Crystalline compositions

Abstract

Disclosed are crystalline forms of, and compositions comprising, a compound of formula (I), along with methods of making the forms and compositions, uses of the forms and compositions and devices containing the forms and compositions.

Description

[0001] CRYSTALLINE COMPOSITIONS

[0002] TECHNICAL FIELD

[0003] This invention relates to crystalline forms of, and compositions comprising, particles of INHAL-101 (SF2523). The invention further relates to methods of making the forms and compositions, uses of the forms and compositions, and devices containing the forms and compositions.

[0004] In particular, though not exclusively, the invention relates to novel and inventive polymorphs of INHAL-101, in substantially pure form, and methods of making them.

[0005] BACKGROUND

[0006] INHAL-101 (also known as SF2523) is a PI-3 kinase (PI3K) inhibitor with the following structure:

[0007] INHAL-101 has shown promising potential therapeutic efficacy. For example, US8,557,807 demonstrates the potency of INHAL-101 against a broad spectrum of cancer cell lines. INHAL-101 is also a known inhibitor of mTOR and BRD-4.

[0008] An essential requirement when formulating a pharmaceutical drug product is to ensure the quality of the product is established, maintained, and meets the demanding requirements set out by the international regulatory agencies. In terms of active pharmaceutical ingredients (APIs) in such products, the term quality embraces a wide range of chemical and physical properties of the materials most generally used as solid powder forms. Desirable properties include a high level of chemical purity, but also consistency and purity of the solid-state phase. A high degree of crystallinity is desirable, with amorphous material undermining stability, as well as a pure crystalline form (i.e., a single polymorph). Reliable batch-to-batch formation is crucial for crystalline APIs as two different polymorphs of the same drug may function differently in the body.

[0009] Further desirable attributes include good bioavailability and ease of formulation for administration. In this respect, drug particle shape, size and morphology are particularly important. Needle-shaped particles with high aspect ratios are problematic from a drug formulation point of view: flowability, dissolution rate, bioavailability, content, and dose uniformity can all be negatively affected.

[0010] Milling / micronisation is sometimes used to try and mitigate the problems associated with needle-shaped APIs by mechanically breaking them down into smaller particles. However, this introduces other problems, including undesirable agglomeration of the milled material. Milling / micronisation generally results in highly charged, very cohesive material which causes severe downstream handling and processing issues. In addition, amorphous hygroscopic domains varying in content between batches of product tend to be formed which can lead to particle recrystallisation and growth upon uptake of water. Milling produces irregular shaped and sized particles because of uncontrolled particle fracture and breakage.

[0011] A further problem with milling is that a disturbed particle size distribution is generally obtained. For example, a bimodal distribution may be obtained due to the presence of a proportion of primary particles, a significant number of larger particles and a degree of agglomeration. It is also generally observed that for micronised powders a large number of smaller particles adhere to the surfaces of larger particles, due to the highly charged and energised surfaces formed by milling / micronisation.

[0012] Formulation of APIs for pulmonary administration (e.g., by inhalation) can be an attractive option. Advantages of pulmonary administration can include local or systemic delivery to the lungs, rapid onset of action, non-invasive self-administration, and improved bioavailability. However, to enable effective pulmonary administration further stringent criteria must be met by the API. These include: small particle size (1-5 pm), narrow particle size distribution, aerodynamic shape (preferably equant or near equant shaped), low aspect ratio (3: 1 or lower), low interparticle surface forces resulting from low surface energetics and low cohesive forces, and low agglomeration tendency.

[0013] If these criteria are not met, little or none of the inhaled drug will reach the lower airways, where it has its therapeutic effect. A large part of the inhaled drug will instead be deposited in the mouth and throat, after which it is swallowed and absorbed in the gastrointestinal tract.

[0014] Improved forms of INHAL-101 would be desirable. SUMMARY OF THE INVENTION

[0015] The invention provides forms and compositions of a compound of formula I:

[0016] I, methods of making the forms and compositions, uses of the forms and compositions and devices containing the forms and compositions.

[0017] In a first aspect, the invention provides a crystalline form of the compound of formula I, having an x-ray powder diffraction (XRPD) pattern with peaks at 20 values of about 5.8°, 8.2°, and 9.2°.

[0018] In a second aspect, the invention provides a composition comprising particles of the compound of formula I, the composition having one or more of the following characteristics: i. a Dio of from 0.2 pm to 1.5 pm; ii. a D50of from 0.5 pm to 5.0 pm; iii. a D90of from 1.0 pm to 10.0 pm; iv. a volume mean diameter of from 0.5 pm to 5.0 pm; v. an aspect ratio of from 1: 1 to 3: 1.

[0019] In a third aspect, the invention provides a crystalline form of the compound of formula I, having an X-ray powder diffraction pattern with peaks at 20 values of about 6.5°, 8.1° and 9.9°.

[0020] In a fourth aspect, the invention provides a crystalline form of the compound of formula I, having an X-ray powder diffraction pattern with peaks at 20 values of about 5.4°, 7.7° and 10.9°.

[0021] In a fifth aspect, the invention provides a crystalline form or composition of the compound of Formula I, obtained by supercritical anti-solvent (SAS) precipitation. In a sixth aspect, the invention provides a method of preparing a crystalline form of the compound of formula I, the method comprising contacting a fluid anti-solvent with a solution comprising the compound of formula I in a solvent, to precipitate said crystalline form of the compound of formula I.

[0022] In a seventh aspect, the invention provides a crystalline form of the compound of formula I, obtained by a method according to the sixth aspect.

[0023] In an eighth aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form or composition of the compound of formula I according to any of the first, second, third, fourth, fifth or seventh aspects.

[0024] In a ninth aspect, the invention provides the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects for use as a medicament.

[0025] In a tenth aspect, the invention provides the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects for use in a method of inhibiting PI-3 kinase, mTOR, BRD-4 or a combination thereof.

[0026] In an eleventh aspect, the invention provides a method of treating a disorder in a patient, the method comprising administering to said patient a therapeutically effective amount of the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects.

[0027] In a twelfth aspect, the invention provides a method of inhibiting PI-3 kinase, mTOR, BRD-4 or a combination thereof in a patient, the method comprising administering to said patient a therapeutically effective amount of the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects.

[0028] In a thirteenth aspect, the invention provides an inhalation or insufflation device having therein the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] One or more embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0031] Figure 1 shows twoXH-NMR spectra of INHAL-101. Figure 1A shows theXH-NMR spectrum of INHAL-101 starting material (Form A). Figure IB shows an exemplaryXH-NMR spectrum of the INHAL-101 product following supercritical antisolvent processing.

[0032] Figure 2 shows the Powder X-ray Diffraction (PXRD) pattern of the INHAL-101 starting material (Form A). Figure 3 shows a scanning electron microscopy image of the INHAL-101 starting material (Form A).

[0033] Figure 4 shows the thermal profile of the INHAL-101 starting material (Form A).

[0034] Figure 5 shows the PXRD pattern of INHAL-101 Form B.

[0035] Figure 6 shows a scanning electron microscopy (SEM) image of INHAL-101 Form B.

[0036] Figure 7 shows the thermal profile of INHAL-101 Form B.

[0037] Figure 8 shows the PXRD pattern of INHAL-101 Form C.

[0038] Figure 9 shows an SEM image of INHAL-101 Form C.

[0039] Figure 10 shows the thermal profile of INHAL-101 Form C.

[0040] Figure 11 shows the PXRD pattern of INHAL-101 Form D.

[0041] Figure 12 shows a series of SEM images of INHAL-101 Form D samples formed under different precipitation conditions.

[0042] Figure 13 shows the thermal profile of INHAL-101 Form D.

[0043] Figure 14 shows a series of hot stage microscopy images of the thermal transition of Form D into Form C.

[0044] Figure 15 shows the PXRD pattern of INHAL-101 Form E.

[0045] Figure 16 shows an SEM image of INHAL-101 Form E.

[0046] Figure 17 shows the thermal profile of INHAL-101 Form E.

[0047] Figure 18 shows results from Next Generation Impactor (NGI) analysis of INHAL-101 Form D.

[0048] DETAILED DESCRIPTION

[0049] Disclosed herein are novel crystalline forms of the compound of Formula I (also referred to as INHAL-101 or SF2523), methods of making them and uses of them. The inventors have surprisingly prepared three separate pure polymorphic forms of INHAL-101. It is believed the polymorphs are conformational polymorphs. Conformational polymorphs are extremely challenging to separate from each other due to the low energy difference between the different conformations, and separation can be impossible using usual methods (e.g., standard crystallisation techniques). The inventors have surprisingly found that by employing a modified supercritical antisolvent precipitation process, pure crystalline polymorphic forms having desirable properties can be prepared. This was previously unknown. It is believed that previously known forms of INHAL-101 are mixed forms (i.e., mixtures of polymorphs and / or amorphous material).

[0050] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and do not exclude other components, integers or steps. Moreover, the singular encompasses the plural unless the context otherwise requires: in particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0051] Preferred features of each aspect of the invention may be as described in connection with any of the other aspects. Within the scope of this application, it is expressly intended that the various aspects, embodiments, examples and alternatives set out in the preceding paragraphs, in the claims and / or in the following description and drawings, and in particular the individual features thereof, may be taken independently or in any combination. That is, all embodiments and / or features of any embodiment can be combined in any way and / or combination, unless such features are incompatible.

[0052] Where upper and lower limits are quoted for a property, then a range of values defined by a combination of any of the upper limits with any of the lower limits may also be implied.

[0053] In this specification, references to properties are - unless stated otherwise - to properties measured under standard temperature and pressure, i.e., at atmospheric pressure and at a temperature of 20°C.

[0054] All 20 values disclosed herein may be subject to an error margin of ±0.2°, or ±0.1°. The powder x-ray diffraction patterns are preferably obtained using Cu-Ko radiation and an x- ray wavelength of 1.5406 A. Melting points and enthalpies of fusion are preferably determined using differential scanning calorimetry.

[0055] All particle sizes (diameters) herein are volume-based particle diameters, measured for example by laser diffraction, and relate to the maximum particle diameter.

[0056] For acicular particles, average particle lengths can be determined from analysis of scanning electron microscopy (SEM) images. Aspect ratios may also be determined from analysis of SEM images.

[0057] Further details on the techniques used to determine the properties and characteristics of the invention are provided in the examples section.

[0058] The term "polymorph" refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms, these forms having different arrangements and / or conformations of the molecules in the crystal lattice. Polymorphs can differ in such chemical, physical, and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. One skilled in the art will appreciate that a polymorph can exhibit beneficial effects (e.g., suitability for preparation of useful formulations, improved solubility, etc.), relative to another polymorph or a mixture of polymorphs of the same compound.

[0059] In a first aspect, the invention provides a crystalline form of a compound of formula I:

[0060] I, having an x-ray powder diffraction pattern with peaks at 20 values of about 5.8°, 8.2°, and 9.2°. Preferably, the x-ray powder diffraction pattern has further peaks at 20 values of about 11.7°, 17.0° and 17.5°. More preferably, the x-ray powder diffraction pattern has further peaks at 20 values of about 11.7°, 17.0° and 17.5°, 20.7°, 23.7° and 25.2°.

[0061] The crystalline form of the first aspect surprisingly exhibits an advantageous combination of properties that make it an ideal candidate for drug formulation, particularly for administration by inhalation. These include desirable morphology and particle size characteristics (small particle size, narrow monomodal particle size distribution, low aspect ratio), and are present in the as formed material obtained directly from the supercritical antisolvent precipitation process, with no further processing (such as milling, etc.) required. The crystalline form also exhibits high polymorphic purity and good stability.

[0062] The crystalline form according to the first aspect may have an x-ray powder diffraction pattern with further peaks (in addition to the peaks outlined above) at about any or all of the following 20 values: 13.0°, 14.8°, 16.5°, 17.0°, 17.5°, 18.9°, 20.2°, 20.7°, 22.0°, 22.3°, 23.5°, 23.7°, 24.2°, 25.2°, 26.2°, 26.9°, 27.9°, 29.1°, 29.4°, 31.4° and 31.8°. The crystalline form according to the first aspect may have an x-ray powder diffraction pattern substantially as shown in Figure 11.

[0063] Advantageously, the crystalline form according to the first aspect may be a substantially pure polymorph. This may be defined by the absence of x-ray powder diffraction peaks characteristic of other polymorphs. Accordingly, the x-ray powder diffraction pattern of the crystalline form of the first aspect, preferably does not have peaks at 20 values of about 6.5° and 9.9°. Alternatively, or in addition, the x-ray powder diffraction pattern of the crystalline form of the first aspect preferably does not have peaks at 20 values of about 7.7° and 10.9°.

[0064] The crystalline form according to the first aspect may have an X-ray powder diffraction pattern that does not have peaks at about any or all of the following 20 values: 5.4°, 6.5°, 7.7°, 9.9°, 10.9°, 15.1°, 15.4°, 17.9°, 21.0°, 25.7° and 28.1°.

[0065] The crystalline form according to the first aspect may have a melting point of from 190 °C to 200 °C, preferably 193 °C to 198 °C, more preferably from 194 °C to 197 °C, still more preferably from 195 °C to 196 °C. The crystalline form according to the first aspect may have a differential scanning calorimetry (DSC) profile exhibiting an endothermic peak with onset at from 190°C to 200 °C, preferably 193 °C to 198 °C, more preferably from 194 °C to 197 °C, still more preferably from 195 °C to 196 °C. The crystalline form according to the first aspect may have an enthalpy of fusion of from 10 to 30 J / g, preferably from 15 to 25 J / g, e.g., about 20 J / g.

[0066] It has been found that the crystalline form according to the first aspect is a metastable polymorphic form of the compound of formula I, recrystallising to a more thermodynamically stable polymorphic form upon melting. The crystalline form according to the first aspect may, thus, have a differential scanning calorimetry (DSC) profile exhibiting a first endothermic peak with onset at from 193 °C to 198 °C, preferably from 194 °C to 197 °C, more preferably from 195 °C to 196 °C and a second endothermic peak with onset at from 207 °C to 219 °C, preferably from 210 °C to 217 °C, more preferably from 211 °C to 215 °C. The first endothermic peak corresponds to the melting of the crystalline form according to the first aspect whilst the second endothermic peak corresponds to the melting of the more stable form. Surprisingly, the inventors have been able to reproducibly prepare and isolate the pure metastable polymorphic form according to the first aspect without contamination by, or conversion to, the more stable polymorphic form, or any other form. It is advantageous because the crystalline form of the first aspect has an ideal morphology for administration by inhalation / insufflation, whilst other polymorphic forms have less advantageous morphology. The differing morphologies of the different polymorphs can be readily observed via scanning electron microscopy (SEM).

[0067] The advantageous morphology of the crystalline form of the first aspect may be defined with reference to particle size characteristics. Preferably, the crystalline form according to the first aspect has a Di0of 2.0 pm or less, preferably 1.5 pm or less, more preferably 1.0 pm or less, e.g., 0.8 pm or less. The crystalline form according to the first aspect preferably has a Dio of from 0.1 m to 2.0 pm, more preferably from 0.2 pm to 1.5 pm, still more preferably from 0.5 pm to 1.0 pm, e.g., from 0.6 pm to 0.8 pm.

[0068] Preferably, the crystalline form according to the first aspect has a D50of 10.0 pm or less, preferably 5.0 pm or less, more preferably 3.0 pm or less, e.g., 2.0 pm or less. The crystalline form according to the first aspect preferably has a D50of from 0.5 pm to 5.0 pm, more preferably from 0.7 pm to 3.0 pm, still more preferably from 1.0 pm to 2.0 pm, e.g., from 1.2 pm to 1.8 pm.

[0069] Preferably, the crystalline form according to the first aspect has a D90of 20.0 pm or less, preferably 10.0 pm or less, more preferably 5.0 pm or less, e.g., 2.0 pm or less. The crystalline form according to the first aspect preferably has a D90of from 1.0 pm to 10.0 pm, more preferably from 2.0 pm to 5.0 pm, still more preferably from 3.0 pm to 4.0 pm.

[0070] A small particle size, along with a narrow particle size distribution, aids aerosolisation, and therefore is advantageous for deep lung delivery by inhalation / insufflation.

[0071] Preferably, the crystalline form according to the first aspect has a volume mean diameter of 10.0 pm or less, preferably 5.0 pm or less, more preferably 3.0 pm or less, e.g., 2.0 pm or less. The crystalline form according to the first aspect preferably has a volume mean diameter of from 0.5 pm to 5.0 pm, more preferably from 0.7 pm to 3.0 pm, still more preferably from 1.0 pm to 2.0 pm.

[0072] Preferably, the crystalline form according to the first aspect has an aspect ratio (e.g. an average aspect ratio) of from 1 : 1 to 5: 1, more preferably from 1: 1 to 4: 1, still more preferably from 1: 1 to 3: 1. A lower aspect ratio advantageously means that particles have a similar length and width. This provides a preferred shape for drug delivery to the lung by inhalation / insufflation. High aspect ratios (e.g., of greater than 1 :5) are associated with long acicular, needle-like particles which are not suitable for pulmonary administration.

[0073] Preferably, the crystalline form according to the first aspect has a monomodal particle size distribution. Advantageously this provides a uniform powder formulation of a single polymorph with advantageous morphology for pulmonary administration. Mixtures of different forms (e.g., mixtures of two or more polymorphs) would be expected to exhibit multimodal particle size distributions.

[0074] The crystalline form according to the first aspect advantageously is produced directly with the desirable morphology and particle characteristics described above, from the modified supercritical antisolvent solution process. No additional processing, such as milling or micronisation, is required to achieve the desired particle size and morphology characteristics. The crystalline form according to the first aspect is thus preferably not micronized or milled. The crystalline form according to the first aspect is preferably substantially free of amorphous material. The presence of amorphous material is disadvantageous because amorphous domains tend to be hygroscopic, leading to water-induced bridging and particle growth over time. The crystalline form according to the first aspect preferably contains less than 10% by weight, more preferably less than 5% by weight, still more preferably less than 1% by weight amorphous material. Preferably, the crystalline form according to the first aspect is a single polymorph. Preferably, the crystalline form according to the first aspect is a substantially pure single polymorph, e.g., having at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% purity. Purity may, for example, be determined using powder x-ray diffraction, IR / Raman spectroscopy or HPLC.

[0075] Despite being only metastable, the inventors have found that the crystalline form according to the first aspect, once formed, is surprisingly stable under ambient conditions, with no conversion to the more stable (or any other) polymorphic form observed, and no significant changes in particle size characteristics or morphology. This advantageously makes the crystalline form according to the first aspect well suited for use in pharmaceutical applications, where stability and consistency are key. Storage stability may be assessed by determining changes in the crystal form (e.g., by PXRD) and / or particle size characteristics (Dio, D50, D90, VMD) over time.

[0076] The crystalline form according to the first aspect preferably exhibits no change in the crystal structure, as measured by powder x-ray diffraction, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0077] The Dio of the crystalline form according to the first aspect preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0078] The D50of the crystalline form according to the first aspect preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, still more preferably no more than 10%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0079] The D90of the crystalline form according to the first aspect preferably changes by no more than 20%, more preferably no more than 10%, still more preferably no more than 5%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity. The volume mean diameter of the crystalline form according to the first aspect preferably changes by no more than 20%, more preferably no more than 10%, still more preferably no more than 5%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0080] The aspect ratio of the crystalline form according to the first aspect preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, e.g., by no more than 10%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0081] The crystalline form according to the first aspect advantageously has optimum morphology and particle size characteristics for pulmonary delivery, enabling for the first time effective INHAL-101 drug deposition in the deep lung compartments. The fine particle fraction (FPF) generated during the patient inhalation reaches the lungs and gives the necessary therapeutic action either locally, or through absorption into the bloodstream for systemic delivery. To develop a stable dry powder inhalation product with the consistent delivery of fine particle fraction for the product shelf life is a challenge.

[0082] The crystalline form according to the first aspect preferably exhibits a fine particle fraction of at least 75%, more preferably at least 80%, still more preferably at least 90%. The fine particle fraction can be determined by various techniques including glass twin impinger (GTI), Anderson Cascade Impactor (ACI) and next generation impactor (NGI). Preferably the fine particle fraction is determined by next generation impactor (NGI), for example at a flow rate of 100 litres per minute.

[0083] The crystalline form according to the first aspect may further preferably have any of the characteristics disclosed in relation to Form / Polymorph D in the examples below, alone or in any combination.

[0084] In a second aspect, the invention provides a composition comprising particles of a compound of formula I: I, the composition having one or more of the following characteristics: vi. a Dio of from 0.2 pm to 1.5 pm; vii. a D50of from 0.5 pm to 5.0 pm; viii. a D90of from 1.0 pm to 10.0 pm; ix. a volume mean diameter of from 0.5 pm to 5.0 pm; x. an aspect ratio of from 1: 1 to 3: 1.

[0085] The composition according to the second aspect has an advantageous morphology and particle shape / size for administration by inhalation / insufflation. Preferably, the composition according to the second aspect has a D10of 2.0 pm or less, preferably 1.5 pm or less, more preferably 1.0 pm or less, e.g., 0.8 pm or less. The composition according to the second aspect preferably has a D10of from 0.1 pm to 2.0 pm, more preferably from 0.2 pm to 1.5 pm, still more preferably from 0.5 pm to 1.0 pm, e.g., from 0.6 pm to 0.8 pm.

[0086] Preferably, the composition according to the second aspect has a D50of 10.0 pm or less, preferably 5.0 pm or less, more preferably 3.0 pm or less, e.g., 2.0 pm or less. The composition according to the second aspect preferably has a D50of from 0.5 pm to 5.0 pm, more preferably from 0.7 pm to 3.0 pm, still more preferably from 1.0 pm to 2.0 pm, e.g., from 1.2 pm to 1.8 pm.

[0087] Preferably, the composition according to the second aspect has a D90of 20.0 pm or less, preferably 10.0 pm or less, more preferably 5.0 pm or less, e.g., 2.0 pm or less. The composition according to the second aspect preferably has a D90of from 1.0 pm to 10.0 pm, more preferably from 2.0 pm to 5.0 pm, still more preferably from 3.0 pm to 4.0 pm.

[0088] A small particle size, along with a narrow particle size distribution, aids aerosolisation, and therefore is advantageous for deep lung delivery by inhalation / insufflation.

[0089] Preferably, the composition according to the second aspect has a volume mean diameter of 10.0 pm or less, preferably 5.0 pm or less, more preferably 3.0 pm or less, e.g., 2.0 pm or less. The composition according to the second aspect preferably has a volume mean diameter of from 0.5 pm to 5.0 pm, more preferably from 0.7 pm to 3.0 pm, still more preferably from 1.0 pm to 2.0 pm.

[0090] Preferably, the composition according to the second aspect has an aspect ratio (e.g., an average aspect ratio) of from 1 : 1 to 5: 1, more preferably from 1: 1 to 4: 1, still more preferably from 1: 1 to 3: 1. A lower aspect ratio advantageously means that particles have a similar length and width. This provides a preferred shape for drug delivery to the lung by inhalation / insufflation. High aspect ratios (e.g., of greater than 1 :5) are associated with long acicular, needle-like particles which are not suitable for pulmonary administration.

[0091] The composition according to the second aspect is preferably a dry powder composition. The composition according to the second aspect is preferably in crystalline form.

[0092] The composition according to the second aspect may advantageously have any of the characteristics disclosed above in relation to the first aspect of the invention, for example with regard to the powder x-ray diffraction pattern, melting point, enthalpy of fusion, differential scanning calorimetry characteristics, stability, particle size distribution, and fine particle fraction. The composition according to the second aspect may preferably have any of the characteristics disclosed in relation to Form / Polymorph D in the examples below, alone or in any combination. Any of the features described herein with regard to the composition of the second aspect may apply equally to the particles of a compound of Formula I which the composition according to the second aspect comprises.

[0093] In a third aspect, the invention provides a crystalline form of a compound of formula I:

[0094] I, having an X-ray powder diffraction pattern with peaks at 20 values of about 6.5°, 8.1° and 9.9°

[0095] The inventors have surprisingly been able to prepare and isolate this particularly stable crystalline form of INHAL-101 for the first time, in pure form, not as an admixture with other polymorphs or amorphous material.

[0096] Preferably, the x-ray powder diffraction pattern of the crystalline form according to the third aspect has further peaks at 20 values of about 15.1° and 19.8°. More preferably, the x-ray powder diffraction pattern has further peaks at 20 values of about 15.1°, 19.8°, 27.2°, and 28.1°. The crystalline form according to the third aspect may have an x-ray powder diffraction pattern with further peaks (in addition to the peaks outlined above) at about any or all of the following 29 values: 12.3°, 13.1°, 14.9°, 16.3°, 17.9°, 18.8°, 21.0°, 22.3°, 22.7°, 23.4°, 24.3°, 24.8°, 26.1°, 26.5° and 30.0°. The crystalline form according to the third aspect may have an x-ray powder diffraction pattern substantially as shown in Figure 8.

[0097] Advantageously, the crystalline form according to the third aspect may be a substantially pure polymorph. This may be defined by the absence of x-ray powder diffraction peaks characteristic of other polymorphs. Accordingly, the x-ray powder diffraction pattern of the crystalline form of the third aspect, preferably does not have peaks at 29 values of about 5.8° and 9.2°. Alternatively, or in addition, the x-ray powder diffraction pattern of the crystalline form of the third aspect preferably does not have peaks at 29 values of about 5.4° and 9.0°.

[0098] The crystalline form according to the third aspect may have an X-ray powder diffraction pattern that does not have peaks at about any or all of the following 29 values: 5.4°, 5.8°, 7.7°, 9.0°, 9.2°, 10.9°, 11.7°, 15.4°, 17.5°, 20.7°, 22.0° and 25.2.

[0099] The crystalline form according to the third aspect may have a melting point of from 205 °C to 220 °C, preferably from 210 °C to 217 °C, more preferably from 211 °C to 215 °C. The crystalline form according to the third aspect may have a differential scanning calorimetry (DSC) profile exhibiting an endothermic peak with onset at from 205 °C to 220 °C, preferably from 210 °C to 217 °C, more preferably from 211 °C to 215 °C. The crystalline form according to the third aspect may have an enthalpy of fusion of from 70 to 100 J / g, preferably from 75 to 95 J / g, more preferably from 80 to 90 J / g.

[0100] It has been found that the crystalline form according to the third aspect is the most thermodynamically stable polymorphic form of the compound of formula I. The crystalline form according to the third aspect may, thus, have a differential scanning calorimetry (DSC) profile exhibiting only a single endothermic peak and no further endothermic peaks. The onset values and enthalpy of fusion associated with the single endothermic peak are as described above. The inventors have unexpectedly successfully isolated the most stable polymorph of IHAL-001, in pure form, for the first time.

[0101] The crystalline form of the compound of formula I according to the third aspect may have an average particle length (longest dimension) of greater than 25 pm, preferably greater than 50 pm, more preferably greater than 100 pm. The crystalline form of the compound of formula I according to the third aspect may have an average particle length of from 25 pm to 300 pm, preferably from 50 pm to 200 pm, e.g., from 50 pm to 100 pm. The particle length may be determined from analysis of SEM images, e.g., as described in the examples below. Preferably, the crystalline form according to the third aspect has a monomodal particle size distribution.

[0102] The crystalline form of the compound of formula I according to the third aspect may have an aspect ratio (e.g., an average aspect ratio) of from 5: 1 to 200: 1, preferably from 10: 1 to 100: 1, more preferably from 20: 1 to 50: 1.

[0103] The crystalline form according to the third aspect is preferably substantially free of amorphous material. The presence of amorphous material is disadvantageous because amorphous domains tend to be hygroscopic, leading to water-induced bridging and particle growth over time. The crystalline form according to the third aspect preferably contains less than 10% by weight, more preferably less than 5% by weight, still more preferably less than 1% by weight amorphous material. Preferably, the crystalline form according to the third aspect is a single polymorph. Preferably, the crystalline form according to the third aspect is a substantially pure single polymorph, e.g., having at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% purity. Purity may, for example, be determined using powder x-ray diffraction, IR / Raman spectroscopy or HPLC.

[0104] The crystalline form according to the third aspect is stable under ambient conditions, with no conversion to other polymorphic forms observed. The crystalline form according to the third aspect preferably exhibits no change in the crystal structure, as measured by powder x-ray diffraction, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0105] The average particle length of the crystalline form according to the third aspect preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, e.g., no more than 10%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0106] The aspect ratio of the crystalline form according to the third aspect preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, e.g., no more than 10%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0107] The crystalline form according to the third aspect may further preferably have any of the characteristics disclosed in relation to Form / Polymorph C in the examples below, alone or in any combination.

[0108] In a fourth aspect, the invention provides a crystalline form of a compound of formula I:

[0109] I, having an X-ray powder diffraction pattern with peaks at 20 values of about 5.4°, 7.7° and 10.9°. Preferably, the x-ray powder diffraction pattern of the crystalline form according to the fourth aspect has further peaks at 20 values of about 9.0°, 15.4° and 16.3°.

[0110] The crystalline form according to the fourth aspect may have an x-ray powder diffraction pattern with further peaks (in addition to the peaks outlined above) at about any or all of the following 20 values: 17.9°, 18.1°, 19.8°, 21.8°, 22.6°, 23.9°, 25.0°, 25.3°, 26.9° and 27.9°. The crystalline form according to the fourth aspect may have an x-ray powder diffraction pattern substantially as shown in Figure 15.

[0111] Advantageously, the crystalline form according to the fourth aspect may be a substantially pure polymorph. This may be defined by the absence of x-ray powder diffraction peaks characteristic of other polymorphs. Accordingly, the x-ray powder diffraction pattern of the crystalline form of the fourth aspect preferably does not have peaks at 20 values of about 11.7° and 17.0°. Alternatively, or in addition, the x-ray powder diffraction pattern of the crystalline form of the fourth aspect preferably does not have peaks at 20 values of about 6.5° and 14.9°.

[0112] The crystalline form according to the fourth aspect may have an X-ray powder diffraction pattern that does not have peaks at about any or all of the following 20 values: 5.8°, 6.5°, 11.7°, 14.9°, 15.1°, 17.0°, 18.5°, 20.7°, 23.5°, 26.5° and 27.2°.

[0113] The crystalline form according to the fourth aspect may have a melting point of from 180 °C to 195 °C, preferably from 186 °C to 192 °C, more preferably from 187 °C to 191 °C. The crystalline form according to the fourth aspect may have a differential scanning calorimetry (DSC) profile exhibiting an endothermic peak with onset at from 180 °C to 195 °C, preferably from 186 °C to 192 °C, more preferably from 187 °C to 191 °C. The crystalline form according to the fourth aspect may have an enthalpy of fusion of from 2 to 10 J / g, preferably from 3 to 8 J / g, more preferably from 4 to 6 J / g. It has been found that the crystalline form according to the fourth aspect is a metastable polymorphic form of the compound of formula I, recrystallising to a more stable polymorphic form upon melting. The crystalline form according to the first aspect may, thus, have a differential scanning calorimetry (DSC) profile exhibiting a first endothermic peak with onset at from 180 °C to 195 °C, preferably from 186 °C to 192 °C, more preferably from 187 °C to 191 °C and a second endothermic peak with onset at from 207 °C to 219 °C, preferably from 210 °C to 217 °C, more preferably from 211 °C to 215 °C. The first endothermic peak corresponds to the melting of the crystalline form according to the fourth aspect whilst the second endothermic peak corresponds to the melting of the more stable form. Surprisingly, the inventors have been able to reproducibly prepare and isolate the pure metastable polymorphic form according to the fourth aspect without contamination by, being in admixture with, or being converted to, the more stable polymorphic form, or any other form.

[0114] The crystalline form of the compound of formula I according to any of claims 12 to 15, having one or more of the following characteristics: i. an average particle length of greater than 25 pm; ii. an aspect ratio of from 10: 1 to 30: 1.

[0115] The crystalline form of the compound of formula I according to the fourth aspect may have an average particle length (longest dimension) of greater than 5 pm, preferably greater than 10 pm, more preferably greater than 25 pm. The crystalline form of the compound of formula I according to the fourth aspect may have an average particle length of from 5 pm to 50 pm, preferably from 10 pm to 40 pm, e.g., from 15 pm to 25 pm. The particle length may be determined from analysis of SEM images, e.g., as described in the examples below. Preferably, the crystalline form according to the fourth aspect has a monomodal particle size distribution.

[0116] The crystalline form of the compound of formula I according to the fourth aspect may have an aspect ratio (e.g., an average aspect ratio) of from 5: 1 to 50: 1, preferably from 10: 1 to 30: 1, more preferably from 15: 1 to 25: 1.

[0117] The crystalline form according to the fourth aspect is preferably substantially free of amorphous material. The presence of amorphous material is disadvantageous because amorphous domains tend to be hygroscopic, leading to water-induced bridging and particle growth over time. The crystalline form according to the fourth aspect preferably contains less than 10% by weight, more preferably less than 5% by weight, still more preferably less than 1% by weight amorphous material. Preferably, the crystalline form according to the fourth aspect is a single polymorph. Preferably, the crystalline form according to the fourth aspect is a substantially pure single polymorph, e.g., having at least 90%, preferably at least 95%, more preferably at least 98%, still more preferably at least 99% purity. Purity may, for example, be determined using powder x-ray diffraction, IR / Raman spectroscopy or HPLC.

[0118] Despite being only metastable, the crystalline form according to the fourth aspect is stable under ambient conditions, with no conversion to other polymorphic forms observed. The crystalline form according to the fourth aspect preferably exhibits no change in the crystal structure, as measured by powder x-ray diffraction, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0119] The average particle length of the crystalline form according to the fourth aspect preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, e.g., no more than 10%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0120] The aspect ratio of the crystalline form according to the fourth aspect preferably changes by no more than 25%, preferably no more than 20%, more preferably no more than 15%, e.g., no more than 10%, after 3 months, preferably 6 months, more preferably 12 months, still more preferably 24 months, at ambient conditions or at 40 °C and 60% relative humidity.

[0121] The crystalline form according to the fourth aspect may further preferably have any of the characteristics disclosed in relation to Form / Polymorph E in the examples below, alone or in any combination.

[0122] In a fifth aspect, the invention provides a crystalline form or composition of the compound of Formula I as hereinbefore described, obtained by supercritical anti-solvent (SAS) precipitation. Preferred features of the supercritical anti-solvent precipitation process are as described below in relation to the sixth aspect.

[0123] In a sixth aspect, the invention provides a method of preparing a crystalline form of a compound of formula I:

[0124] I, the method comprising contacting a fluid anti-solvent with a solution comprising the compound of formula I in a solvent, to precipitate said crystalline form of the compound of formula I.

[0125] The inventors have surprisingly found that by using an anti-solvent precipitation process, crystalline forms of the compound of formula I may be prepared. Advantageously, the process allows for the preparation of single polymorphs of the compound of formula having desirable properties such as beneficial morphologies or high stability. The preparation of specific crystalline forms of the compound of formula I, particularly in substantially pure form, has not previously been achieved. The isolation of pure polymorphs of the compound of formula I is especially surprising given that the polymorphs are believed to be conformational polymorphs. As is known, low energy differences between conformational polymorphs render them particularly challenging to produce independently of one another or to isolate from one another, and doing so may be impossible using standard techniques (e.g. standard crystallisation). Advantageously, the inventors have developed a specific process and conditions that enable this to be achieved.

[0126] The starting compound of formula I used in the method according to the sixth aspect (i.e., the compound of formula I in the solution) may be an amorphous form of the compound of formula I, a crystalline form of the compound of formula I or a mixture thereof. The method of the sixth aspect provides a reliable, reproducible method of preparing specific desired polymorphs of the compound of formula I regardless of the form of the starting compound of formula I. Conversion of amorphous material to crystalline material, and / or the transformation of an undesired polymorph or of mixtures of polymorphs to a single pure desired polymorphic form (e.g., a different polymorphic form) can be achieved. In the method of sixth aspect, the solution may therefore comprise the compound of formula I in crystalline form according to one or more of the first, second, third or fourth aspects hereinbefore described. Preferably, the solution may comprise (or consist of) the compound of formula I in crystalline form according to the third or fourth aspects hereinbefore described, or a mixture thereof.

[0127] In the method according to the sixth aspect, said contacting the fluid anti-solvent with the solution of the compound of formula I in a solvent may preferably comprise providing a stream of the solution of the compound of formula I to a precipitation chamber, providing a stream of the fluid anti-solvent to the precipitation chamber, and contacting the stream of the solution with the stream of the fluid anti-solvent within the precipitation chamber to precipitate said crystalline form of the compound of formula I within the precipitation chamber.

[0128] The anti-solvent may in principle be any fluid consistent with achieving desired crystalline particle formation. As is known in the art, an anti-solvent for precipitation is generally chosen such that the product, in this case the crystalline form of INHAL-101, is substantially insoluble therein. The role of the anti-solvent is to extract the solvent from the solution of INHAL-101 and to precipitate crystalline particles of INHAL-101. Preferably, the fluid antisolvent is carbon dioxide.

[0129] Preferably, the anti-solvent is a supercritical fluid, although in some embodiments near- critical fluids may also be suitable. A "supercritical fluid" is a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. In practice, the pressure of the fluid is likely to be in the range between 1.01 and 7.0 of its critical pressure, and its temperature in the range between 1.01 and 4.0 of its critical temperature (in Kelvin). However, some fluids (e.g., helium and neon) have particularly low critical pressures and temperatures, and may need to be used under operating conditions well in excess of those critical values, such as up to 200 times the relevant critical value. The term "near-critical fluid" encompasses both high pressure liquids, which are fluids at or above their critical pressure but below (although preferably close to) their critical temperature, and dense vapors, which are fluids at or above their critical temperature but below (although preferably close to) their critical pressure. By way of example, a high-pressure liquid might have a pressure between about 1.01 and 7 times its Pc, and a temperature between about 0.5 and 0.99 times its Tc. A dense vapour might, correspondingly, have a pressure between about 0.5 and 0.99 times its Pc, and a temperature between about 1.01 and 4 times its Tc.

[0130] The fluid anti-solvent and the solution of the compound of formula I may form a supercritical or near-critical mixture on contact.

[0131] The fluid anti-solvent may preferably be carbon dioxide having a pressure of from 75 to 150 bar absolute or from 80 to 120 bar absolute. The carbon dioxide may preferably have a temperature of from 35 °C to 80°C or from 40 °C to 70 °C. The fluid anti-solvent may have a density of from 0.20 to 0.75 g / cm3, preferably from 0.25 to 0.60 g / cm3, e.g., from 0.30 to 0.50 g / cm3, in particular from 0.30 to 0.40 g / cm3.

[0132] Preferably, a high excess of the anti-solvent is contacted with the solution of the compound of formula I. For example, the ratio of the mass fraction of contacted anti-solvent to the mass fraction of contacted INHAL-101 solution may be 10 or more, preferably 20 or more, more preferably 30 or more. The ratio of the mass fraction of contacted anti-solvent to the mass fraction of contacted INHAL-101 solution may be from 5 to 200, preferably from 10 to 100, more preferably from 20 to 75, e.g., from 30 to 60.

[0133] Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid anti-solvent (e.g. the stream of fluid anti-solvent) at a pressure of from 75 to 150 bar absolute or from 80 to 120 bar absolute. Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid antisolvent (e.g., the stream of fluid anti-solvent) at a temperature of from 35 °C to 80°C or from 40 °C to 70 °C. This may be achieved by maintaining the pressure and temperature in the precipitation chamber at the desired levels whilst the solution and anti-solvent are contacted.

[0134] The anti-solvent and the solution of INHAL-101 may be contacted in any manner consistent with desired crystalline particle formation. In general, to achieve precipitation, the antisolvent and solution are contacted such that extraction of a solvent system of the solution occurs by the action of the anti-solvent. Suitably, this may occur in the precipitation chamber, for example in which temperature and pressure are controlled to desired levels. Mixing energy may be provided by shear between the anti-solvent and the solution, as is known in the art. Advantageously, the anti-solvent and solution may be contacted such that dispersion and extraction of the solvent system occur substantially simultaneously by the action of the anti-solvent. Suitably, the energy of mixing may be arranged to provide a virtually instantaneous homogeneous fluid mixture of the anti-solvent and solution.

[0135] The stream of anti-solvent and the stream of solution of INHAL-101 may be introduced into the precipitation chamber via respective passages with respective outlets, the outlets being arranged relative to one another such that stream of anti-solvent introduced through a first passage and the stream of solution of INHAL-101 introduced through a second passage contact each other in the precipitation chamber.

[0136] The stream of the solution of the compound of formula I and the stream of anti-solvent may be provided to the precipitation chamber at substantially the same point. The stream of solution and the stream of anti-solvent may be co-fed into the precipitation chamber using a nozzle arrangement having co-axial passages which terminate adjacent to one another. Preferably, the stream (or more than one stream) of anti-solvent is arranged to impinge on the stream (or more than one stream) of the solution. This arrangement advantageously provides high shear and thus a high degree of contact between the anti-solvent and the solution.

[0137] However, any arrangement which provides for good levels of mixing and dispersion may be used, such as those disclosed in WO-95 / 01221, WO-96 / 00610, WO-98 / 36825, WO- 99 / 44733, WO-99 / 59710, WO-01 / 03821, and WO-03 / 008082, which are incorporated herein by reference.

[0138] The method may comprise contacting a relatively high velocity anti-solvent stream, with a relatively low velocity stream solution of INHAL-101. The relative velocities of the two fluid streams may suitably be managed by varying the diameter and cross-sectional area of respective jets or nozzles for delivering the streams, and controlling the flow rate of each fluid stream. For example, the velocity of a stream may be controlled by an orifice plate of fixed diameter. This diameter may be arranged so as to maintain a set temperature and pressure on the upstream side of the orifice plate, while maintaining a specific flow rate through the orifice. The velocity of the resulting stream can be calculated using the density of the fluid upstream of the orifice plate (by referencing the fluid temperature and pressure), the mass flow of the fluid, the cross sectional area of the orifice, and the differential pressure across the orifice (equation given in Crystallization process in turbulent supercritical flows, Shekunov, B Yu, Hanna M, York P J, Crystal Growth, 198-199, 1345- 1351 (1999)).

[0139] The amount of kinetic energy suitable for mixing the two fluid streams and initiating supersaturation varies between each solute and each solvent mixture used. In an embodiment, the anti-solvent stream velocity is in the range of from 10 to 300 m / sec-1, preferably from 20 to 150 m / sec-1, e.g., from 30 to 75 m / sec-1. The velocity of the solution of INHAL-101 is typically lower than the velocity of the anti-solvent stream and not critical to the invention. In an embodiment, the velocity ratio between the anti-solvent stream and the solution stream is in the range of from 100: 1 to 1200: 1, preferably from 250: 1 to 1000: 1, e.g., from 350: 1 to 600: 1.

[0140] In a preferred method, upon contacting the fluid anti-solvent with the solution of INHAL- 101, the solvent is extracted from the solution by the fluid anti-solvent to form a mixture of the solvent and the fluid anti-solvent, thereby precipitating said crystalline form of the compound of formula I, e.g., in the precipitation chamber. Preferably, the mixture of the solvent and the fluid anti-solvent are removed from the precipitation chamber, e.g., via a vent. Preferably, the method further comprises recovering the crystalline form of the compound of formula I from the precipitation chamber. This may involve depressurisation of the precipitation chamber followed by removal of the crystalline form of the compound of formula I from the precipitation chamber.

[0141] The concentration of the compound of formula I in the solvent may be from 5 mg / ml to 200 mg / ml, preferably from 10 mg / ml to 100 mg / ml, more preferably from 15 mg / ml to 50 mg / ml.

[0142] The solvent preferably comprises an organic solvent. Preferred organic solvents comprise dichloromethane (DCM), dimethylformamide (DMF) and alcohols such as a Ci-C6alkanol, preferably methanol, ethanol, propanol (e.g., isopropanol (IPA)) or a mixture thereof. Preferably, the solvent comprises dichloromethane, although one of skill in the art would appreciate that an alternative could be used. Common DCM alternatives include ethyl acetate, methyl tert-butyl ether, toluene, tetra hydrofuran and 2-methyl tetra hydrofuran. Preferably, the solvent comprises an alcohol, such as a Ci-C6alkanol, preferably methanol, ethanol, propanol (e.g., isopropanol) or a mixture thereof. Most preferably, the solvent comprises DCM, alone or in combination with an alcohol, said alcohol preferably selected from methanol, ethanol, propanol (e.g., isopropanol) and a mixture thereof. In solvents comprising DCM and an alcohol, the ratio (by volume) of DCM to alcohol (such as Ci-C6alkanol) may preferably be from 1:20 to 20: 1, more preferably from 1 : 10 to 10: 1, still more preferably from 1:5 to 10: 1. In some preferred methods, the solvent may be substantially devoid of water (e.g. does not contain water other than trace water present in the organic solvent). Alternatively, the solvent may comprise water. For example, the solvent may comprise a mixture of DMF and water.

[0143] The method according to the sixth aspect of the invention provides good mass recovery of the product. Preferably, the crystalline form of the compound of formula I is prepared in yield of at least 25%, more preferably at least 50%, still more preferably at least 70%, yet more preferably at least 75%. Yields of up to 100% may advantageously be obtained, for example yields of from 50% to 98%, or from 70% to 95%. Yield is based on the mass of the recovered crystalline form, as a percentage of the mass of the compound of formula I starting material.

[0144] Preferably, the crystalline form of the compound of formula I prepared by the method of the sixth aspect may be as hereinabove described with respect to the foregoing aspects of the invention. For example, the crystalline form of the compound of formula I prepared by the method may preferably comprise the crystalline form of the first aspect as hereinbefore described, the crystalline form of the second aspect as hereinbefore described, the crystalline form of the third aspect as hereinbefore described, the crystalline form of the fourth aspect as hereinbefore described, or any combination thereof. Preferably the crystalline form of the compound of formula I prepared by the method is a single crystalline form (i.e., a single polymorph).

[0145] Advantageously, the method of the sixth aspect can be tuned to produce a desired crystalline form, e.g., a specific single polymorph having desired properties.

[0146] Preferably, the method conditions may be selected such that the crystalline form of the compound of formula I according to the first aspect of the invention is formed. Thus, the method preferably comprises contacting the fluid anti-solvent with the solution of the compound of formula I in a solvent under conditions suitable to precipitate the crystalline compound of formula I according to the first aspect of the invention. The skilled person would readily determine suitable conditions based on the teaching of the application, e.g., as provided in the examples. Especially preferred conditions are described below.

[0147] Preferably, the fluid anti-solvent is carbon dioxide having a pressure of from 100 to 150 bar absolute, preferably from 100 to 125 bar absolute, more preferably from 100 to 120 bar absolute, e.g., from 105 to 115 bar absolute. The carbon dioxide preferably has a temperature of from 55 °C to 80°C or from 55 °C to 75 °C, e.g., from 60 °C to 70 °C.

[0148] Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid anti-solvent (e.g. the stream of fluid anti-solvent) at a pressure of from 100 to 150 bar absolute, preferably from 100 to 125 bar absolute, more preferably from 100 to 120 bar absolute, e.g. from 105 to 115 bar absolute. Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid anti-solvent (e.g. the stream of fluid anti-solvent) at a temperature of from 55 °C to 80°C or from 55 °C to 75 °C, e.g. from 60 °C to 70 °C. This may be achieved by maintaining the pressure and temperature in the precipitation chamber at the desired levels whilst the solution and anti-solvent are contacted.

[0149] Preferably, the ratio of the mass fraction of contacted anti-solvent to the mass fraction of contacted INHAL-101 solution is less than 50, e.g., from 10 to 50, preferably from 20 to 50, more preferably from 30 to 50.

[0150] Preferably, the concentration of the compound of formula I in the solvent is greater than 20 mg / ml, e.g., greater than 25 mg / ml. For example, the concentration of the compound of formula I in the solvent may be from 25 mg / ml to 100 mg / ml, preferably from 25 mg / ml to 50 mg / ml, or from 25 mg / ml to 45 mg / ml.

[0151] Preferably, the solvent comprises dichloromethane (DCM), or one of the DCM alternatives described above. Preferably, the solvent comprises dichloromethane (DCM). The solvent may preferably comprise DCM alone (e.g., may consist of DCM) or may comprise (or consists of) DCM in combination with another organic solvent such as a Ci-C6alkanol, preferably methanol, ethanol, propanol (e.g., isopropanol) or a mixture thereof. More preferably, the solvent comprises DCM alone (e.g., consists of DCM) or comprises (or consists of) DCM and an alcohol selected from methanol and propanol (preferably isopropanol). In solvents comprising DCM and an alcohol, the ratio (by volume) of DCM to alcohol is preferably from 1: 1 to 20: 1, more preferably from 1 : 1 to 10: 1. Preferably, the solvent is substantially devoid of water (e.g., does not contain water other than trace water present in the organic solvent). Preferably the solvent does not contain DMF.

[0152] As described, these conditions preferably result in the formation of the crystalline form of the compound of formula I according to the first aspect of the invention. Preferred features of the crystalline form of the compound of formula I prepared under these conditions are as hereinbefore described with respect to the first aspect of the invention.

[0153] Alternatively, the method conditions may be selected such that the crystalline form of the compound of formula I according to the third aspect of the invention is formed. In such an embodiment, the method preferably comprises contacting the fluid anti-solvent with the solution of the compound of formula I in a solvent under conditions suitable to precipitate the crystalline compound of formula I according to the third aspect of the invention. The skilled person would readily determine suitable conditions based on the teaching of the application, e.g. as provided in the examples. Especially suitable conditions for this embodiment are described below.

[0154] Preferably, the fluid anti-solvent is carbon dioxide having a pressure of from 75 to 100 bar absolute, preferably from 80 to 100 bar absolute, e.g., from 85 to 95 bar absolute. The carbon dioxide preferably has a temperature of from 35 °C to 55°C, e.g., from 40 °C to 50 °C.

[0155] Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid anti-solvent (e.g., the stream of fluid anti-solvent) at a pressure of from 75 to 100 bar absolute, preferably from 80 to 100 bar absolute, e.g., from 85 to 95 bar absolute. Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid anti-solvent (e.g., the stream of fluid anti-solvent) at a temperature of from 35 °C to 55°C, e.g., from 40 °C to 50 °C. This may be achieved by maintaining the pressure and temperature in the precipitation chamber at the desired levels whilst the solution and anti-solvent are contacted.

[0156] Preferably, the ratio of the mass fraction of contacted anti-solvent to the mass fraction of contacted INHAL-101 solution is greater than 45 or greater than 50, e.g., from 50 to 100, preferably from 50 to 75.

[0157] Preferably, the concentration of the compound of formula I in the solvent is less than 30 mg / ml, e.g., less than 25 mg / ml. For example, the concentration of the compound of formula I in the solvent may be from 5 mg / ml to 25 mg / ml, preferably from 10 mg / ml to 25 mg / ml, or from 15 mg / ml to 20 mg / ml.

[0158] Preferably, the solvent comprises dichloromethane (DCM), or one of the DCM alternatives described above. Preferably, the solvent comprises dichloromethane (DCM). The solvent preferably comprises (or consists of) DCM in combination with another organic solvent such as an alcohol, e.g., a Ci-C6alkanol, preferably methanol, ethanol, propanol (e.g., isopropanol) or a mixture thereof. More preferably, the solvent comprises DCM and methanol. In solvents comprising DCM and an alcohol, the ratio (by volume) of DCM to alcohol is preferably from 1:20 to 1 : 1, more preferably from 1 : 10 to 1:5. When the solvent comprises DCM, preferably the solvent is substantially devoid of water (e.g., does not contain water other than trace water present in the organic solvent). Alternatively, the solvent may comprise dimethylformamide (DMF). When the solvent comprises DMF, it preferably further comprises water (is an aqueous solvent system). When the solvent comprises water and / or DMF, it preferably does not comprise DCM or methanol.

[0159] As described, these conditions preferably result in the formation of the crystalline form of the compound of formula I according to the third aspect of the invention. Preferred features of the crystalline form of the compound of formula I prepared under these conditions are as hereinbefore described with respect to the third aspect of the invention.

[0160] In a further alternative, the method conditions may be selected such that the crystalline form of the compound of formula I according to the fourth aspect of the invention is formed. In such an embodiment, the method preferably comprises contacting the fluid anti-solvent with the solution of the compound of formula I in a solvent under conditions suitable to precipitate the crystalline compound of formula I according to the fourth aspect of the invention. The skilled person would readily determine suitable conditions based on the teaching of the application, e.g., as provided in the examples. Especially suitable conditions for this embodiment are described below.

[0161] Preferably, the fluid anti-solvent is carbon dioxide having a pressure of from 75 to 100 bar absolute, preferably from 80 to 100 bar absolute, e.g., from 90 to 95 bar absolute. The carbon dioxide preferably has a temperature of from 35 °C to 60°C, e.g., from 45 °C to 55 °C, or about 50 °C.

[0162] Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid anti-solvent (e.g., the stream of fluid anti-solvent) at a pressure of from 75 to 100 bar absolute, preferably from 80 to 100 bar absolute, e.g., from 90 to 95 bar absolute. Preferably, the solution (e.g., the stream of the solution) of the compound of formula I is contacted with the fluid anti-solvent (e.g., the stream of fluid anti-solvent) at a temperature of from 35 °C to 60°C, e.g., from 45 °C to 55 °C, or about 50 °C. This may be achieved by maintaining the pressure and temperature in the precipitation chamber at the desired levels whilst the solution and anti-solvent are contacted.

[0163] Preferably, the ratio of the mass fraction of contacted anti-solvent to the mass fraction of contacted INHAL-101 solution is less than 50, e.g., from 10 to 50, preferably from 20 to 50, more preferably from 30 to 50.

[0164] Preferably, the concentration of the compound of formula I in the solvent is greater than 10 mg / ml, e.g., greater than 15 mg / ml. For example, the concentration of the compound of formula I in the solvent may be from 15 mg / ml to 45 mg / ml, preferably from 20 mg / ml to 40 mg / ml.

[0165] Preferably, the solvent comprises dichloromethane (DCM), or one of the DCM alternatives described above. Preferably, the solvent comprises dichloromethane (DCM). The solvent may preferably comprise DCM alone (e.g., may consist of DCM) but preferably comprises (or consists of) DCM in combination with another organic solvent such as a Ci-C6alkanol, preferably methanol, ethanol, propanol (e.g., isopropanol) or a mixture thereof. More preferably, the solvent comprises (or consists of) DCM and an alcohol selected from methanol and propanol (preferably isopropanol). In solvents comprising DCM and an alcohol, the ratio (by volume) of DCM to alcohol is preferably from 1: 1 to 20: 1, more preferably from 1: 1 to 10: 1. Preferably, the solvent is substantially devoid of water (e.g., does not contain water other than trace water present in the organic solvent). Preferably the solvent does not contain DMF.

[0166] As described, these conditions preferably result in the formation of the crystalline form of the compound of formula I according to the fourth aspect of the invention. Preferred features of the crystalline form of the compound of formula I prepared under these conditions are as hereinbefore described with respect to the fourth aspect of the invention.

[0167] In a seventh aspect, the invention provides a crystalline form of a compound of formula I:

[0168] I, obtained by a method according to the sixth aspect. Preferred features of the method by which the crystalline form according to the seventh aspect is maintained are as hereinbefore described with respect to the sixth aspect of the invention. Preferred features of the crystalline form according to the seventh aspect are as hereinbefore described with respect to the first to fourth aspects of the invention.

[0169] In an eighth aspect, the invention provides a pharmaceutical composition comprising (or consisting of) a therapeutically effective amount of a crystalline form or composition of the compound of formula I according to any of the first, second, third, fourth, fifth or seventh aspects, preferably the first or second aspects, e.g., the first aspect.

[0170] The pharmaceutical composition is preferably a dry powder composition. However, the pharmaceutical composition may take any suitable form known in the art. Suitably, the crystalline form or composition may be suspended in a non-solvent vehicle.

[0171] The pharmaceutical composition may further comprise a suitable excipient. Suitable amounts of excipient are known to a skilled person. For example, one or more excipients may be present in an amount of from 20 to 99.9% by weight of the total composition, preferably 50 to 99 % by weight of the total composition, suitably 60 to 95% by weight of the total composition. The excipient may be of conventional type and may be obtained by any suitable process. An example of a suitable excipient is inhalable lactose.

[0172] A preferred pharmaceutical composition does not, however, contain any excipients. Advantageously, the inventors have prepared a form of the compound of formula I that can be directly used as a pharmaceutical composition without the need for excipients. This is especially the case when the pharmaceutical composition comprises the crystalline form or composition according to the first or second aspects hereinbefore described, e.g., the first aspect. In this case the crystalline form or composition has an optimum morphology for use as a pharmaceutical composition, particularly for pulmonary administration (e.g., by inhalation or insufflation).

[0173] In a ninth aspect, the invention provides the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects for use as a medicament. The use may preferably involve treatment of a disorder that is alleviated by inhibition of PI-3 kinase, mTOR, BRD-4 or a combination thereof. The disorder may preferably be alleviated by inhibition of PI-3 kinase. The disorder may preferably be alleviated by inhibition of mTOR. The disorder may preferably be alleviated by inhibition of BRD-4. Preferably, the disorder may be alleviated by inhibition of PI-3 kinase, mTOR and BRD-4.

[0174] INHAL-101 is a known inhibitor of PI-3 kinase, mTOR and BRD-4. Thus, in a tenth aspect, the invention provides the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects for use in a method of inhibiting PI-3 kinase, mTOR, BRD- 4 or a combination thereof. The crystalline form or composition for use according to the tenth aspect may preferably be for use in a method of inhibiting PI-3 kinase. The crystalline form or composition for use according to the tenth aspect may preferably be for use in a method of inhibiting mTOR. The crystalline form or composition for use according to the tenth aspect may preferably be for use in a method of inhibiting BRD-4. Preferably, the crystalline form or composition for use according to the tenth aspect may be for use in a method of inhibiting PI-3 kinase, mTOR and BRD-4. The method may preferably involve treatment of a disorder that is alleviated by inhibition of PI-3 kinase, mTOR, BRD-4 or a combination thereof. The disorder may preferably be alleviated by inhibition of PI-3 kinase. The disorder may preferably be alleviated by inhibition of mTOR. The disorder may preferably be alleviated by inhibition of BRD-4. Preferably, the disorder may be alleviated by inhibition of PI-3 kinase, mTOR and BRD-4.

[0175] In an eleventh aspect, the invention provides a method of treating a disorder in a patient (e.g., a human or other mammal, preferably a human), the method comprising administering to said patient a therapeutically effective amount of the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects.

[0176] In a twelfth aspect, the invention provides a method of inhibiting PI-3 kinase, mTOR, BRD-4 or a combination thereof in a patient (e.g., a human or other mammal, preferably a human), the method comprising administering to said patient a therapeutically effective amount of the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects. The method may preferably be a method of inhibiting PI-3 kinase. The method may preferably be a method of inhibiting mTOR. The method may preferably be a method of inhibiting BRD-4. Preferably, the method is a method of inhibiting PI-3 kinase, mTOR and BRD-4. The patient may preferably suffer from a disorder that is alleviated by inhibition of PI-3 kinase, mTOR, BRD-4 or a combination thereof. The disorder may preferably be alleviated by inhibition of PI-3 kinase. The disorder may preferably be alleviated by inhibition of mTOR. The disorder may preferably be alleviated by inhibition of BRD-4. Preferably, the disorder may be alleviated by inhibition of PI-3 kinase, mTOR and BRD-4.

[0177] The ninth to twelfth aspects may preferably comprise administering a therapeutically effective amount of the crystalline form or composition to a patient (e.g., human or other mammal, preferably a human) in need thereof. Administration is preferably by pulmonary administration, e.g., by inhalation or insufflation, more preferably inhalation. The patient may preferably suffer from a disorder that may be alleviated by inhibition of PI-3 kinase, mTOR, BRD-4 or a combination thereof. The disorder may preferably be alleviated by inhibition of PI-3 kinase. The disorder may preferably be alleviated by inhibition of mTOR. The disorder may preferably be alleviated by inhibition of BRD-4. Preferably, the disorder may be alleviated by inhibition of PI-3 kinase, mTOR and BRD-4.

[0178] In a thirteenth aspect, the invention provides an inhalation or insufflation device having therein the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects. The device is preferably an inhalation device, e.g., an inhaler such as a metered dose inhaler or a dry powder inhaler. More preferably, the device is a dry powder inhaler. The dry powder inhaler may have therein a capsule containing the crystalline form or composition according to any of the first to fifth, seventh and eighth aspects.

[0179] EXAMPLES

[0180] Synthesis of INHAL-101 starting material

[0181] INHAL-101 starting material may be made using the synthesis route disclosed in US8,557,807 for compounds of the general formula V (e.g., at column 25, lines 28-40). This is exemplified in US8,557,807 for the preparation of related compounds "6" and "3" (see columns 32-35). Synthesis of INHAL-101 by this route may be achieved by following this method and simply substituting the appropriate boronic acid.

[0182] Analysis of INHAL-101 starting material

[0183] INHAL-101 starting material (designated "Form A") was analysed by Proton Nuclear magnetic resonance (XH-NMR, Bruker AVIII 400 MHz FT NMR spectrometer) TheXH-NMR spectrum is shown in Figure 1A. Solid state characterisation of the INHAL-101 starting material was carried out by Powder X-ray Diffraction, PXRD (Rigaku Miniflex 600) (Figure 2), scanning electron microscopy analysis (HIROX SH4000M) (Figure 3) and thermal analysis (Seteram Labsys Evo DSC / TGA) (Figure 4). Further details of the characterisation methods are provided below.

[0184] Following the solid-state screening (details below), it was identified that Form A was a mixture of polymorphs C and E.

[0185] Solid state screen

[0186] Particle formation was conducted using a modified supercritical antisolvent solution technology, mSAS®.

[0187] For the mSAS® process the antisolvent and drug (in this case INHAL-101 Form A) solution are introduced continuously via respective passages into a pressurised precipitation vessel (also referred to as a precipitation chamber). The flow rates of each feed line, typically carbon dioxide as the antisolvent and a solution of drug in an organic solvent, are monitored. The pressure in the precipitation vessel is controlled and maintained by a back pressure regulator connected in line at the single outlet vent passage from the precipitation vessel. The temperature of the whole assembly is controlled, typically using an oven when at laboratory and small-scale operation. In this way, supercritical or near critical antisolvent fluid conditions are created within the precipitation vessel.

[0188] The outlets of the two feed lines enter into the precipitation vessel at substantially the same point which is where the antisolvent and solution meet. In order to achieve a high degree of contact between the antisolvent and solution, mixing and dispersion, the antisolvent and solution are, for example, co-fed into the precipitation vessel using a nozzle arrangement having co-axial passages which terminate adjacent to one another. Alternatively, one or more streams of the antisolvent can be arranged to impinge on a stream of the solution to provide a high degree of contact between the antisolvent and the solution, mixing and dispersion. Other contact, mixing and dispersion arrangements are known with examples of suitable equipment, inter alia, from WO95 / 01221, W096 / 00610, WO98 / 36825, WO- 99 / 44733, WO99 / 59710, W001 / 03821, and W0008082, which are incorporated herein by reference.

[0189] Following contact, mixing and dispersion of the antisolvent and solution under supercritical or near critical antisolvent fluid conditions, the solvent from the solution is extracted by, and dissolved in, the supercritical fluid or near critical supercritical fluid to form respectively a supercritical solution or near critical antisolvent solution which exits from the precipitation vessel via the vent line. Following the extraction of the solvent, the drug particles precipitate and are retained in the precipitation vessel and collected, typically in a collecting device such as a basket. The precipitated particulate powder is subsequently recovered following depressurisation of the precipitation vessel.

[0190] A study was carried out of process parameters such as pressure, temperature, solution composition, solution concentration, to examine the solid-state landscape with the aim to isolate a pure solid-state powdered form. For this study a vessel size of 200 ml (volume of precipitation chamber) was used, and a multi-channel nozzle arrangement was used, arranged such that the carbon dioxide antisolvent impinged on a stream of the INHAL-101 solution to provide high shear. Crystalline particles of INHAL-101 were formed.XH-NMR data shows that mSAS® processing did not change the chemical composition of INHAL-101 (see Figure IB for an exemplaryXH-NMR spectrum of the mSAS®-processed product).

[0191] Particle formation conditions that were varied are listed in Table 1, together with particle size results. In more detail, Table 1 refers to the following particle formation conditions / results:

[0192] ° / oYield : The % yield of the INHAL-101 product, i.e. the mass of INHAL-101 product collected as a percentage of the mass of INHAL-101 starting material used ([mass collected / mass in]*100).

[0193] Mass (mg): The mass of INHAL-101 starting material, indicated in milligrams (mg). Vol ml: The volume of solvent / solvent mixture in which the INHAL-101 starting material was dissolved.

[0194] Solution concentration mg / ml: The concentration of INHAL-101 in the solvent / solvent mixture, indicated in milligrams per millilitre of solvent / solvent mixture (mg / ml).

[0195] Solvent: The solvent or mixture of solvents in which the INHAL-101 starting material was dissolved.

[0196] % v / v: the ratio, by volume, of solvents when more than one solvent was used for dissolution of INHAL-101.

[0197] P bar: The pressure in the precipitation chamber, indicated in bars (bar)

[0198] T °C: The temperature of the precipitation chamber, indicated in degrees Celsius (°C)

[0199] Density g / cm3: The density of the stream of carbon dioxide, indicated in grams per cubic centimetre (g / cm3)

[0200] CO2g / min: The flow rate of carbon dioxide into the precipitation chamber, indicated in grams per minute (g / min)

[0201] TS g / min: The flow rate of the solution of INHAL-101 into the precipitation chamber, indicated in grams per minute (g / min)

[0202] Mass fractions CO2 / Solution: The ratio of the mass fraction of the carbon dioxide flow rate into the precipitation chamber (CO2Flow I [CO2Flow + INHAL-101 Solution Flow]) over the mass fraction of the solution of INHAL-101 solution flow rate into the precipitation chamber (INHAL-101 solution flow I [CO2Flow + INHAL-101 solution flow]), dimensionless.

[0203] Form: The INHAL-101 products isolated were designated as Forms B, C, D or E.

[0204] able 1

[0205] During the solid-state screen, a mixed form of INHAL-101 was isolated designated as Form 'B', along with three pure solid-state forms designated Form 'C', 'D' and 'E'. Yields in runs 1, 4 and 20 were relatively low due to the small scale of the process, meaning that full recovery of the mass and accurate calculation of yield was challenging.

[0206] Characterisation Methods

[0207] NMR Spectroscopy

[0208] XH Nuclear Magnetic Resonance Spectroscopy was carried out using a Bruker AVIII 400 MHz

[0209] FT NMR spectrometer. Analysis parameters were: ID Proton NMR, 16 scans, 10 mg INHAL- 101 dissolved in 0.8 ml deuterated DMSO.

[0210] Powder X-ray Diffraction (PXRD)

[0211] PXRD was carried out using Rigaku Miniflex 600 P-XRD. Cu-Ko radiation (A = 1.5406 A) was used as x-ray source. Further details of the apparatus and method are set out below. Differential calorimetry and thermal gravimetric analysis

[0212] Simultaneous differential calorimetry and thermal gravimetric analysis (TGA) was carried out using Seteram labsys evo. Further details of the apparatus and method are set out below.

[0213] Scanning Electron Microscopy (SEM)

[0214] SEM was carried out using HIROX SH4000M. Further details of the apparatus and method are set out below.

[0215] Particle size analysis

[0216] Details of the equipment and method used for particle size analysis are set out below. Aspect ratio

[0217] Aspect ratio is the ratio of the length (longest dimension) of a particle to the width (shortest dimension). Aspect ratios were calculated from SEM images of the particles (which also show a 'size scale reference bar'). The maximum length and width of a representative number of individual particles were measured and recorded to obtain an estimate of average aspect ratio and estimate of the range of aspect ratios for a given powder sample.

[0218] Particle lengths (longest dimension) were also measured from the SEM images in this way for particles having a needle-like morphology. Particles with needle-like morphology are unsuitable for particle size analysis using the method described above (Sympatec HELOS / KF Analyser) because these types of particles are broken up in the machine, leading to unrepresentative results.

[0219] Characterisation: Form B

[0220] Solid state analysis revealed Form B to be a mixture of polymorphs C, D and E. The PXRD pattern of Form B is shown in Figure 5. Figure 6 shows a representative SEM image of Form B, showing the mixed morphology of the particles. Figure 7 shows the thermal analysis of Form B.

[0221] Characterisation: Form C

[0222] The PXRD pattern of Form C is shown in Figure 8. Peak positions are set out in Table 2 below.

[0223] Table 2

[0224] Selected characteristic X-ray diffraction peaks for Form C are: 6.5°, 8.1° and 9.9° 20 (±0.2° 20).

[0225] Precipitation of Form 'C' from a range of process conditions resulted in lengthy needle shaped (acicular) crystals, an unhelpful morphology for the formulation and manufacture. Figure 9 shows a representative SEM image of Form C. The average needle-like particle length for Form 'C' was > 100 pm with an aspect ratio range of 5: 1 to 50: 1.

[0226] Figure 10 shows the thermal analysis of Form C. Form 'C' has a higher melting point (represented by the onset value) and enthalpy of fusion than other identified forms. Therefore, Form 'C' is the most stable polymorph.

[0227] Characterisation: Form D

[0228] The PXRD pattern of Form D is shown in Figure 11. Peak positions are set out in Table 3 below.

[0229] Table 3

[0230] Selected characteristic X-ray diffraction peaks for Form D are: 5.8°, 8.2° and 9.2° 20 (±0.2° 20).

[0231] Surprisingly, samples of Form D exhibited a preferred morphology and particle size (D90<5 pm) for pharmaceutical product development. Figure 12 shows representative SEM images of Form D, from different precipitation conditions (Figure 12A - from ID10 of Table 1; Figure 12B - from ID12 of Table 1; Figure 12C - from ID14 of Table 1). Particle size and morphology for Form D are highly reproducible. Table 4 below shows the reproducibility of particle characteristics for Form D.

[0232] Table 4

[0233] Table 4 refers to the following characteristics:

[0234] The particle diameter where a cumulative particle diameter distribution of the precipitated INHAL-101 particles reaches 10% by volume, i.e., 10% by volume of the particles have a smaller diameter than this value, and 90% by volume of the particles have a larger diameter than this value ("D10"), indicated in micrometres (pm).

[0235] The particle diameter where a cumulative particle diameter distribution of the precipitated INHAL-101 particles reaches 50% by volume, i.e., 50% by volume of the particles have a smaller diameter than this value, and 50% by volume of the particles have a larger diameter than this value ("D50"), indicated in micrometres (pm). The particle diameter where a cumulative particle diameter distribution of the precipitated INHAL-101 particles reaches 90% by volume, i.e., 90% by volume of the particles have a smaller diameter than this value, and 10% by volume of the particles have a larger diameter than this value ("D90"), indicated in micrometres (pm).

[0236] The volume mean diameter ("VMD") of the precipitated INHAL-101 particles, indicated in micrometres (pm).

[0237] The average particle length for Form D was between 1 and 3 microns with an aspect ratio range of 1 : 1 to 3: 1. This is a preferred morphology and particle shape for drug delivery to the pulmonary tract.

[0238] Figure 13 shows the thermal analysis of Form D. Two endothermic melting peaks are observed. Form D is metastable, therefore after melt it recrystalises into Form C which then melts at the higher melting point.

[0239] Hot stage microscopy data (see Figure 14) confirm the thermal transition of Form D into Form C, and that Form D is metastable to Form C. The inventors have surprisingly developed a method that allows the isolation of Form D in pure form, without contamination by or conversion to Form C.

[0240] Characterisation: Form E

[0241] The PXRD pattern of Form E is shown in Figure 15. Peak positions are set out in Table 5 below.

[0242] Table 5

[0243] Selected characteristic X-ray diffraction peaks for Form E are: 5.4°, 7.7°, 10.9° and 15.4° 29 (±0.2° 29).

[0244] Precipitation of Form E from a range of process conditions resulted in lengthy needle shaped (acicular) crystals, an unhelpful morphology for formulation and manufacture of pharmaceutical products. This can be seen from the SEM images (see Figure 16 for a representative example). The average particle length for Form E was > 25 pm with an aspect ratio range of 10: 1 to 30: 1.

[0245] Figure 17 shows the thermal analysis of Form E. The melting points of forms C, D and E are quite close to each other, indicating that they are likely to be conformational polymorphs. Typically, it is challenging using conventional technologies to separate pure forms of conformational polymorphs.

[0246] Accelerated stability study

[0247] Accelerated stability studies were carried out as follows: Samples (approximately 20-50 mg) were placed in a loose-topped, 20 ml glass scintillation vial and stored at 40 °C and 60% relative humidity for the study duration. The form of INHAL-101 present in the samples at the end of the study duration was assessed using PXRD as described above. Particle characteristics were analysed using the Sympatec HELOS method described above.

[0248] Table 6 shows that all tested solid-state forms of INHAL-101 remained unchanged at the 9- month time point. I I (no change)

[0249] Table 6

[0250] Table 7 shows additional data for Form D, showing that particle size characteristics remained unchanged at the 6-month time point.

[0251] Table 7

[0252] Stability of Form D to different mSAS® processing times

[0253] Table 8 shows the effect of process time on particle control of Form D. Particle characteristics were analysed using the Sympatec HELOS method described above. The 60- minute run corresponds to ID8 from Table 1. The 180-minute run corresponds to ID10 from Table 1.

[0254] Table 8

[0255] Longer run times enable the processing of greater quantities of material in a batch. This shows the process can be successfully scaled up whilst maintaining consistency of the favourable morphology and particle size characteristics of the Form D product.

[0256] Next Generation Impactor study

[0257] A study of the aerosolization characteristics of Form D was conducted using a Next Generation Impactor (NGI, Copley Scientific, UK). This apparatus enables the classification of aerosolised particles into size fractions corresponding to the different dimensions of the airways in the pulmonary tract where the particles will be deposited following drug delivery.

[0258] The apparatus consists of a series of impactor plates with decreasing cut off diameters, such that the particles deposited at each stage are those with a diameter between the diameter of the specific impactor plate and the impactor plate immediately up-stream. In operation, a dose or bolus, of powder is delivered from a suitable device into the NGI. The powder particles are aerosolised by a controlled flow of air into the NGI and fractionated and collected on the different impactor plates according to particle size. The amounts of particles collected on the individual plates are determined analytically to provide a particle size distribution. The NGI apparatus provides particle size information for the size range 0.2 to 11 microns and generally contains seven impactor plates (designated Pl to P7).

[0259] From the NGI particle size distribution data, the following measurements can be determined: - Total / percentage emitted dose (TED) - the amount / percentage of drug emitted from the administration device

[0260] Fine particle dose (FPD) - amount of drug delivered to a selected number of impactor plates (to represent deposition of drug particles across size range eg P2 - P7) - Fine particle fraction (FPF), as a percentage of TED

[0261] Mass median aerodynamic diameter (MMAD)

[0262] - Geometric standard deviation (GSD).

[0263] The conditions used are set out below. Results are depicted in Figure 18 and in Table 9 below. NG stages P2-P7 were used for fine particle fraction collection.

[0264] Table 9

[0265] These results show that 93% fine particle fraction was achieved. Such a high fine particle fraction indicates exceptional aerodynamic performance. This demonstrates the potential to achieve excellent levels of deep lung delivery from a simple, off-the-shelf capsule-based inhaler.

[0266] Preliminary study on pharmacokinetics and bioavailabilitv

[0267] A preliminary pharmacokinetic and bioavailability study was performed using a polymorph D sample of INHAL-101 using 12 Sprague Dawley rats with the powder administered by intravenous and pulmonary routes. For the pulmonary administration, the rats were constrained with snouts exposed to a generated powder aerosol cloud. Drug levels in plasma samples collected over a 24-hour period were measured as well as drug levels remaining in lung tissues after 24 hours. Results showed an absolute bioavailability figure for pulmonary administration of 36.8%, and a high level of retained drug in the lung tissue after 24 hours. These findings provide good indicators for the successful administration of INHAL-101 using a dry powder inhaler for localised drug delivery to the pulmonary tract.

Claims

CLAIMS1. A crystalline form of a compound of formula I:I, having an X-ray powder diffraction pattern with peaks at 29 values of about 5.8°, 8.2°, and 9.2°.

2. The crystalline form of the compound of formula I according to claim 1, wherein the X- ray powder diffraction pattern has further peaks at 29 values of about 11.7°, 17.0°, 17.5°, 20.7°, 23.7° and 25.2°.

3. The crystalline form of the compound of formula I according to claim 1 or claim 2, wherein the X-ray powder diffraction pattern does not have peaks at 29 values of about 6.5°, 9.9°, 7.7° and 10.9°.

4. The crystalline form of the compound of formula I according to any preceding claim, which has a melting point of from 193 °C to 198 °C.

5. The crystalline form of the compound of formula I according to any preceding claim, having one or more of the following characteristics: i. a Dio of from 0.2 pm to 1.5 pm; ii. a D50of from 0.5 pm to 5.0 pm; iii. a D90of from 1.0 pm to 10.0 pm; iv. a volume mean diameter of from 0.5 pm to 5.0 pm; v. an aspect ratio of from 1: 1 to 3: 1.

6. A composition comprising particles of a compound of formula I:the composition having one or more of the following characteristics: i. a Dio of from 0.2 pm to 1.5 pm; ii. a D50of from 0.5 pm to 5.0 pm; iii. a D90of from 1.0 pm to 10.0 pm; iv. a volume mean diameter of from 0.5 pm to 5.0 pm; v. an aspect ratio of from 1: 1 to 3: 1.

7. A crystalline form of a compound of formula I:I having an X-ray powder diffraction pattern with peaks at 29 values of about 6.5°, 8.1° and 9.9°8. The crystalline form of the compound of formula I according to claim 7, wherein the X- ray powder diffraction pattern has further peaks at 29 values of about 15.1°, 19.8°, 27.2°, and 28.1°.

9. The crystalline form of the compound of formula I according to claim 7 or claim 8, wherein the X-ray powder diffraction pattern does not have peaks at 20 values of about 5.4°, 5.8°, 9.0° and 9.2°.

10. The crystalline form of the compound of formula I according to any of claims 7 to 9, which has a melting point of from 210 °C to 217 °C.

11. The crystalline form of the compound of formula I according to any of claims 7 to 10, having one or more of the following characteristics: i. an average particle length of greater than 100 pm; ii. an aspect ratio of from 5: 1 to 50: 1.

12. A crystalline form of a compound of formula I:I having an X-ray powder diffraction pattern with peaks at 20 values of about 5.4°, 7.7° and 10.9°.

13. The crystalline form of the compound of formula I according to claim 12, wherein the X- ray powder diffraction pattern has further peaks at 20 values of about 9.0°, 15.4° and 16.3°.

14. The crystalline form of the compound of formula I according to claim 12 or claim 13, wherein the X-ray powder diffraction pattern does not have peaks at 20 values of about 6.5°, 11.7°, 14.9° and 17.0°.

15. The crystalline form of the compound of formula I according to any of claims 12 to 14, which has a melting point of from 186 °C to 192 °C.

16. The crystalline form of the compound of formula I according to any of claims 12 to 15, having one or more of the following characteristics:I . an average particle length of greater than 25 pm; ii. an aspect ratio of from 10: 1 to 30: 1.

17. The crystalline form or composition according to any preceding claim, obtained by supercritical anti-solvent (SAS) precipitation.

18. A method of preparing a crystalline form of a compound of formula I:I, the method comprising contacting a fluid anti-solvent with a solution comprising the compound of formula I in a solvent, to precipitate said crystalline form of the compound of formula I.

19. The method of claim 18, wherein the anti-solvent is a supercritical fluid.

20. The method of claim 18 or claim 19, wherein the anti-solvent is carbon dioxide, preferably having a pressure in the range of from 75 to 150 bar absolute and a temperature in the range of from 35 to 80 °C.

21. The method of any of claims 18 to 20 wherein the anti-solvent and the solution are cofed into a precipitation chamber via a nozzle having co-axial passages which terminate adjacent to one another.

22. The method of any of claims 18 to 21, wherein one or more streams of the anti-solvent are arranged to impinge on a stream of the solution.

23. The method of any of claims 18 to 22, wherein the anti-solvent is contacted with the solution at a temperature of from 55 °C to 80 °C and / or at a pressure of from 100 bar to 150 bar absolute.

24. The method of any of claims 18 to 22, wherein the anti-solvent is contacted with the solution at a temperature of from 35 °C to 55 °C and / or at a pressure of from 75 bar to 100 bar absolute.

25. A crystalline form of a compound of formula I:I, obtained by a method according to any of claims 18 to 24.

26. The crystalline form or composition according to any of claims 1 to 17 and 25, for use as a medicament.

27. The crystalline form or composition according to any of claims 1 to 17 and 25, for use in a method of inhibiting PI-3 kinase, mTOR, BR.D-4 or a combination thereof.

28. The crystalline form or composition for use according to claim 26 or claim 27, comprising administering the crystalline form or composition by inhalation or insufflation.

29. An inhalation or insufflation device having therein the crystalline form or composition according to any of claims 1 to 17 and 25.

30. An inhalation or insufflation device according to claim 29, wherein the device is a dry powder inhaler.

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