Polymorphs of hydrobromate of linaraben glutarate

Abstract

The present invention relates to polymorphs of the hydrobromate of 5-{2-[({8-[(2, 6-dimethylbenzyl) amino]-2, 3-dimethylimidazo [1, 2-a] pyridin-6-yl} carbonyl)-amino] ethoxy}-5-oxovaleric acid (linaraben glutarate), and more particularly to Form A, Form B and Form C of the HBr salt of linaraben glutarate. The present invention also relates to pharmaceutical compositions comprising the polymorphs, and to the use of these polymorphs in the treatment or prevention of gastroenteritis diseases or gastric acid related diseases, in particular erosive gastroesophageal reflux disease (eGERD).

Description

Technical Field

[0001] The present invention relates to polymorphs of the hydrobromide salt of 5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid (linalaxan glutarate), and more specifically to Forms A, B, and C of the HBr salt of linalaxan glutarate. The present invention also relates to pharmaceutical compositions containing the polymorphs, and the use of these polymorphs in treating or preventing gastrointestinal inflammatory diseases or gastric acid-related diseases, particularly erosive gastroesophageal reflux disease (eGERD). Background Art

[0002] WO 2010 / 063876 discloses the compound linalaxyl glutarate (5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid; formerly known as X842). Its structure is shown below. It is a potassium-competitive acid blocker (P-CAB) that competitively inhibits the gastric potassium hydrogen pump (H+ / K+ ATPase) in parietal cells. Therefore, linalaxyl glutarate can be used to control gastric acid secretion in the stomach.

[0003]

[0004] Linarasen glutarate is a prodrug of linarasen, which is disclosed in WO 99 / 55706 and has previously been studied in Phase I and Phase II studies. These studies show that linarasen is well tolerated, has a rapid onset, and has a complete effect in the first dose. However, linarasen is rapidly removed from the body, and the duration of acid suppression is too short. In comparison, the in vivo half-life of linarasen glutarate is longer, showing complete control of gastric acid production over a longer period of time compared to linarasen. Clinical Phase I studies show that a single dose of linarasen glutarate can maintain gastric acidity at more than pH 4 for 24 hours. Therefore, linarasen glutarate is suitable for patients with severe erosive gastroesophageal reflux disease (eGERD).

[0005] For pharmaceutical preparation purposes, it is desirable that the active pharmaceutical ingredient (API) is in a highly crystalline form. Non-crystalline (i.e., amorphous) materials may contain high residual solvent levels, which is undesirable. Moreover, due to the low chemical and physical stability of amorphous materials, amorphous materials may exhibit faster degradation compared to crystalline materials and may spontaneously form crystals with different degrees of crystallinity. This may result in irreproducible dissolution rates and difficulties in storing and handling the material.

[0006] Two crystalline forms of linarasen glutarate free base are disclosed in CN 10627915. The free bases of Forms A and B were found to be anhydrous, and Form A was shown to have very low hygroscopicity. Although Form A has good physical and chemical stability and can be obtained with high crystallinity, in practice it is insoluble in water at pH 6.8 and only slightly soluble at pH 1. Low solubility limits the development of formulations with desirable properties.

[0007] There is therefore a need for other crystalline forms of linarasen glutarate having better properties than amorphous linarasen glutarate and its previously disclosed crystalline forms. In particular, the object of the present invention is to provide a stable crystalline form of linarasen glutarate which has good solubility, contains low levels of residual solvents, has high chemical stability and low hygroscopicity, and can be obtained with a high level of crystallinity. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Shown is the X-ray powder diffraction pattern of Form A of the HBr salt of linarasen glutarate synthesized as described in Example 1.

[0010] Figure 2 Shown is an X-ray powder diffraction pattern of Form B of the HBr salt of linarasen glutarate, obtained from a 4:1 methanol / toluene slurry ("Sample 1").

[0011] Figure 3 Shown is the X-ray powder diffraction pattern of Form B of the HBr salt of linarasen glutarate obtained from a 4:1 methanol / water slurry, showing additional peaks of a putative channel solvate ("Sample 2").

[0012] Figure 4 Shown is the X-ray powder diffraction pattern of Form C of the HBr salt of linarasen glutarate, obtained from a 1:1 DMF / toluene slurry.

[0013] Figure 5 Thermogravimetric analysis (TGA) weight loss curve of Form A (prepared in Example 1) is shown.

[0014] Figure 6 The TGA weight loss curve of Form B (Sample 1) is shown.

[0015] Figure 7 The TGA weight loss curve of Form C is shown.

[0016] Figure 8 A differential scanning calorimetry (DSC) thermogram of Form A is shown.

[0017] Figure 9 A differential scanning calorimetry (DSC) thermogram of Form B is shown.

[0018] Figure 10 A differential scanning calorimetry (DSC) thermogram of Form C is shown.

[0019] FIG11 shows a dynamic vapor sorption (DVS) weight change graph (A) and a DVS isotherm graph (B) of Form A.

[0020] FIG12 shows a DVS weight change graph (A) and a DVS isotherm graph (B) of Form B.

[0021] FIG13 shows a DVS weight change graph (A) and a DVS isotherm graph (B) of Form C. Detailed Description of the Invention

[0023] It has been discovered that under certain conditions, linarasen glutarate hydrobromide can form stable crystalline forms (polymorphs) with high crystallinity and high chemical stability. These novel polymorphs are therefore promising for use in pharmaceutical compositions of linarasen glutarate. Therefore, a first aspect of the present invention relates to the crystalline linarasen glutarate HBr salt.

[0024] In one embodiment, the present invention provides a crystalline linarasen glutarate HBr salt, wherein the crystalline HBr salt is stable at 94% relative humidity (RH) at room temperature. Such crystalline hydrobromide salts can be stable under these conditions for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, or even longer.

[0025] In some embodiments, the crystalline hydrobromide salt is an anhydrate. In one embodiment, the crystalline anhydrate is Form A. This form can be prepared directly from linaprenyl glutarate free base, or using its hydrobromide salt by certain crystallization techniques, such as from a slurry in 1,4-dioxane; by antisolvent crystallization from MeOH, pyridine, or DMF and certain antisolvents; or by reverse crystallization from DMF and MTBE. In one embodiment, Form A has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation having at least two peaks located at °2θ values selected from the group consisting of: 5.4±0.2, 18.3±0.2, 19.4±0.2, 22.4±0.2, 23.9±0.2, 24.0±0.2, 25.4±0.2, 26.5±0.2, 31.2±0.2, and 32.9±0.2. In some embodiments, Form A has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 5.4±0.2 and 19.4±0.2, or at the following °2θ values: 5.4±0.2 and 22.4±0.2, or at the following °2θ values: 5.4±0.2 and 25.4±0.2, or at the following °2θ values: 19.4±0.2 and 22.4±0.2, or at the following °2θ values: 19.4±0.2 and 25.4±0.2, or at the following °2θ values: 22.4±0.2 and 25.4±0.2. In some embodiments, Form A has an XRPD pattern obtained by CuKa-radiation having at least four peaks at °2θ values selected from the group consisting of: 5.4±0.2, 18.3±0.2, 19.4±0.2, 22.4±0.2, 23.9±0.2, 24.0±0.2, 25.4±0.2, 26.5±0.2, 31.2±0.2, and 32.9±0.2. In some embodiments, Form A has an XRPD pattern obtained by CuKa-radiation having at least four peaks at °2θ values selected from the group consisting of: 5.4±0.2, 18.3±0.2, 19.4±0.2, 22.4±0.2, and 25.4±0.2. In some embodiments, Form A has an XRPD pattern obtained by CuKα1-radiation having at least peaks at the following °2θ values: 5.4±0.2, 19.4±0.2, 22.4±0.2, and 25.4±0.2 and one or more peaks at the following °2θ values: 18.3±0.2, 23.9±0.2, 24.0±0.2, 26.5±0.2, 31.2±0.2, and 32.9±0.2.In some embodiments, Form A has an XRPD pattern obtained by CuKa-radiation, the XRPD pattern having peaks at at least the following °2θ values: 5.4±0.2, 19.4±0.2, 22.4±0.2, 23.9±0.2, 25.4±0.2, 31.2±0.2, and 32.9±0.2. In some embodiments, Form A has an XRPD pattern obtained by CuKa-radiation, the XRPD pattern having peaks at at least the following °2θ values: 5.4±0.2, 18.3±0.2, 19.4±0.2, 22.4±0.2, 23.9±0.2, 24.0±0.2, 25.4±0.2, 26.5±0.2, 31.2±0.2, and 32.9±0.2. In some embodiments, Form A has an XRPD pattern obtained by CuKα1-radiation having at least peaks at the following °2θ values: 5.4±0.2, 18.3±0.2, 19.4±0.2, 22.4±0.2, 23.9±0.2, 24.0±0.2, 25.4±0.2, 26.5±0.2, 31.2±0.2, and 32.9±0.2 and one or more peaks at the following °2θ values: 13.5±0.2, 14.4±0.2, 20.6±0.2, 25.8±0.2, and 26.8±0.2. In a specific embodiment, the present invention relates to Form A having an XRPD pattern obtained using CuKα1-radiation that is substantially as described. Figure 1 In another embodiment, the present invention is directed to Form A having an XRPD pattern obtained by CuKα1-radiation having the peaks shown in Table 8.

[0026] In some embodiments, the DSC curve of Form A comprises an endotherm between about 194°C and about 198°C, for example, at about 196°C. In a specific embodiment, the DSC curve of Form A comprises an endotherm between about 194°C and about 198°C, for example, at about 196°C, followed by another endotherm between about 220°C and about 224°C, for example, at about 222°C. The DSC curve of Form A is as follows Figure 8 shown.

[0027] Dynamic vapor sorption analysis shows that Form A has very low hygroscopicity, with a water absorption rate of approximately 0.15% at 80% relative humidity. This low hygroscopicity is considered advantageous because the water content of the crystals remains essentially constant even when the humidity varies within the normal relative humidity range of about 30% to about 80% RH. In some embodiments, Form A remains stable at 25°C and relative humidity up to 90%. A DVS plot of Form A is shown in Figure 11.

[0028] In another embodiment, the crystalline hydrobromide salt is Form B. This form can be prepared by certain crystallization techniques using the hydrobromide salt of X842, for example, crystallization from a slurry in MeOH or a mixture of methanol and toluene; evaporation from ethanol; reverse antisolvent crystallization from benzyl alcohol and isopropyl acetate or MTBE, or from pyridine and MTBE; or cooling from methanol. In one embodiment, Form B has an X-ray powder diffraction (XRPD) pattern obtained using CuKα1 radiation having at least two peaks at °2θ values selected from the group consisting of: 9.1±0.2, 12.2±0.2, 14.5±0.2, 21.1±0.2, 21.4±0.2, 21.8±0.2, 23.6±0.2, 24.8±0.2, 25.8±0.2, and 27.3±0.2. In some embodiments, Form B has an XRPD pattern obtained by CuKα1-radiation having at least four peaks at °2θ values selected from the group consisting of: 9.1±0.2, 12.2±0.2, 14.5±0.2, 21.1±0.2, 21.4±0.2, 21.8±0.2, 23.6±0.2, 24.8±0.2, 25.8±0.2, and 27.3±0.2. In some embodiments, Form B has an XRPD pattern obtained by CuKα1-radiation, the XRPD pattern having at least peaks at the following °2θ values: 14.5±0.2, 23.6±0.2, 24.8±0.2, and 25.8±0.2. In some embodiments, Form B has an XRPD pattern obtained by CuKα1-radiation, the XRPD pattern having at least peaks at the following °2θ values: 14.5±0.2, 23.6±0.2, 24.8±0.2, and 25.8±0.2 and one or more peaks at the following °2θ values: 9.1±0.2, 12.2±0.2, 21.1±0.2, 21.4±0.2, 21.8±0.2, and 27.3±0.2. In some embodiments, Form B has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 12.1±0.2, 14.5±0.2, 21.1±0.2, 23.6±0.2, 24.8±0.2, 25.8±0.2, and 27.3±0.2.In some embodiments, Form B has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 9.1±0.2, 12.2±0.2, 14.5±0.2, 21.1±0.2, 21.4±0.2, 21.8±0.2, 23.6±0.2, 24.8±0.2, 25.8±0.2, and 27.3±0.2. In some embodiments, Form B has an XRPD pattern obtained by CuKα1-radiation having at least peaks at the following °2θ values: 9.1±0.2, 12.2±0.2, 14.5±0.2, 21.1±0.2, 21.4±0.2, 21.8±0.2, 23.6±0.2, 24.8±0.2, 25.8±0.2, and 27.3±0.2 and one or more peaks at the following °2θ values: 7.6±0.2, 20.4±0.2, 27.8±0.2, 29.6±0.2, and 30.9±0.2. In a specific embodiment, the invention relates to Form B having an XRPD pattern obtained using CuKα1-radiation that is substantially as described. Figure 2 In another embodiment, the present invention is directed to Form B having an XRPD pattern obtained by CuKα1-radiation having the peaks shown in Table 9.

[0029] It was found that the X-ray diffraction pattern of Form B sometimes exhibits some additional peaks, for example, in experiments in which Form B is formed in methanol or a methanol mixture, in acetonitrile, or by evaporation of ethanol. These additional peaks are believed to belong to a small amount of putative channel solvate. Therefore, in some embodiments, the present invention relates to Form B, which has an XRPD pattern obtained using CuKα1 radiation substantially as follows: Figure 3 The channel solvate appears to convert to Form B upon drying.

[0030] In some embodiments, Form B has a DSC curve comprising an endotherm at about 115°C to about 121°C, such as about 118°C. In a specific embodiment, Form B has a DSC curve comprising an endotherm at about 115°C to about 121°C, such as about 118°C, followed by another endotherm at about 202°C to about 206°C, such as about 204°C. The DSC curve of Form B is as follows: Figure 9 shown.

[0031] As shown in Figure 12, the water content of Form B was found to vary between approximately 0 and 3% depending on the relative humidity. The significant water interaction of Form B suggests that it forms a hydrate at high humidity (approximately 3% of which corresponds to the monohydrate) and returns to the anhydrate upon drying.

[0032] In another embodiment, the crystalline anhydrate is Form C. This form can also be prepared using the hydrobromide salt by certain crystallization techniques, such as from a slurry in EtOH, or a DMF / toluene mixture, a benzyl alcohol / toluene mixture, a DMF / isopropyl acetate mixture, or an ethanol / water mixture; by antisolvent crystallization from DMF or benzyl alcohol with certain antisolvents; or by reverse antisolvent crystallization from DMF and acetone. In one embodiment, Form C has an X-ray powder diffraction (XRPD) pattern obtained using CuKα1 radiation having at least two peaks at °2θ values selected from the group consisting of 18.6±0.2, 19.9±0.2, 22.4±0.2, 22.8±0.2, 23.4±0.2, 24.3±0.2, 24.5±0.2, 25.5±0.2, 26.6±0.2, and 34.8±0.2. In some embodiments, Form C has an XRPD pattern obtained by CuKα1-radiation having at least four peaks at °2θ values selected from the group consisting of 18.6±0.2, 19.9±0.2, 22.4±0.2, 22.8±0.2, 23.4±0.2, 24.3±0.2, 24.5±0.2, 25.5±0.2, 26.6±0.2, and 34.8±0.2. In some embodiments, Form C has an XRPD pattern obtained by CuKα1-radiation, the XRPD pattern having at least peaks at the following °2θ values: 19.9±0.2, 23.4±0.2, 24.5±0.2, and 26.6±0.2. In some embodiments, Form C has an XRPD pattern obtained by CuKα1-radiation, the XRPD pattern having at least peaks at the following °2θ values: 19.9±0.2, 23.4±0.2, 24.5±0.2, and 26.6±0.2 and one or more peaks at the following °2θ values: 18.6±0.2, 22.4±0.2, 22.8±0.2, 24.3±0.2, 25.5±0.2, and 34.8±0.2. In some embodiments, Form C has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 18.6±0.2, 19.9±0.2, 23.4±0.2, 24.3±0.2, 24.5±0.2, 26.6±0.2, and 34.8±0.2.In some embodiments, Form C has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 18.6±0.2, 19.9±0.2, 22.4±0.2, 22.8±0.2, 23.4±0.2, 24.3±0.2, 24.5±0.2, 25.5±0.2, 26.6±0.2, and 34.8±0.2. In some embodiments, Form C has an XRPD pattern obtained by CuKα1-radiation having at least peaks at the following °2θ values: 18.6±0.2, 19.9±0.2, 22.4±0.2, 22.8±0.2, 23.4±0.2, 24.3±0.2, 24.5±0.2, 25.5±0.2, 26.6±0.2, and 34.8±0.2 and one or more peaks at the following °2θ values: 23.1±0.2, 24.8±0.2, 25.3±0.2, 26.9±0.2, and 27.7±0.2. In a specific embodiment, the invention relates to Form C having an XRPD pattern obtained using CuKα1-radiation that is substantially as described. Figure 4 In another embodiment, the present invention relates to Form C having an XRPD pattern obtained by CuKα1-radiation having the peaks shown in Table 10.

[0033] In some embodiments, Form C has a DSC curve comprising an endotherm at about 214 °C to about 230 °C, such as about 226 °C, such as Figure 10 shown.

[0034] Dynamic vapor sorption analysis showed that Form C has very low humidity interaction, with a water content of no more than approximately 0.05% at 90% RH. A DVS plot of Form C is shown in Figure 13.

[0035] In one embodiment, the present invention relates to a crystalline linarasen glutarate HBr salt having a crystallinity greater than 99%.

[0036] In a second aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline linarasen glutarate HBr salt disclosed herein, and one or more pharmaceutically acceptable excipients. The excipients may include, for example, fillers, binders, surfactants, disintegrants, glidants, and lubricants. In some embodiments, the crystalline linarasen glutarate HBr salt is in Form A. In some embodiments, the crystalline linarasen glutarate HBr salt is in Form B. In some embodiments, the crystalline linarasen glutarate HBr salt is in Form C.

[0037] In some embodiments, the pharmaceutical composition comprises a crystalline linarasen glutarate HBr salt, such as Form A, Form B, or Form C, having a polymorph purity of at least about 90%. In some embodiments, the polymorph purity is at least about 95%. In some embodiments, the polymorph purity is at least about 98%. For example, the polymorph purity may be at least about 98.5%, such as at least about 99%, such as at least about 99.5%, such as at least about 99.8%, or such as at least about 99.9%. In some embodiments, the pharmaceutical composition comprising the crystalline linarasen glutarate HBr salt is substantially free of other forms of linarasen glutarate. For example, in some embodiments, the pharmaceutical composition comprising Form A is substantially free of other forms of linarasen glutarate, such as Form B or Form C of linarasen glutarate. In some embodiments, Form A comprises less than about 15% by weight of Form B, Form C, or any other polymorph of linarasen glutarate. For example, Form A comprises less than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1% or less by weight of Form B, Form C, or any other polymorph of linarasen glutarate. In some embodiments, Form B comprises less than about 15% by weight of Form A, Form C, or any other polymorph of linarasen glutarate. For example, Form B comprises less than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1% or less by weight of Form A, Form C, or any other polymorph of linarasen glutarate. In some embodiments, Form C comprises less than about 15% by weight of Form A, Form B, or any other polymorph of linarasen glutarate. For example, Form C contains less than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1% or less by weight of Form A, Form B, or any other polymorph of linarasen glutarate.

[0038] In some embodiments, the pharmaceutical composition may comprise from about 1% to about 100%, such as from about 1% to about 50%, or such as from about 1% to about 20% by weight of the crystalline linapsen glutarate HBr salt. For example, the composition may comprise from about 1% to about 15%, or from about 5% to about 20%, such as from about 1% to about 10%, from about 5% to about 15%, and from about 10% to about 20%, or such as from about 1% to about 5%, from about 5% to about 10%, from about 10% to about 15%, and from about 15% to about 20% by weight of the crystalline linapsen glutarate HBr salt. In some embodiments, the composition comprises about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% by weight of the crystalline linapsen glutarate HBr salt.

[0039] In some embodiments, the composition comprises a unit dose of about 25 mg to about 150 mg of the crystalline linapaxen glutarate HBr salt. For example, the composition can comprise about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, or about 125 mg to about 150 mg. In some embodiments, the composition comprises about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg of crystalline linapsen glutarate HBr salt. The daily dose can be administered as a single dose or divided into two, three, or more unit doses.

[0040] In some embodiments, the pharmaceutical composition comprises a surfactant. The surfactant can be a cationic surfactant, an anionic surfactant or a nonionic surfactant. Examples of cationic surfactants include, but are not limited to, cetyl trimethylammonium bromide (cetrimonium bromide) and cetyl pyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium lauryl sulfate (sodium lauryl sulfate) and lauryl ammonium sulfate (ammonium lauryl sulfate). Examples of nonionic surfactants include, but are not limited to, glyceryl monooleate, glyceryl monostearate, polyoxyethylene castor oil (Cremophor El), poloxamer (e.g., poloxamer 407 or 188), polysorbate 80 and sorbitan esters (Tween).

[0041] In some embodiments, the pharmaceutical composition comprises a filler. Examples of suitable fillers include, but are not limited to, dibasic calcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0042] In some embodiments, the pharmaceutical composition comprises a binder. Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., gum arabic and tragacanth, etc.), sodium alginate, cellulose derivatives (e.g., hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, and ethyl cellulose, etc.), and synthetic polymers (e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers, and polyvinyl pyrrolidone (povidone), etc.).

[0043] In some embodiments, the pharmaceutical composition comprises a disintegrant. Examples of suitable disintegrants include, but are not limited to, dry starch, modified starch (e.g., (partially) pregelatinized starch, sodium starch glycolate, and sodium carboxymethyl starch), alginic acid, cellulose derivatives (e.g., sodium carboxymethyl cellulose, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose (L-HPC)), and cross-linked polymers (e.g., carboxymethyl ether cellulose, croscarmellose sodium, carboxymethyl ether cellulose calcium, and cross-linked PVP (crospovidone)).

[0044] In some embodiments, the pharmaceutical composition comprises a glidant or lubricant. Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, colloidal anhydrous silica, hydrous silica, synthetic magnesium silicate, fine-grained silica, starch, sodium lauryl sulfate, boric acid, magnesium oxide, wax (e.g., carnauba wax), hydrogenated oil, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0045] Typically, pharmaceutical compositions can be prepared in a conventional manner using conventional excipients. In some embodiments, the ingredients of the preparation are mixed into a uniform mixture and then formulated as tablets or capsules. Conventional techniques such as rotary tableting can be used to press the uniform mixture of ingredients into tablets. The mixture of ingredients can also be granulated. For example, the mixture of ingredients can be moistened by adding liquids such as water and / or suitable organic solvents (such as ethanol or isopropanol), then granulated and dried. Alternatively, particles can be prepared by dry granulation such as roller compaction. The obtained particles can be pressed into tablets using conventional techniques. Capsules can contain a powder mixture or small multi-granules (such as particles, extruded pellets or tablets) of the ingredients. If desired, any of the tablets, capsules, particles, extruded pellets and tablets mentioned above can be coated with one or more coating layers. Such coating layers can be applied by methods known in the art, for example, by film coating involving an orifice plate and a fluidized bed. In some embodiments, the preparation is in tablet form.

[0046] After being absorbed into the bloodstream, linarasen glutarate is rapidly metabolized to the active metabolite linarasen. Although the plasma concentration of linarasen glutarate is only very low and difficult to measure, the plasma concentration of linarasen, unlike this, can be measured. Phase I studies have shown that certain doses of linarasen glutarate should be able to maintain the intragastric pH at more than 4 for 24 hours after administration. It is estimated that this requires a minimum plasma concentration (C ) of linarasen after 22 hours. min ) is at least about 240 nmol / L. At such a dose, oral administration of the formulation once a day is sufficient. Thus, in some embodiments, a single unit dose of the linarasen glutarate pharmaceutical composition provides at least about 240 nmol / L of linarasen C in a human 22 hours after oral administration of the pharmaceutical composition. min In other embodiments, daily administration of two unit doses of the linarasen glutarate pharmaceutical composition provides at least about 240 nmol / L of linarasen C in the human 10 hours after oral administration of the last unit dose of the pharmaceutical composition. min .

[0047] In one aspect, the present invention relates to crystalline linarasen glutarate HBr salt for use in therapy.

[0048] The crystalline form of the linarasen glutarate HBr salt disclosed herein can be used to treat or prevent diseases or conditions in which it is necessary or desirable to inhibit gastric acid secretion, such as in Helicobacter pylori eradication. Examples of such diseases and conditions include inflammatory diseases of the gastrointestinal tract and gastric acid-related diseases, such as gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), Helicobacter pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcer and duodenal ulcer), bleeding gastric ulcer, gastroesophageal reflux disease symptoms (including heartburn, regurgitation and nausea), gastrinoma, and acute upper gastrointestinal bleeding.

[0049] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline linarasen glutarate HBr salt disclosed herein for use in treating or preventing gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0050] In another aspect, the present invention relates to a method for treating or preventing a gastrointestinal inflammatory disease or a gastric acid-related disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a crystalline linarasen glutarate HBr salt disclosed herein. In some embodiments, the crystalline linarasen glutarate HBr salt is in Form A. In other embodiments, the crystalline linarasen glutarate HBr salt is in Form B. In other embodiments, the crystalline linarasen glutarate HBr salt is in Form C.

[0051] In some embodiments, the gastrointestinal inflammatory disease or gastric acid-related disease is erosive gastroesophageal reflux disease (eGERD).

[0052] In a further embodiment, the treatment of GERD is an on-demand treatment of GERD.

[0053] As used herein, the term "polymorph" refers to crystals of the same molecule that have different physical properties due to the molecular ordering in the crystal lattice. Polymorphs of a single compound have one or more chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties that differ from each other. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rate (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, compactability, and particle morphology. Stability differences can be caused by changes in chemical reactivity (e.g., differential oxidation, causing a dosage form to change color more quickly when containing one polymorph than when containing another polymorph) or mechanical changes (e.g., changes in crystal structure during storage as a kinetically favored polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). Some transformations can affect efficacy and / or toxicity due to differences in solubility / dissolution. Additionally, the physical properties of the crystals may be important in processing; for example, one polymorph may more readily form solvates or may be difficult to filter and wash free of impurities (i.e., the particle shape and size distribution may differ from one polymorph to another). "Polymorphs" does not encompass amorphous forms of a compound.

[0054] As used herein, the term "amorphous" refers to a non-crystalline form of a compound, which may be a solid state form of the compound or a dissolved form of the compound. For example, "amorphous" means that the compound does not have a regularly repeating molecular arrangement or external surface planes.

[0055] As used herein, the term "anhydrate" or "anhydrous form" refers to a polymorph of linarasen glutarate having 0.5% or less by weight water, e.g., 0.4% or less, or 0.3% or less, or 0.2% or less, or 0.1% or less by weight water.

[0056] As used herein, the term "anhydrate" refers to a polymorph of linarasen glutarate having 0.5% or less by weight water, such as 0.4% or less, or 0.3% or less, or 0.2% or less, or 0.1% or less by weight water.

[0057] As used herein, the term "polymorphic purity," when used in reference to a composition comprising a polymorph of linarasen glutarate, refers to the percentage of one particular polymorph of linarasen glutarate relative to another polymorph or amorphous form in the composition. For example, a composition comprising Form A having a polymorphic purity of 90% comprises 90 parts by weight of Form A of linarasen glutarate and 10 parts by weight of other crystalline and / or amorphous forms, such as Form B or Form C.

[0058] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of linaprenyl glutarate that, upon administration to a subject, is sufficient to provide some relief from one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs and symptoms, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic use is the amount of linaprenyl glutarate required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0059] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting a disease or disorder described herein or one or more symptoms thereof. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual before the onset of symptoms (e.g., in view of a history of symptoms and / or in view of genetic or other predisposing factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0060] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for human pharmaceutical use and that are generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0061] As used herein, if a compound or composition does not include a significant amount of one or more other components, then the compound or composition is "substantially free of" such other components. Such components may include starting materials, residual solvents, or any other impurities that may result from the preparation and / or separation of the compounds and compositions provided herein. In some embodiments, the polymorphic forms provided herein are "substantially free of" impurities. The purity of a particular polymorph is preferably greater than about 90% (w / w), for example, greater than about 95% (w / w), for example, greater than about 97% (w / w), or for example, greater than about 99% (w / w). In some embodiments, the purity of a particular polymorph is greater than 99.5% (w / w), or even greater than 99.9% (w / w). In some embodiments, the impurities in a particular polymorph are less than about 1% (w / w), for example, less than about 0.5% (w / w), or for example, less than about 0.1% (w / w). The total amount of impurities can be determined, for example, by high performance liquid chromatography (HPLC).

[0062] In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of linarasen glutarate is "substantially free" of other polymorphs if the particular polymorph of linarasen glutarate comprises at least about 95% by weight of the linarasen glutarate present. In some embodiments, a particular polymorph of linarasen glutarate is "substantially free" of other polymorphs if the particular polymorph of linarasen glutarate comprises at least about 97%, about 98%, about 99%, or about 99.5% by weight of the linarasen glutarate present.

[0063] As used herein, a compound is "substantially" present as a given polymorph if at least about 50% by weight of the compound is in that polymorphic form, for example, if at least about 60%, at least about 70%, at least about 80%, or at least about 90% by weight of the compound is in that polymorphic form. In some embodiments, at least about 95%, such as at least about 96%, such as at least about 97%, such as at least about 98%, such as at least about 99%, or such as at least about 99.5% by weight of the compound is in that polymorphic form.

[0064] As used herein, the term "stable" means that a polymorph does not exhibit a change over time in one or more of the polymorphic form (e.g., an increase or decrease in a certain form), appearance, pH, percentage of impurities, activity (measured by an in vitro assay), or osmotic pressure. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, or 4 weeks. For example, the polymorph does not exhibit a change in one or more of the polymorphic form (e.g., an increase or decrease in a certain form), appearance, pH, percentage of impurities, activity (measured by an in vitro assay), or osmotic pressure for at least 1, 2, 3, or 4 weeks. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. For example, the polymorph does not exhibit a change in one or more of the polymorphic form (e.g., an increase or decrease in a certain form), appearance, pH, percentage of impurities, activity (measured by an in vitro assay), or osmotic pressure for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. As used hereinabove, the phrase "does not exhibit a change" means that any parameter changes by less than 5% (eg, less than 4%, less than 3%, less than 2%, less than 1%) when measured over the relevant time period.

[0065] The crystallinity of the linapaxan glutarate HBr salt polymorph can be measured, for example, by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). When referring to a crystalline compound in this article, it is preferred that the crystallinity is greater than about 70%, such as greater than about 80%, particularly greater than about 90%, and more particularly greater than about 95%. In some embodiments, the crystallinity is greater than about 98%. In some embodiments, the crystallinity is greater than about 99%. % crystallinity refers to the weight percentage of the total mass of the sample that is crystallized.

[0066] As used herein, the term "about" refers to a value or parameter herein that includes (and describes) embodiments relating to the value or parameter itself. For example, a description relating to "about 20" includes a description of "20." Numerical ranges include numbers that define the range. In general, the term "about" refers to the variable value shown and all variable values within the experimental error of the shown value (e.g., for the mean value, within a 95% confidence interval) or ±10% of the shown value, whichever is greater.

[0067] The invention will now be described by the following examples, which do not limit the invention in any way.All citations and references mentioned herein are incorporated by reference in their entirety.

[0068] abbreviation

[0069] DMFN,N-dimethylformamide

[0070] DMSO dimethyl sulfoxide

[0071] EtOAcEthyl acetate

[0072] EtOH

[0073] MeCNAcetonitrile

[0074] MeOH

[0075] MTBE methyl tert-butyl ether

[0076] RH relative humidity

[0077] Experimental methods

[0078] General approach

[0079] The results were obtained on a Bruker 400 MHz instrument at 25 °C and the deuterated solvent used was DMSO-d6 (δ H 2.50 ppm) of residual protic solvent, record 1 H-NMR spectrum.

[0080] Analytical HPLC-MS detection was performed using an Agilent 1100 series liquid chromatograph / mass selective detector (MSD) (single quadrupole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed using an ACE 3C8 (3.0 x 50 mm) column with a gradient of acetonitrile in 0.1% TFA in water over 3 minutes at a flow rate of 1 mL / min.

[0081] Unless otherwise stated, all solvents were dried by adding molecular sieves before preparing solutions.

[0082] X-ray powder diffraction (XRPD) analysis

[0083] The analysis was performed using a Cu anode (45 kV, 40 mA), Monochromator (1.540598 ) and PanAlytical of Pixcel detectors The diffractometer was used. The 2θ range was 2–35°, with a scan speed of 0.03° or 0.10° / s and a step size of 0.013°. A slowly rotating sample holder was used. The sample was smeared onto a zero-background Si wafer to create a flat powder surface. During a single measurement, the sample was covered with a plastic film to prevent solvent evaporation. Measurements were performed using a programmable incident divergence slit.

[0084] It is known in the art that, depending on the measurement conditions (e.g., the equipment, sample preparation, or the machine used), the X-ray powder diffraction pattern obtained may have one or more measurement errors. Specifically, it is generally known that, depending on the measurement conditions and sample preparation, the intensity of the XRPD pattern may fluctuate. For example, those skilled in the art of XRPD will understand that the relative intensity of the peaks may vary depending on the orientation of the sample during the test and the type and setting of the instrument used. Those skilled in the art will also understand that the position of the reflections may be affected by the exact height at which the sample is positioned in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Therefore, those skilled in the art will appreciate that the diffraction patterns presented herein should not be interpreted as absolute, and any crystalline form that provides a powder diffraction pattern substantially identical to the powder diffraction pattern disclosed herein falls within the scope of the present disclosure (for further information, see R. Jenkins and RL Snyder, "Introduction to X-ray powder diffractometry", John Wiley & Sons, 1996).

[0085] Thermogravimetric analysis (TGA)

[0086] Analyses were performed using a PerkinElmer TGA8000 instrument. Several milligrams of sample were gently placed in an open platinum pan and gravimetrically analyzed under a flow of dry nitrogen (40 ml / min) to ensure an inert atmosphere. The sample was scanned from 25°C to 200°C at a continuous scan rate of 10°C / min.

[0087] Differential Scanning Calorimetry (DSC)

[0088] The analysis was performed on a DSC 204F1 instrument. A few milligrams of sample were gently placed in an aluminum pan and weighed. A lid with a pre-formed pinhole was fitted and crimped onto the pan. A conventional DSC was used with a heating rate of 10°C / min. The minimum temperature (start) was 0°C, and the maximum temperature was 230°C.

[0089] Dynamic Vapor Sorption (DVS)

[0090] The analysis was performed on an SMS DVS Advantage instrument. Several milligrams of material were placed in an aluminum pan and exposed to a RH stepwise ramp from 0 to 90 to 20% in 10% RH steps using open-loop mode. The experiment was conducted at 25°C with a gas flow rate of 200 mL / min. A dm / dt criterion of 0.001% / min was applied, and within a 5-minute window, the maximum allowed time for all steps was 150 minutes and the minimum allowed time was 50 minutes, except for the step at 0% RH, which had no criterion but was set to 6 hours. Example

[0091] Example 1

[0092] Preparation of Linarasen Glutarate Hydrobromide

[0093] Linarasen glutarate (0.500 g, 1.04 mmol) was suspended in 2-propanol (25 mL) at 22 °C. A 48% aqueous HBr solution (0.175 g, 1.04 mmol) was added, resulting in a slurry that subsequently dissolved completely. The solution was cooled in an ice bath for 10 minutes and then filtered through a P3 fritted glass filter funnel. The resulting solid was dried under vacuum. Yield: 92% (0.539 g; colorless powder); LCMS purity: 100%.

[0094] 1H NMR (400 MHz, DMSO-d6): δ 13.65 (s, 1H), 12.05 (s, 1H), 8.98 (t, J = 5.6Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 7.35 (d, J = 1.3 Hz, 1H), 7.30 – 7.05 (m, 3H), 6.18 (s, 1H), 4.43 (d, J = 3.8 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 3.59 (q, J = 5.7 Hz, 2H), 2.51 – 2.30 (m, 11H), 2.24 (t, J = 7.4 Hz, 2H), 1.74 (p, J = 7.4 Hz, 2H). MS: (ESI+)m / z 481 (M+H).

[0095] Example 2

[0096] Polymorph screening

[0097] Polymorph screening of the HBr salt of linarasen glutarate was performed to determine its solubility, polymorphic form, and thermodynamic stability.

[0098] X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) indicated that the drug used for screening was Form A. Prior to crystallization experiments, the solubility of the drug was determined in >20 solvents and solvent mixtures.

[0099] Serum experiment:

[0100] Slurry experiments were conducted in various solvents, with the HBr salt of linarasen glutarate found to have moderate solubility. Unless otherwise stated, approximately 10 to 220 mg of the drug were slurried in 14 different solvents (pure and binary) at room temperature and 40°C for two weeks. The solid phase was isolated and analyzed by XRPD. Table 1 summarizes the slurry experiments and indicates which solid form was obtained.

[0101] Table 1. Slurry test results

[0102]

[0103]

[0104] *: Analyzed after 2, 3, and 4 weeks. Form B was predominant at 2 weeks, gradually transitioning to the channel solvate.

[0105] **: Analyze after 5 or 6 days.

[0106] Evaporation experiment:

[0107] Experiments were conducted in seven solvents, among which the HBr salt of linarasen glutarate was found to have sufficiently high solubility. Approximately 10 mg of the drug was dissolved and slowly evaporated in a vial at room temperature, 10°C, or 50°C. The results are shown in Table 2 below.

[0108] Table 2. Evaporation experiment results

[0109]

[0110] * A vial covered with adhesive aluminum tape with a pinhole.

[0111] Room temperature antisolvent crystallization experiment:

[0112] Crystallization was performed in five solvents with high solubility for the linarasen glutarate HBr salt and five antisolvents with low solubility for the linarasen glutarate HBr salt. The drug was dissolved in solvent 1 at room temperature. The solution was then heated to 40°C and then cooled to room temperature. Subsequently, 0.5 mL portions of solvent 2 were added. Samples were analyzed after 6 days. The solid phase was separated by vacuum filtration and analyzed by XRPD. The crystalline solid forms obtained in the experiment are shown in Table 3.

[0113] Table 3. Antisolvent crystallization results

[0114]

[0115] * After 6 days, place the sample in the refrigerator; after 2 weeks, add a piece of wire; after 2.5 weeks, place the sample in the freezer.

[0116] * Place samples in refrigerator after 6 days; analyze after 2 weeks.

[0117] Cooling antisolvent crystallization experiments at 5 °C

[0118] Cooling experiments were conducted using five solvents in which the X842 HBr salt had high solubility and five solvents in which the X842 HBr salt had low solubility. Sample preparation was as follows: the drug was dissolved in solvent 1, and the solution was placed in a 5°C refrigerator. All solutions were then filtered through a 0.2 µm syringe filter, and solvent 2, precooled to 5°C, was added. Unless otherwise stated, samples were analyzed after 2 weeks. The solid phase was isolated by vacuum filtration and analyzed by XRPD. The crystalline solid forms obtained in the experiments are shown in Table 4 below.

[0119] Table 4. Cooling antisolvent experimental results

[0120]

[0121] * The samples were placed in the freezer after 3 days; a piece of wire was added after one week.

[0122] ** Add a length of wire after three weeks.

[0123] Reverse antisolvent crystallization experiments

[0124] Five solvents with high solubility for the X842 HBr salt were used, along with six antisolvents with low solubility. 100 µL portions of solvent were added until the solution became clear, creating a saturated solution. The solution was placed in a cooling block at 18°C. It was then filtered through a 0.2 µm syringe filter and returned to room temperature (see Table 5). Finally, the solution was added with an antisolvent (Solvent 2) (see Table 6). Unless otherwise noted, samples were analyzed after 3 to 5 days.

[0125] Table 5. X842 HBr salt saturated solution

[0126]

[0127] Table 6. Reverse antisolvent experiment results

[0128]

[0129] * Place in freezer after 3 days; Place in freezer after 1 week; Analyze after 1.5 weeks.

[0130] ** After analysis, the mixture was slurried at room temperature for five to six days, after which Form C formed.

[0131] *** Following analysis, the mixture was slurried at room temperature for six days, after which Form A formed.

[0132] Cooling experiment

[0133] Cooling experiments were conducted in five different solvents with high enough drug solubility to dissolve reasonable amounts of the drug. The solutions were then cooled until a solid phase formed. Saturated solutions were prepared at room temperature. The temperature was then raised to 40°C, and the solutions were filtered using a 0.2 μm syringe filter and heated again to 40°C before being placed in a 5°C refrigerator. After five days, a wire was inserted into the solution. Samples were analyzed after 1.5 weeks. The results are shown in Table 7 below.

[0134] Table 7. Cooling test results

[0135]

[0136] * Place in freezer after 1.5 weeks; analyze after 2 weeks.

[0137] The XRPD peaks of Form A obtained by the synthesis described in Example 1 are listed in Table 8 below. The diffraction pattern of Form A is shown in Figure 1 shown.

[0138] Table 8. XRPD Peaks of Form A

[0139]

[0140]

[0141] *Relative strength depends on grain orientation, grain size / shape, strain, and sample thickness.

[0142] Table 9 below lists the XRPD peaks for Form B ("Sample 1") obtained from a 4:1 methanol / toluene slurry. Figure 2 The diffraction pattern of Form B Sample 1 is shown. Figure 3 Shown is the diffraction pattern of Form B ("Sample 2") obtained from a 4:1 slurry in methanol / water.

[0143] Table 9. XRPD Peaks of Form B Sample 1

[0144]

[0145]

[0146] *Relative strength depends on grain orientation, grain size / shape, strain, and sample thickness.

[0147] The XRPD peaks of Form C (obtained from a 1:1 slurry of DMF / toluene) are listed below in Table 10. The diffraction pattern of Form C is shown in Table 10. Figure 4 shown.

[0148] Table 10. XRPD Peaks of Form C

[0149]

[0150]

[0151] *Relative strength depends on grain orientation, grain size / shape, strain, and sample thickness.

[0152] The various solvates are not considered pharmaceutically feasible and are therefore not described further herein.

[0153] Example 3

[0154] Thermogravimetric analysis

[0155] A sample of Form A obtained according to the synthesis described in Example 1 showed a weight loss of 0.3% when heated to 175°C. This confirms that Form A is anhydrous. The TGA weight loss curve of Form A is shown in FIG. Figure 5 shown.

[0156] A sample of Form B (obtained from a 4:1 methanol / toluene slurry) showed a 0.3% weight loss upon heating to 175°C. This confirms that Form B is also anhydrous. The TGA weight loss curve for Form A is shown in FIG. Figure 6 shown.

[0157] A sample of Form C (prepared from a 1:1 slurry of DMF / toluene) showed a weight loss of 0.2% upon heating to 175°C. This confirms that Form C is also anhydrous. The TGA weight loss curve of Form A is shown in FIG. Figure 7 shown.

[0158] Example 4

[0159] Differential Scanning Calorimetry (DSC) Analysis

[0160] A sample of Form A (obtained from the synthesis described in Example 1) exhibited an endothermic event beginning at approximately 195°C, followed by an exothermic event (overlapping with an exothermic event), which was interpreted as crystallization into another crystalline form. Subsequently, the new, unknown crystalline form melted in a second endothermic event beginning at approximately 220°C. The DSC thermogram of Form A is shown in FIG. Figure 8 shown.

[0161] A sample of Form B (prepared from a 4:1 methanol / water slurry) exhibited two endothermic events. First, a smaller endothermic event was observed at approximately 118°C (onset temperature: approximately 116°C), which was interpreted as a solid-state transition to another form. Then, a new (unknown) form began to melt at approximately 205°C (onset temperature: approximately 202°C). The DSC thermogram of Form B is shown in Figure 2. Figure 9 shown.

[0162] The Form C sample (prepared from an ethanol slurry) exhibited a thermal event at approximately 223°C with an onset temperature of approximately 214°C. The DSC thermogram is shown in FIG. Figure 10 shown.

[0163] Example 5

[0164] Dynamic Vapor Sorption (DVS) Analysis

[0165] The hygroscopicity of Form A (obtained from the synthesis described in Example 1), Form B (obtained from a 4:1 methanol / water slurry), and Form C (obtained from an ethanol slurry) was studied using GVS analysis at 25°C. The weight change plot and adsorption isotherm plot for Form A showed a water uptake of approximately 0.22% over a humidity range of 0–90%; see respectively. Figure 11A and 11B Therefore, Form A can be classified as non-hygroscopic.

[0166] For Form B, the weight change plot and adsorption isotherm plot show a significant increase in water uptake with increasing humidity. At elevated humidity, the weight increase is approximately 3%, suggesting the formation of a hydrate. Upon drying, Form B returns to its anhydrate form; see respectively Figure 12A and 12B .

[0167] For Form C, the weight change graph and adsorption isotherm graph show that the water absorption is only about 0.05% in the humidity range of 0-90%; see respectively Figure 13A and 13B Therefore, Form C is classified as non-hygroscopic.

Claims

1. Crystalline linarasen glutarate HBr salt.

2. The crystalline linarasen glutarate HBr salt according to claim 1, wherein the crystalline HBr salt is stable at room temperature at a relative humidity of 94%.

3. The crystalline linarasen glutarate HBr salt according to claim 1 or 2, which is an anhydrate.

4. The crystalline linarasen glutarate HBr salt of any one of the preceding claims, which is in Form A, having an XRPD pattern obtained using CuKα1-radiation, the XRPD pattern having at least two peaks at °2θ values selected from the group consisting of 5.4±0.2, 18.3±0.2, 19.4±0.2, 22.4±0.2, 23.9±0.2, 24.0±0.2, 25.4±0.2, 26.5±0.2, 31.2±0.2, and 32.9±0.

2.

5. The crystalline linarasen glutarate HBr salt according to any one of the preceding claims, which is in Form A, having an XRPD pattern obtained using CuK α-radiation, the XRPD pattern having peaks at at least the following °2θ values: 5.4±0.2, 19.4±0.2, 22.4±0.2 and 25.4±0.

2.

6. The crystalline linarasen glutarate HBr salt according to any one of the preceding claims, which is in Form A, having an XRPD pattern obtained using CuK α-radiation, the XRPD pattern having peaks at at least the following °2θ values: 5.4±0.2, 19.4±0.2, 22.4±0.2, 23.9±0.2, 25.4±0.2, 31.2±0.2 and 32.9±0.

2.

7. The crystalline linarasen glutarate HBr salt according to any one of the preceding claims which is in Form A having an XRPD pattern substantially as shown in Figure 1, obtained using CuKα-radiation.

8. The crystalline linarasen glutarate HBr salt according to any one of the preceding claims, which is in Form A, having a DSC curve comprising an endotherm at about 194°C to about 198°C, such as about 196°C.

9. The crystalline linarasen glutarate HBr salt of claim 8, wherein Form A has a DSC curve comprising an endotherm at about 194°C to about 198°C, such as about 196°C, and another endotherm at about 220°C to about 224°C, such as about 222°C.

10. The crystalline linarasen glutarate HBr salt of any one of claims 1 to 3, which is in Form B, having an XRPD pattern obtained using CuKα1-radiation, the XRPD pattern having at least two peaks at °2θ values selected from the group consisting of: 9.1±0.2, 12.2±0.2, 14.5±0.2, 21.1±0.2, 21.4±0.2, 21.8±0.2, 23.6±0.2, 24.8±0.2, 25.8±0.2, and 27.3±0.

2.

11. The crystalline linarasen glutarate HBr salt of claim 10, wherein Form B has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 14.5±0.2, 23.6±0.2, 24.8±0.2, and 25.8±0.

2.

12. The crystalline linarasen glutarate HBr salt of any one of claims 10-11, wherein Form B has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 12.1±0.2, 14.5±0.2, 21.1±0.2, 23.6±0.2, 24.8±0.2, 25.8±0.2, and 27.3±0.

2.

13. The crystalline linarasen glutarate HBr salt according to any one of claims 10 to 12, wherein Form B has an XRPD pattern obtained by CuK α-radiation substantially as shown in Figure 2 or Figure 3.

14. The crystalline linarasen glutarate HBr salt according to any one of claims 10 to 13, wherein Form B has a DSC curve comprising an endotherm at about 115°C to about 121°C, such as about 118°C.

15. The crystalline linarasen glutarate HBr salt according to any one of claims 10 to 14, wherein Form B has a DSC curve comprising an endotherm at about 115°C to about 121°C, such as about 118°C, and another endotherm at about 202°C to about 206°C, such as about 204°C.

16. The crystalline linarasen glutarate HBr salt of any one of claims 1 to 3, which is in Form C, having an XRPD pattern obtained using CuKα1-radiation, the XRPD pattern having at least two peaks at °2θ values selected from the group consisting of: 18.6±0.2, 19.9±0.2, 22.4±0.2, 22.8±0.2, 23.4±0.2, 24.3±0.2, 24.5±0.2, 25.5±0.2, 26.6±0.2, and 34.8±0.

2.

17. The crystalline linarasen glutarate HBr salt of claim 16, wherein Form C has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 19.9±0.2, 23.4±0.2, 24.5±0.2, and 26.6±0.

2.

18. The crystalline linarasen glutarate HBr salt of any one of claims 16-17, wherein Form C has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 18.6±0.2, 19.9±0.2, 23.4±0.2, 24.3±0.2, 24.5±0.2, 26.6±0.2, and 34.8±0.

2.

19. The crystalline linarasen glutarate HBr salt according to any one of claims 16 to 18, wherein Form C has an XRPD pattern substantially as shown in Figure 4, obtained by CuKα-radiation.

20. The crystalline linarasen glutarate HBr salt of any one of claims 16-19, wherein Form C has a DSC curve comprising an endotherm at about 214 °C to about 230 °C, such as about 226 °C.

21. The crystalline linarasen glutarate HBr salt according to any one of the preceding claims, having a crystallinity greater than 99%.

22. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline linarasen glutarate HBr salt according to any one of claims 1 to 21, and one or more pharmaceutically acceptable excipients.

23. Crystalline linarasen glutarate HBr salt according to any one of claims 1 to 21 for use in therapy.

24. The crystalline linarasen glutarate HBr salt according to any one of claims 1 to 21, for use in treating or preventing gastrointestinal inflammatory diseases or gastric acid-related diseases.

25. The crystalline linarasen glutarate HBr salt for use according to claim 24, wherein the gastrointestinal inflammatory disease or gastric acid-related disease is gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), Helicobacter pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcer and duodenal ulcer), bleeding gastric ulcer, gastroesophageal reflux disease symptoms (including heartburn, regurgitation and nausea), gastrinoma or acute upper gastrointestinal bleeding.

26. The crystalline linarasen glutarate HBr salt for use according to any one of claims 24-25, wherein the gastrointestinal inflammatory disease or gastric acid-related disease is erosive gastroesophageal reflux disease (eGERD).

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