 6-OH CBDV.

Figure 8 is a DSC thermogram of Form A 6-OH CBDV.

Figure 9 is a photomicrographic image of Form A 6-OH CBDV.

Figure 10 shows the XRPD pattern of Form A material before (top) and after (bottom) compression.

Figure 11 is an XRPD spectrum of Form B 6-OH CBDV.

Figure 12 is a TG/DTA thermogram of Form B 6-OH CBDV (after drying under vacuum for approx.. 2 hr).

Figure 13 is an XRPD spectrum of Form C 6-OH CBDV.

Figure 14 is a TG/DTA thermogram of Form C 6-OH CBDV.

Figure 15 is an XRPD spectrum of Form D 6-OH CBDV.

Figure 16 is a TG/DTA thermogram of Form D 6-OH CBDV.

Figure 17 is an XRPD spectrum of Form E 6-OH CBDV.

Figure 18 is a TG/DTA thermogram of Form E 6-OH CBDV.

Figure 19 shows the XRPD spectrum of Form E (pink; top) and Form E after drying under vacuum for approx. 2 hr (blue; bottom).

Figure 20 shows the TG/DTA thermogram of Form E 6-OH CBDV (after drying under vacuum for approx. 2 hr).

DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention relates provides a crystalline form of 6-OH CBDV.

[0033] Characterisation of a crystalline material, such as a crystalline form of 6-OH CBDV, and differentiation of a crystalline material from an amorphous material can be achieved using known techniques. In particular, verification of the form can be achieved using techniques such as melting point, differential scanning calorimetry, thermogravimetric differential thermal analysis, optical microscopy and X-ray powder diffraction.

Form A

[0034] In one aspect, the present invention provides crystalline Form A 6-OH CBDV. Crystalline Form A material is particularly preferred because it has excellent chemical stability. Form A displays good stability to compression and milling, which aids processing and handling during formulation of a pharmaceutical product. Form A also has a high melting-point, further improving processability.

[0035] The XRPD pattern of crystalline Form A 6-OH CBDV displays characteristic peaks (see, e.g., Figure 6). The XRPD pattern of the material may be determined using standard techniques, such as using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1 D-Medipix3 detector system. Sample analysis may be performed at, for example, ambient temperature in transmission mode, with a spin rate of 60 rpm. Characteristic peaks may be identified based on their position (°20). Characteristic peaks may be further identified by their relative intensity in comparison to the largest identified peak using a suitable cut-off value (for example, a relative intensity of greater than 15%).

[0036] In one embodiment, the Form A 6-OH CBDV is characterised by an XRPD pattern comprising at least one peak at a position (°20) selected from 7.83, 12.50, 13.01 , 14.64, 18.30, 20.79, 23.90, 24.60, 25.43, and 26.22 ±0.2, such as measured using Cu-K _a irradiation (1.54060 A).

[0037] Preferably, the Form A 6-OH CBDV is characterised by an XRPD pattern comprising at least two peaks, more preferably at least three peaks, even more preferably at least five peaks, and most preferably at least seven peaks at positions (°20) selected from 7.83, 12.50, 13.01 , 14.64, 18.30, 20.79, 23.90, 24.60, 25.43, and 26.22 ±0.2, such as measured using Cu-K _a irradiation (1.54060 A).

[0038] In one embodiment, the Form A 6-OH CBDV is characterised by an XRPD pattern comprising peaks at 7.83, 12.50, 13.01 , 14.64, 18.30, 20.79, 23.90, 24.60, 25.43, and 26.22 ±0.2 (°20), such as measured using Cu-K _a irradiation (1.54060 A).

[0039] In one embodiment, the Form A 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 9.26, 10.75, 11.24, 12.03, 17.28, 18.52, 23.70, and 24.08 ±0.2 (°20), such as measured using Cu-K _a irradiation (1.54060 A).

[0040] In one embodiment, the Form A 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 17.52, 19.31 , and 19.94 ±0.2 (°20), such as measured using Cu- Ka irradiation (1 .54060 A).

[0041] In one embodiment, the Form A 6-OH CBDV has an XRPD pattern substantial as shown in Figure 6.

[0042] The DSC thermogram of crystalline Form A 6-OH CBDV displays characteristic peaks (Figure 8). The DCS thermogram may be determined using standard techniques, such as using a Perkin Elmer Jade Differential Scanning Calorimeter with a heating rate of 10°C/minute to a maximum of 235°C.

[0043] In one embodiment, the Form A 6-OH CBDV is characterised by a DSC thermogram comprising a peak with an onset temperature (T _on set) of between 142 °C and 153 °C, such as measured at a heating rate of 10 °C/min. Preferably, the Form A 6-OH CBDV is characterised by a DSC thermogram comprising a peak with T _onS et of 151 ±2 °C, such as measured at a heating rate of 10 °C/min. [0044] In one embodiment, the Form A 6-OH CBDV has a DSC thermogram substantial as shown in Figure 8.

[0045] In one embodiment, the Form A 6-OH CBDV comprises rod-like crystals.

[0046] In one embodiment, the Form A 6-OH CBDV is substantially as shown in Figure 9.

[0047] In one embodiment, the Form A 6-OH CBDV is anhydrous (does not contain bound water). In a preferred embodiment the Form A 6-OH CBDV does not contain any bound solvent.

[0048] In one aspect, the invention provides a composition comprising 6-OH CBDV, wherein 5 wt% or more of the 6-OH CBDV is Form A 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 10 wt% or more, more preferably 50 wt% or more, of the 6-OH CBDV is Form A 6-OH CBDV.

[0049] In another aspect, the invention provides a composition comprising 6-OH CBDV, wherein 85 wt% or more of the 6-OH CBDV is Form A 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 90 wt% or more, more preferably 95 wt% or more, even more preferably 98 wt% or more, of the 6-OH CBDV is Form A 6-OH CBDV.

[0050] In one aspect, the invention provides a method for preparing crystalline Form A 6-OH CBDV, the method comprising the following steps:

(a) providing a composition comprising 6-OH CBDV and a solvent selected from water and a hydrocarbon solvent;

(b) heating the composition;

(c) cooling the composition; and

(d) isolating the solids.

[0051] The 6-OH CBDV used in the preparation step (step a) may be any form of 6-OH CBDV. Typically, the 6-OH CBDV used in the preparation method is or comprises amorphous 6-OH CBDV.

[0052] The hydrocarbon solvent may be an aliphatic or aromatic hydrocarbon solvent.

[0053] Examples of suitable aliphatic hydrocarbon solvents include linear alkanes such as pentane, hexane, heptane and octane; cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane; and petroleum fractions such as kerosene and petroleum ether. Examples of suitable aromatic hydrocarbon solvents include benzene, toluene and xylene.

[0054] In one embodiment, the organic solvent is an aliphatic hydrocarbon solvent, preferably the organic solvent is heptane or pentane.

[0055] In a preferred embodiment, the organic solvent is an aromatic hydrocarbon solvent, more preferably the organic solvent is toluene. [0056] The heating step (step b) may be carried out to a predetermined maximum temperature. Typically, the predetermined maximum temperature is the lower of i) 10 °C lower than the solvent boiling point, preferably 5 °C or 3°C lower than the solvent boiling point; or ii) 100°C.

[0057] The heating step (step b) may be carried out at a predetermined heating rate. Typically, the predetermined heating rate is from 0.2 °C/min to 20 °C/min, preferably from 0.2 °C/min to 10 °C/min, or 0.5 °C/min to 5 °C/min.

[0058] The cooling step (step c) may be carried out to a predetermined minimum temperature. Typically, the predetermined minimum temperature is ambient temperature (~20 °C).

[0059] The cooling step (step c) may be carried out at a predetermined cooling rate. Typically, the predetermined heating rate is from 0.05 °C/min to 10 °C/min, preferably from 0.05 °C/min to 5 °C/min, or 0.1 °C/min to 2 °C/min.

[0060] The isolation step (step d) may comprise isolating the solid material by any suitable method. Suitable methods include filtration and centrifugation.

[0061] Optionally, the method for preparing crystalline Form A 6-OH CBDV comprising repeated heating and cooling cycles (e.g. repeating steps b and c). In one embodiment, the preparation method may comprise 2 or 3 repetitions.

[0062] In another aspect, the invention provides a method for preparing crystalline Form A 6-OH CBDV, the method comprising the following steps:

(a) providing a composition comprising 6-OH CBDV and a solvent selected from water and a hydrocarbon solvent;

(b) heating the composition;

(c) seeding the composition with crystalline Form A 6-OH CBDV;

(d) cooling the composition; and

(e) isolating the solids.

[0063] Preferences for the steps (a), (b), (d) and (e) are set out above.

[0064] In one aspect, the invention provides crystalline Form A 6-OH CBDV prepared by the method outline in paragraphs [0048] to [0059] or [0060] to [0061],

Form B

[0065] In one aspect, the present invention provides crystalline Form B 6-OH CBDV.

[0066] The XRPD pattern of crystalline Form B 6-OH CBDV displays characteristic peaks (see, e.g., Figure 11). The XRPD pattern of the material may be determined using standard techniques (e.g., as set out for Form A, above).

[0067] In one embodiment, the Form B 6-OH CBDV is characterised by an XRPD pattern comprising at least one peak at a position (°2B) selected from 9.44, 10.10, 13.95, 15.89, 16.31 , 20.51. 21.17, 21.76, and 26.21 ±0.2, such as measured using Cu-K _a irradiation (1.54060 A).

[0068] Preferably, the Form B 6-OH CBDV is characterised by an XRPD pattern comprising at least two peaks, more preferably at least three peaks, even more preferably at least five peaks, and most preferably at least seven peaks at positions (°20) selected from 9.44, 10.10, 13.95, 15.89, 16.31 , 20.51. 21.17, 21.76, and 26.21 ±0.2, such as measured using Cu-K _a irradiation (1 .54060 A).

[0069] In one embodiment, the Form B 6-OH CBDV is characterised by an XRPD pattern comprising peaks at 9.44, 10.10, 13.95, 15.89, 16.31 , 20.51. 21.17, 21.76, and 26.21 ±0.2 (°20), such as measured using Cu-K _a irradiation (1.54060 A).

[0070] In one embodiment, the Form B 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 15.58, 17.33, 23.84, and 24.23 ±0.2 (°20), such as measured using Cu-K _a irradiation (1 .54060 A).

[0071] In one embodiment, the Form B 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 19.26 and 20.19 ±0.2 (°20), such as measured using Cu-K _a irradiation (1 .54060 A).

[0072] In one embodiment, the Form B 6-OH CBDV has an XRPD pattern substantial as shown in Figure 11.

[0073] The TG/DTA thermogram of crystalline Form B 6-OH CBDV displays characteristic peaks (Figure 12). The TG/DTA thermogram may be determined using standard techniques, such as using a Mettler Toledo TGA/DSC1 STARe using iridium and tin as calibration standards and with a heating rate of 10°C/minute to a maximum of 300°C.

[0074] In one embodiment, the Form B 6-OH CBDV is characterised by a TG/DTA thermogram comprising a peak with an onset temperature (T _on set) of from 78 ±2 °C, such as measured at a heating rate of 10 °C/min. Typically, the onset temperature is associated with a weight loss of from 10 wt% to 20 wt%, such as 14 wt% to 18 wt%, such as about 15.7 wt%.

[0075] In one embodiment, the Form B 6-OH CBDV is characterised by a TG/DTA thermogram comprising a peak with an onset temperature (T _onS et) of 147 ±2 °C, such as measured at a heating rate of 10 °C/min.

[0076] In one embodiment, the Form B 6-OH CBDV has a TG/DTA thermogram substantial as shown in Figure 12.

[0077] In one embodiment, the Form B 6-OH CBDV is an MEK (methyl ethyl ketone) solvate, such as an MEK mono-solvate.

[0078] In one aspect, the invention provides a composition comprising 6-OH CBDV, wherein 5 wt% or more of the 6-OH CBDV is Form B 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 10 wt% or more, more preferably 50 wt% or more, of the 6-OH CBDV is Form B 6-OH CBDV. [0079] In another aspect, the invention provides a composition comprising 6-OH CBDV, wherein 85 wt% or more of the 6-OH CBDV is Form B 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 90 wt% or more, more preferably 95 wt% or more, even more preferably 98 wt% or more, of the 6-OH CBDV is Form B 6-OH CBDV.

[0080] In one aspect, the invention provides a method for preparing crystalline Form B 6-OH CBDV, the method comprising the following steps:

(a) providing a composition comprising 6-OH CBDV and MEK;

(b) evaporating the solvent; and

(c) isolating the solids.

[0081] The 6-OH CBDV used in the preparation step (step a) may be any form of 6-OH CBDV. Typically, the 6-OH CBDV used in the preparation method is or comprises amorphous 6-OH CBDV.

[0082] The evaporation step (step b) may be carried out at any suitable temperature. Typically, the evaporation step is carried out at from 15 °C to 30°C, such as about 20 °C.

[0083] In one aspect, the invention provides crystalline Form B 6-OH CBDV prepared by the method outline in paragraphs [0078] to [0080],

Form C

[0084] In one aspect, the present invention provides crystalline Form C 6-OH CBDV.

[0085] The XRPD pattern of crystalline Form C 6-OH CBDV displays characteristic peaks (see, e.g., Figure 13). The XRPD pattern of the material may be determined using standard techniques (e.g., as set out for Form A, above).

[0086] In one embodiment, the Form C 6-OH CBDV is characterised by an XRPD pattern comprising at least one peak at a position (°2B) selected from 9.59, 10.20, 13.96, 14.22,

15.85, 16.14, 16.51 , 20.53, 20.92, 21.40, 21.86, 24.39, and 24.65 ±0.2, such as measured using Cu-K _a irradiation (1 .54060 A).

[0087] Preferably, the Form C 6-OH CBDV is characterised by an XRPD pattern comprising at least two peaks, more preferably at least three peaks, even more preferably at least five peaks, and most preferably at least seven peaks at positions (°20) selected from 9.59, 10.20, 13.96, 14.22, 15.85, 16.14, 16.51 , 20.53, 20.92, 21.40, 21.86, 24.39, and 24.65 ±0.2, such as measured using Cu-K _a irradiation (1.54060 A).

[0088] In one embodiment, the Form C 6-OH CBDV is characterised by an XRPD pattern comprising peaks at 9.59, 10.20, 13.96, 14.22, 15.85, 16.14, 16.51 , 20.53, 20.92, 21.40,

21.86, 24.39, and 24.65 ±0.2 (°20), such as measured using Cu-K _a irradiation (1.54060 A).

[0089] In one embodiment, the Form C 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 9.21 , 16.97, and 24.22 ±0.2 (°20), such as measured using Cu- Ka irradiation (1 .54060 A). [0090] In one embodiment, the Form C 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 17.58, 19.27, and 19.67 ±0.2 (°20), such as measured using Cu- KQ irradiation (1 .54060 A).

[0091] In one embodiment, the Form C 6-OH CBDV has an XRPD pattern substantial as shown in Figure 13.

[0092] The TG/DTA thermogram of crystalline Form C 6-OH CBDV displays characteristic peaks (Figure 14). The TG/DTA thermogram may be determined using standard techniques(e.g., as set out for Form B, above).

[0093] In one embodiment, the Form C 6-OH CBDV is characterised by a TG/DTA thermogram comprising a peak with an onset temperature (T _onS et) of 80 ±2 °C, such as measured at a heating rate of 10 °C/min. Typically, the onset temperature is associated with a weight loss of from 10 wt% to 20 wt%, such as 14 wt% to 18 wt%, such as about 16.3 wt%.

[0094] In one embodiment, the Form C 6-OH CBDV is characterised by a TG/DTA thermogram comprising a peak with an onset temperature (T _on set) of 148 ±2 °C, such as measured at a heating rate of 10 °C/min.

[0095] In one embodiment, the Form C 6-OH CBDV has a TG/DTA thermogram substantial as shown in Figure 14.

[0096] In one embodiment, the Form C 6-OH CBDV is an acetone solvate, such as an acetone mono-solvate.

[0097] In one aspect, the invention provides a composition comprising 6-OH CBDV, wherein 5 wt% or more of the 6-OH CBDV is Form C 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 10 wt% or more, more preferably 50 wt% or more, of the 6-OH CBDV is Form C 6-OH CBDV.

[0098] In another aspect, the invention provides a composition comprising 6-OH CBDV, wherein 85 wt% or more of the 6-OH CBDV is Form C 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 90 wt% or more, more preferably 95 wt% or more, even more preferably 98 wt% or more, of the 6-OH CBDV is Form C 6-OH CBDV.

[0099] In one aspect, the invention provides a method for preparing crystalline Form C 6-OH CBDV, the method comprising the following steps:

(a) providing a first vessel comprising 6-OH CBDV;

(b) exposing the 6-OH CBDV to an atmosphere comprising water and acetone; and

(c) isolating the solids.

[0100] The 6-OH CBDV used in the preparation step (step a) may be any form of 6-OH CBDV. Typically, the 6-OH CBDV used in the preparation method is or comprises amorphous 6-OH CBDV. [0101] The vapour stress step (step b) may be carried out by providing a second container comprising water and acetone, such as a 1 :4 v/v acetone:water mixture, and allowing communication of the atmosphere (the vapours) between the two vessels. For example, the first vessel may be placed inside the second vessel.

[0102] The vapour stress step (step b) may be carried out at any suitable temperature. Typically, the vapour stress step is carried out at from 15 °C to 3CTC, such as about 20 °C.

[0103] In one aspect, the invention provides crystalline Form C 6-OH CBDV prepared by the method outline in paragraphs [0097] to [0100].

Form D

[0104] In one aspect, the present invention provides crystalline Form D 6-OH CBDV.

[0105] The XRPD pattern of crystalline Form D 6-OH CBDV displays characteristic peaks (see, e.g., Figure 15). The XRPD pattern of the material may be determined using standard techniques (e.g., as set out for Form A, above).

[0106] In one embodiment, the Form D 6-OH CBDV is characterised by an XRPD pattern comprising at least one peak at a position (°20) selected from 8.16, 12.46, 22.24, and 26.77 ±0.2, such as measured using Cu-K _a irradiation (1.54060 A).

[0107] Preferably, the Form D 6-OH CBDV is characterised by an XRPD pattern comprising at least two peaks, more preferably at least three peaks at positions (°20) selected from 8.16, 12.46, 22.24, and 26.77 ±0.2, such as measured using Cu-K _a irradiation (1.54060 A).

[0108] In one embodiment, the Form D 6-OH CBDV is characterised by an XRPD pattern comprising peaks at 8.16, 12.46, 22.24, and 26.77 ±0.2 (°20), such as measured using Cu- Ka irradiation (1 .54060 A).

[0109] In one embodiment, the Form D 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 9.25, 10.73, 10.85, 12.00, 15.28, 18.56 ±0.2 (°20), such as measured using Cu-K _a irradiation (1.54060 A).

[0110] In one embodiment, the Form D 6-OH CBDV is characterised by an XRPD pattern further comprising peaks at 17.65, 19.19, and 19.56 ±0.2 (°20), such as measured using Cu- Ka irradiation (1 .54060 A).

[0111] In one embodiment, the Form D 6-OH CBDV has an XRPD pattern substantial as shown in Figure 15.

[0112] The TG/DTA thermogram of crystalline Form D 6-OH CBDV displays characteristic peaks (Figure 16). The TG/DTA thermogram may be determined using standard techniques (e.g., as set out for Form B, above).

[0113] In one embodiment, the Form D 6-OH CBDV is characterised by a TG/DTA thermogram comprising a peak with an onset temperature (T _onS et) of 94 ±2 °C, such as measured at a heating rate of 10 °C/min. Typically, the onset temperature is associated with a weight loss of from 25 wt% to 40 wt%, such as 30 wt% to 35 wt%, such as about 33 wt%.

[0114] In one embodiment, the Form D 6-OH CBDV has a TG/DTA thermogram substantial as shown in Figure 16.

[0115] In one aspect, the invention provides a composition comprising 6-OH CBDV, wherein 5 wt% or more of the 6-OH CBDV is Form D 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 10 wt% or more, more preferably 50 wt% or more, of the 6-OH CBDV is Form D 6-OH CBDV.

[0116] In another aspect, the invention provides a composition comprising 6-OH CBDV, wherein 85 wt% or more of the 6-OH CBDV is Form D 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 90 wt% or more, more preferably 95 wt% or more, even more preferably 98 wt% or more, of the 6-OH CBDV is Form D 6-OH CBDV.

[0117] In one aspect, the invention provides a method for preparing crystalline Form D 6-OH CBDV, the method comprising the following steps:

(a) providing a composition comprising 6-OH CBDV and a solvent comprising NMP and water;

(b) sonicating the composition; and

(c) isolating the solids.

[0118] The 6-OH CBDV used in the preparation step (step a) may be any form of 6-OH CBDV. Typically, the 6-OH CBDV used in the preparation method is or comprises crystalline Form A 6-OH CBDV.

[0119] The solvent used in the preparation step (step a) may comprise a ratio of NMP:water of from 5:95 to 30:70, such as 10:90 (v/v).

[0120] The sonication step (step b) may be carried out intermittently, such as in 30 second intervals. Typically, the sonication step is carried out using a sonication intensity of from 75 W to 100 W, such as from 80 W to 95 W, such as about 91 W.

[0121] In one aspect, the invention provides crystalline Form D 6-OH CBDV prepared by the method outline in paragraphs [0115] to [0118],

Form E

[0122] In one aspect, the present invention provides crystalline Form E 6-OH CBDV.

[0123] The XRPD pattern of crystalline Form E 6-OH CBDV displays characteristic peaks (see, e.g., Figure 17). The XRPD pattern of the material may be determined using standard techniques (e.g., as set out for Form A, above).

[0124] In one embodiment, the Form E 6-OH CBDV is characterised by an XRPD pattern comprising at least one peak at a position (°20) selected from 10.73, 10.96, 12.62, 15.37, 17.52, 18.68, and 19.74 ±0.2, such as measured using Cu-K _D irradiation (1.54060 A). [0125] Preferably, the Form E 6-OH CBDV is characterised by an XRPD pattern comprising at least two peaks, more preferably at least three peaks, even more preferably at least five peaks at positions (°20) selected from 10.73, 10.96, 12.62, 15.37, 17.52, 18.68, and 19.74 ±0.2, such as measured using Cu-K _a irradiation (1.54060 A).

[0126] In one embodiment, the Form E 6-OH CBDV is characterised by an XRPD pattern comprising peaks at 10.73, 10.96, 12.62, 15.37, 17.52, 18.68, and 19.74 ±0.2 (°20), such as measured using Cu-Ka irradiation (1.54060 A).

[0127] In one embodiment, the Form E 6-OH CBDV has an XRPD pattern substantial as shown in Figure 17.

[0128] The TG/DTA thermogram of crystalline Form E 6-OH CBDV displays characteristic peaks (Figure 20). The TG/DTA thermogram may be determined using standard techniques (e.g., as set out for Form B, above).

[0129] In one embodiment, the Form E 6-OH CBDV is characterised by a TG/DTA thermogram comprising a peak with an onset temperature (T _onS et) of 117 ±2 °C, such as measured at a heating rate of 10 °C/min.

[0130] In one embodiment, the Form E 6-OH CBDV has a TG/DTA thermogram substantial as shown in Figure 20.

[0131] In one embodiment, the Form E 6-OH CBDV is a DMAc (dimethylacetamide) solvate, such as an DMAc mono-solvate.

[0132] In one aspect, the invention provides a composition comprising 6-OH CBDV, wherein 5 wt% or more of the 6-OH CBDV is Form E 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 10 wt% or more, more preferably 50 wt% or more, of the 6-OH CBDV is Form E 6-OH CBDV.

[0133] In another aspect, the invention provides a composition comprising 6-OH CBDV, wherein 85 wt% or more of the 6-OH CBDV is Form E 6-OH CBDV. In a preferred embodiment, the invention provides a composition comprising 6-OH CBDV, wherein 90 wt% or more, more preferably 95 wt% or more, even more preferably 98 wt% or more, of the 6-OH CBDV is Form E 6-OH CBDV.

[0134] In one aspect, the invention provides a method for preparing crystalline Form E 6-OH CBDV, the method comprising the following steps:

(a) providing a first vessel comprising 6-OH CBDV and a solvent comprising DMAc and water;

(b) agitating the composition; and

(c) isolating the solids.

[0135] The 6-OH CBDV used in the preparation step (step a) may be any form of 6-OH CBDV. Typically, the 6-OH CBDV used in the preparation method is or comprises crystalline 6-OH CBDV, preferably crystalline Form A 6-OH CBDV. [0136] The slurring step (step b) may be carried out using mechanical agitation, such as stirring.

[0137] The slurring step (step b) may be carried out at any suitable temperature. Typically, the slurring step is carried out at from 0 °C to 15°C, such as from 3 °C to 10 °C, such as about 5 °C.

[0138] In one aspect, the invention provides crystalline Form E 6-OH CBDV prepared by the method outline in paragraphs [0132] to [0135],

Pharmaceutical Compositions

[0139] While it is possible for the crystalline forms A, B, C, D, or E to be administered alone, it is preferable to administer a pharmaceutical composition (e.g., a formulation, preparation, or medicament) comprising crystalline Form A, B, C, D, or E together with one or more other pharmaceutically acceptable ingredients.

[0140] Accordingly, the invention provides a pharmaceutical composition comprising a crystalline form of 6-OH CBDV, such as Form A, B, C, D, or E, together with one or more pharmaceutically acceptable ingredients.

[0141] In a preferred embodiment, the pharmaceutical composition comprises Form A 6-OH CBDV.

[0142] Suitable pharmaceutically acceptable ingredients (e.g. carriers, diluents, excipients, etc.) can be found in standard pharmaceutical texts, for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 9th edition, 2020, pub. Pharmaceutical Press.

[0143] Examples of suitable pharmaceutically acceptable ingredients include pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, binders, disintegrants, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.

[0144] The pharmaceutical composition may be in any suitable form. Examples of suitable forms include tablets (including, e.g., coated tablets), granules, powders, capsules (including, e.g., hard and soft gelatin capsules) and pills.

Medical Treatment

[0145] The Applicant’s earlier work, PCT/GB2020/052944, provides data demonstrating the efficacy of 6-OH CBDV in two mouse models of seizure. Specifically, PCT/GB2020/052944 demonstrates that 6-OH CBDV displays anticonvulsant activity in a mouse model of generalised seizure. As such, crystalline forms of 6-OH CBDV, such as Form A, B, C, D or E, as well as pharmaceutical compositions comprising crystalline forms of 6-OH CBDV, will be useful in medical treatment. [0146] Accordingly, the invention provides a crystalline form of 6-OH CBDV, such as form A, B, C, D, or E, for use in a method of treatment, for example for use in a method of treatment of the human or animal body by therapy (i.e. a method of therapy).

[0147] The invention also provides a crystalline form of 6-OH CBDV, such as Form A, B, C, D, or E, for use as a medicament.

[0148] The invention also provides a method of treatment comprising administering to a subject in need of treatment a therapeutically effective amount of a crystalline form of 6-OH CBDV, such as Form A, B, C, D, or E.

[0149] The invention also provides the use of crystalline form of 6-OH CBDV, such as Form A, B, C, D, or E, for the manufacture of a medicament.

[0150] In preferred embodiments, the crystalline form of 6-OH CBDV is Form A.

Conditions Treated

[0151] The Applicant’s earlier work, PCT/GB2020/052944, provides data demonstrating the efficacy of 6-OH CBDV in a mouse model of generalised seizure. As such, crystalline forms of 6-OH CBDV, such as Form A, B, C, D or E, as well as pharmaceutical compositions comprising crystalline forms of 6-OH CBDV, will be useful in the treatment of certain conditions associated with seizure.

[0152] Similarly, crystalline forms of 6-OH CBDV, such as Form A, B, C, D or E, as well as pharmaceutical compositions comprising crystalline forms of 6-OH CBDV, will be useful as medicaments for treating (and in the manufacture of medicaments for treating) certain conditions associated with seizure.

[0153] In a preferred embodiment, the condition associated with seizure is epilepsy.

[0154] In one embodiment, the condition associated with seizure is generalised seizure, such as generalised seizure associated with epilepsy.

[0155] In one embodiment, the condition associated with seizure is tonic-clonic seizures, such as tonic-clonic seizures associated with epilepsy.

Subject/Patient

[0156] The method of treatment typically comprises administering a crystalline form of 6-OH CBDV, such as Form A, B, C, D or E, to a subject or patient.

[0157] The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orang-utan, gibbon), or a human. [0158] The subject/patient may be any of its forms of development, for example, the subject/patient may be an infant or child.

[0159] In a preferred embodiment, the subject/patient is a human, more preferably an adult human.

[0160] The subject/patient may also be a non-human mammal used in laboratory research, such as a rodent. Rodents include rats, mice, guinea pigs and chinchillas.

Routes of Administration

[0161] The method of treatment may comprise administering a crystalline form of 6-OH CBDV, such as Form A, B, C, D or E, to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e. , at the site of desired action).

[0162] The route of administration may be oral (e.g., by ingestion).

Dosages

[0163] The method of treatment typically comprises administering a therapeutically effective amount of administering a crystalline form of 6-OH CBDV, such as Form A, B, C, D or E, to a subject.

[0164] Appropriate dosages of the crystalline form of 6-OH CBDV, such as Form A, B, C, D or E, as well as pharmaceutical compositions comprising the crystalline form of 6-OH CBDV, such as Form A, B, C, D or E, can vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular crystalline form of 6-OH CBDV, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other active agents, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The dosage and route of administration will ultimately be at the discretion of the clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

[0165] Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating clinician.

Other Aspects and Embodiments

[0166] Each and every compatible combination of the embodiments described above is explicitly discloses herein, as if each and every combination was individually and explicitly recited. [0167] Carious further aspects and embodiment of the present invention will be apparent to those skilled in the arti in view of the present disclosure.

[0168] Where used, “and/or” is to be taken as a specific disclosure of each of the relevant components or features alone as well as a specific disclosure of the combination of the components or features. For example, “A and/or B” is to be taken as specific disclosure of each of i) A, ii) B, and ii) A and B, just as if each were set out individually.

[0169] Unless context dictates otherwise, the descriptions and definitions of the features set out above are not limited to any particular aspect or embodiment of the invention and apply equally to all aspects ad embodiments which are described.

Definitions

[0170] The following definitions are provided are provided in order to aid understanding of the invention.

[0171] Aw is water activity.

[0172] Epilepsy is considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome (A practical clinical definition of epilepsy by the International League Against Epilepsy (ILAE), 2014).

[0173] The term “generalized seizure” (“generalized onset seizures”) refers to seizures conceptualized as originating at some point within the brain and rapidly engaging bilaterally distributed networks (Operational Classification of Seizure Types by the ILAE, 2017).

[0174] The term "pharmaceutically acceptable" pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each ingredient (e.g. carrier, diluent, excipient, etc.) must also be "acceptable" in the sense of being compatible with the other ingredients of the composition.

[0175] The term "therapeutical ly-effective amount" pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

[0176] A “tonic-clonic seizure” occurs in two phases, a tonic phase typically involving muscle stiffening and loss of consciousness, and a clonic phase typically involving rhythmically jerking of the limbs. WORKED EXAMPLES

[0177] Certain aspects and embodiments of the invention will not be illustrated by way of example and with reference to the figures described above.

Analytical Methods

X-ray Powder Diffraction (XRPD)

[0178] XRPD analyses were performed using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1 D-Medipix3 detector system. The samples were analysed at ambient temperature in transmission mode and held between low density PVC films. The XRPD program parameters were: range 3-40 °20 or 4-40 °20, step size 0.01313°, counting time 23sec, ~5 min run time. Samples were spun at 60 rpm during data collection. XRPD patterns were sorted, manipulated using HighScore Plus v4.9 software.

Differential Scanning Calorimetry (DSC)

[0179] DSC analyses were carried out on a Perkin Elmer Jade Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminium pans (i.e. closed but not gas tight). Each sample was heated under nitrogen at a rate of 10°C/minute to a maximum of 235°C. Indium metal was used as the calibration standard. Temperatures were reported at the transition onset to the nearest 0.01 degree.

Hyper Differential Scanning Calorimetry (Hyper DSC)

[0180] Hyper DSC analyses were carried out on a Perkin Elmer DSC8500 Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminium pans (i.e. closed but not gas tight). Each sample was heated and cooled under nitrogen at a rate of 300°C/minute using a set temperature range of -50 to 180°C. Indium metal was used as the calibration standard.

Thermogravimetric Differential Thermal Analysis (TG/DTA)

[0181] Thermogravimetric analyses were carried out on a Mettler Toledo TGA/DSC1 STARe. The calibration standards were indium and tin. Samples were placed in an aluminium sample pan, inserted into the TG furnace and accurately weighed. Under a stream of nitrogen at a rate of 10°C/minute, the heat flow signal was stabilised for one minute at 30°C, prior to heating to 300°C.

Nuclear Magnetic Resonance spectroscopy (NMR)

[0182] NMR analysis was carried out on a Bruker 500MHz instrument in d6-DMSO. Instrumental parameters are listed on the relevant spectrum plots. Optical Microscopy

[0183] Microscopy analyses were carried out using an Olympus BX51 stereomicroscope with cross-polarised light and a 1st order red compensator plate. Photomicrographic images were captured using a ColorView III u digital camera and SynchronizIR basic V5.0 imaging software with objective lens magnification of x10.

Example 1 : Preparation of amorphous 6-OH CBDV

[0184] 6-OH CBDV was prepared as described in PCT/GB2020/052944.

[0185] To CBDV (5.00 g, 17.5 mmol) in anhydrous pyridine (20 mL) was added acetic anhydride (5.63 g, 5.20 mL, 55.2 mmol) and the solution was stirred for 4 h.

Dichloromethane (300 mL) was added and the solution was washed with water (200 ml), 1 M hydrochloric acid (200 mL), saturated aqueous sodium bicarbonate (200 mL), dried (MgSO4) and concentrated to give CBDV diacetate (6.84 g, quantitative), as a yellow oil which was used without further purification.

[0186] To CBDV diacetate (4.00 g, 10.8 mmol) in glacial acetic acid (9 mL) and acetic anhydride (4.96 g, 4.59 mL, 48.6 mmol) was added sodium dichromate (3.86 g, 13.0 mmol) and the mixture was stirred at room temperature for 4 days. The resulting solution was diluted with water (150 mL) and extracted with diethyl ether (2 x 150 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (150 mL), dried (MgSO4) and concentrated to give a yellow oil that was purified using a Biotage Isolera automated chromatography system under normal phase conditions (silica column, gradient of 5 33 % ethyl acetate in petrol) with detection at 254 nm to give 6-oxo-CBDV diacetate

(1 .40 g 33 %), as a colourless oil. (Rf = 0.36 (ethyl acetate - petrol, 1 : 4 v/v))

[0187] To lithium aluminium hydride (0.58 g, 15.3 mmol) in diethyl ether (50 mL) at 0 °C was added 6-oxo-CBDV diacetate (1 .40 g, 3.64 mmol) in diethyl ether (23 mL) and the mixture was stirred at room temperature for 4 h. The resulting mixture was cooled in an ice bath and cautiously quenched with iced water (100 mL). 1 M Hydrochloric acid (60 mL) was added and the mixture was extracted with diethyl ether (100 mL + 50 mL). The combined organic layers were washed with saturated brine (100 mL), dried (MgSO4) and concentrated to give a pale yellow oil that was purified using a Biotage Isolera automated chromatography system under normal phase conditions (silica column, gradient of 7 —> 53 % ethyl acetate in petrol) with detection at 254 nm to give 6-OH-CBDV (0.70 g, 64 %), as a white glassy solid. (Rf = 0.29 (ethyl acetate - petrol, 3 : 7 v/v)).

R- C3H7, CsH ₁₁

Characterisation of amorphous 6-OH CBDV

[0188] The XRPD pattern obtained for amorphous 6-OH CBDV is shown in Figure 1. The XRPD pattern is indicative of an amorphous material.

[0189] A sample of amorphous 6-OH CBDV was analysed by ¹ H NMR in de-DMSO. The sample contained -0.15 mol eq. EtOH.

[0190] Thermogravimetric/Differential Thermal Analysis (TG/DTA) was performed to determine the thermal profile and associated % weight changes of amorphous 6-OH CBDV.

[0191] The thermogram is shown in Figure 2. A weight loss of -2.2% was observed between ~31°C and ~137°C, which could account for up to -0.1 mol eq. water or ~0.4mol eq. EtOH. An exotherm was observed with an onset temperature of ~75°C, followed by and endotherm with an onset temperature of ~148°C.

[0192] The DSC thermogram shown in Figure 3. An exotherm with an onset temperature of ~76°C can be seen, followed by a sharp endotherm with an onset temperature of ~149°C. The data suggest amorphous material may be crystallising at ~76°C followed by the melt of the crystalline material.

[0193] Hyper DSC analysis was carried out on a sample of amorphous 6-OH CBDV. The thermogram is shown in Figure 4, and the temperature of glass transition (T _g ) was determined to be ~57°C.

[0194] Polarised light microscopy showed that the material was composed of a glassy solid. No birefringence was observed. The photomicrograph is shown in Figure 5.

Example 2: Preparation of Crystalline Form A 6-OH CBDV by Temperature Cycling

[0195] Aliquots of the test solvent were added to an accurately weighed sample (-15mg) of amorphous 6-OH-CBDV at ambient temperature. The aliquot volumes were typically 20-100 pL. After the last aliquot of solvent was added (to approx. 40 volumes of solvent), the sample was subjected to two cycles of the following temperature cycling regime:

• Heat from 20°C to within 3°C of solvent boiling point (or 100°C, whichever was lower) at 0.5°C/minute; • Cool to 20°C at 0.2°C/minute;

• Stirrer speed 800 rpm.

[0196] From the infrared (IR) transmission data of the sample vials, dissolution and precipitation events were recorded as the point of complete transmission of IR and the onset of turbidity by IR respectively. Samples were held at ambient temperature for 18 hours to maximise the chance of precipitation. Any recoverable solids were analysed by XRPD.

[0197] The experiments are detailed in Table 6. All solids recovered were found to be composed of crystalline Form A material by XRPD.

Table 1 : Results of temperature cycling experiments

Characterisation of 6-OH CBDV Form A [0198] The XRPD pattern obtained for crystalline Form A 6-OH-CBDV, is shown in

Figure 6. The XRPD pattern is indicative of a crystalline material, however, the slightly elevated baseline may be indicative of some amorphous content. The XRPD peak listing data is given in Table 2.

Table 2: Observed XRPD data for 6-OH CBDV Form A

[0199] Crystalline Form A 6-OH-CBDV was analysed by ¹ H NMR spectroscopy in dg-DMSO. The spectrum was concordant with the molecular structure. No residual solvent was observed in the spectrum. [0200] Crystalline Form A 6-OH-CBDV was analysed by TG/DTA. The thermogram is shown in Figure 7. A weight loss of -0.2% was observed between ~33°C and ~132°C, which may be due to loss of surface solvent or water. An endotherm was observed with an onset temperature of ~150°C, which is likely due to the melt.

[0201] Crystalline Form A 6-OH-CBDV was analysed by DSC. The thermogram is shown in Figure 8 which shows a single sharp endotherm with an onset temperature of ~151°C.

[0202] Photomicrographic images of crystalline Form A 6-OH-CBDV were collected under cross-polarised light. The photomicrograph showed that the material was composed of rod like crystals (Figure 9).

[0203] Based on this analysis, it is likely that crystalline Form A material is anhydrous. Stability of 6-OH CBDV Form A to Compression

[0204] Crystalline Form A material (~60mg) was added to a KBr pellet die and compressed overnight at ~370MPa using a hydraulic press. The resultant solid disc was removed from the press and immediately analysed by XRPD. The resulting diffractogram (Figure 10) showed that the material remained as Form A, indicating good stability to compression, however broader diffraction peaks showed that some disorder was present.

Stability of Form A to Milling

[0205] A ball mill was used to mimic the effects of grinding that would be experienced during formulation steps such as dry blending and wet granulation.

[0206] Approximately 45mg of crystalline Form A material was added to a milling chamber with an agate milling ball. Using a Retsch MM200 mixer mill, the material was milled for 6 minutes at a frequency of 25Hz. Periodically, the milling was stopped and powder that adhered to the milling chamber was scraped down. The resultant milled material was analysed using XRPD. Samples were also milled with addition of a small amount of solvent (~10pL).

[0207] Form A 6-OH CBDV showed no change in form when ball milled dry or in the presence of a small amount of water, however, the material was more disordered.

Table 3: Results of milling experiments

Example 3: Preparation of 6-OH CBDV Form B by Slow Evaporation

[0208] Amorphous 6-OH-CBDV (~30mg) was weighed into a virgin glass vial. MEK (140uL) was added, and the resulting solution was left to evaporate in the fume-hood at ambient temperature (~20 °C) in a vial covered with perforated aluminium foil. The recovered solids were analysed by XRPD which confirmed that it was composed of crystalline Form B material.

Characterisation of 6-OH CBDV Form B

[0209] The XRPD pattern obtained for crystalline Form B 6-OH-CBDV, is shown in Figure 11 . The XRPD pattern is indicative of a crystalline material. The XRPD peak listing data is given in Table 4. Table 4: Observed XRPD data for 6-OH CBDV Form B

[0210] Crystalline Form B 6-OH-CBDV was analysed by ¹ H NMR spectroscopy in dg-DMSO. The ¹ H NMR spectrum of the material conformed to the molecular structure and contained MEK (~1 .0 mol eq).

[0211] Crystalline Form B 6-OH CBDV was dried under vacuum for ~2hr. The dried sample was analysed by TG/DTA. The thermogram is shown in Figure 12. An endotherm with an onset temperature of ~78°C was noted with a corresponding weight loss of ~15.7% which could account for -3.1 mol eq water or ~0.8mol eq MEK. A second thermogram with an onset temperature of ~147°C was observed.

[0212] Based on this analysis, it is likely that crystalline Form B material is an MEK monosolvate (1 :1). Example 4: Preparation of 6-OH CBDV Form C by Vapour Stress

[0213] X-ray amorphous 6-OH-CBDV (~30mg) was weighed into a virgin glass vial. The vial was placed inside a larger vial containing acetone/water (20:80% v/v,1 mL). The larger vial was sealed and left at room temperature (-20 °C) for 7 days. The solids were recovered and analysed by XRPD. The resulting diffractogram confirmed that the recovered solids were composed of crystalline Form C material.

Characterisation of 6-OH CBDV Form C

[0214] The XRPD pattern obtained for crystalline Form C 6-OH-CBDV, is shown in Figure 13. The XRPD pattern is indicative of a crystalline material. The XRPD peak listing data is given in Table 5. Table 5: Observed XRPD data for 6-OH CBDV Form C

[0215] Crystalline Form C 6-OH-CBDV was analysed by ¹ H NMR spectroscopy in dg-DMSO. The ¹ H NMR spectrum of the material conformed to the molecular structure and contained acetone (~1.0 mol eq).

[0216] Crystalline Form C 6-OH-CBDV was analysed by TG/DTA. The thermogram is shown in Figure 14. The TG/DTA thermogram showed an endotherm with an onset temperature of ~80°C. A corresponding weight loss of -16.3% (equivalent to -1 .0 mol eq. acetone) was observed between -30-125 ^D C and is likely due to loss of solvent. A second endotherm with an onset temperature of ~148°C likely to be due to the melt.

[0217] Based on this analysis, it is likely that crystalline Form C material is an acetone mono-solvate (1 :1 ).

Example 5: Preparation of 6-OH CBDV Form D by Sonication

[0218] Crystalline Form A 6-OH-CBDV (~30mg) was weighed into a virgin glass vial. NMP/water (10:90%v/v, 50uL), was added and the mixture was sonicated sonicated at 70% intensity using a Cole-Parmer 130W ultrasonic processor for 3 minutes in 30 second intervals. The solids were recovered and analysed by XRPD. The diffractogram confirmed that the solids were composed of crystalline Form D material.

Characterisation of 6-OH CBDV Form D

[0219] The XRPD pattern obtained for crystalline Form D 6-OH-CBDV, is shown in Figure 15. The XRPD pattern is indicative of a crystalline material. The XRPD peak listing data is given in Table 6.

Table 6: Observed XRPD data for 6-OH CBDV Form D

[0220] Crystalline Form D 6-OH-CBDV was analysed by ¹ H NMR spectroscopy in de-DMSO. The ¹ H NMR spectrum of the material conformed to the molecular structure and contained NMP (~0.8 mol eq). [0221] Crystalline Form D 6-OH-CBDV was analysed by TG/DTA. The thermogram is shown in Figure 16. The thermogram showed a weight loss of -1.2% between ~30-65°C, likely due to surface moisture/solvent. A further weight loss of -33% was observed between -66-142°C, which corresponded to a broad endotherm with an onset temperature of ~94°C. This could be the melt of material, or dissolution of the material in hot NMP. The second weight loss could account for up to -1 ,5mol eq NMP or ~8.3mol eq water and may be due to a loss of a mixture of both NMP and water.

[0222] Crystalline Form D may be an NMP solvate or a hydrate. Example 6: Preparation of 6-OH CBDV Form E

[0223] Crystalline Form A 6-OH-CBDV (~30mg) was weighed into a virgin glass vial.

DMAc/water (10:90%v/v, 100uL) was added, the vial was sealed, and the resulting slurry was stirred at 5°C for 7 days. The solids were isolated by centrifugation and dried under flow of air prior to analysis by XRPD, which confirmed that the solid was composed of crystalline Form E material.

Characterisation of 6-OH CBDV Form E

[0224] The XRPD pattern obtained for crystalline Form E 6-OH-CBDV, is shown in

Figure 17. The XRPD pattern is indicative of a crystalline material, but the elevated baseline may be indicative of some disorder or amorphous content. The XRPD peak listing data is given in Table 7.

Table 7: Observed XRPD data for 6-OH CBDV Form E

[0225] Crystalline Form E 6-OH-CBDV was analysed by ¹ H NMR spectroscopy in dg-DMSO. The ¹ H NMR spectrum of the material conformed to the molecular structure and contained ~1.0 mol eq DMAc.

[0226] Crystalline Form E 6-OH-CBDV was analysed by TG/DTA. The thermogram is shown in Figure 18. The TG/DTA thermogram showed a weight loss of ~28% (which could account for up to -1.4 mol eq DMAc or ~6.6mol eq water) between -30-143°C. This corresponded to a broad, complex endotherm with an onset temperature of ~98°C. The weight loss may be due to a mixture of water (~0.5mol eq, ~5.6%wt loss) and DMAc (~1mol, ~22.4%wt loss). 6-OH-CBDV Form E may be a mixed DMAc solvate/hydrate.

Further Characterisation of Form E

[0227] A sample of 6-OH-CBDV Form E material was dried under vacuum for ~2hr prior to reanalysis by XRPD (Figure 19). The diffractogram showed that the material was still composed of Pattern E material, however, slight peak shifting was noted.

[0228] Dried Pattern E 6-OH-CBDV was analysed by ¹ H NMR spectroscopy. The spectrum was concordant with the molecular structure. DMAc (-1.Omol eq) was present in the sample.

[0229] A sample of the dried Pattern E material was analysed by TG/DTA. The thermogram is shown in Figure 20 and shows a weight loss of -2.5% between 45-148°C. The weight loss could account for ~0.4mol eq water or ~0.09mol eq DMAc and may be due to surface bound residual solvent. A second weight loss of -25.1% was observed between 149-286°C which could account for ~5.6mol eq water or -1 ,2mol eq DMAc, however, some of the weight loss is likely due to the onset of decomposition of the material. An endotherm with an onset temperature of -117°C was observed.

[0230] Based upon this data, it is possible that the initially isolated 6-OH-CBDV Form E may be a mixed hydrate:DMAc solvate (0.5:1) and that the dried Form E 6-OH-CBDV is a mono DMAc solvate (1 :1).

REFERENCES

[0231] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The contents of each of these references is incorporated herein.

1. PCT/GB2020/052944.