Polymorphism of the hydrobromide salt of linaprazan glurate.

Abstract

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 (linaprazangrate), more specifically Form A, Form B, and Form C of the HBr salt of linaprazangrate. The present invention also relates to pharmaceutical compositions containing such polymorphs and to the use of these polymorphs in the treatment or prevention of gastrointestinal inflammatory or gastric acid-related diseases, particularly 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 (linaprazangrate), more specifically Form A, Form B, and Form C of the HBr salt of linaprazangrate. The present invention also relates to pharmaceutical compositions containing such polymorphs and to the use of these polymorphs in the treatment or prevention of gastrointestinal inflammatory or gastric acid-related diseases, particularly erosive gastroesophageal reflux disease (eGERD). [Background technology]

[0002] The compound linaprazangrate (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, is disclosed in WO 2010 / 063876. The structure of linaprazangrate is shown below. Linaprazangrate is a potassium-competitive acid blocker (P-CAB) that competitively inhibits the gastric hydrogen / potassium pump (H / K ATPase) in parietal cells. Therefore, linaprazangrate can be used to control gastric acid secretion in the stomach.

[0003] [ka]

[0004] Linaprazanurate, a prodrug of linaprazan, was disclosed in WO 99 / 55706 and previously studied in Phase I and Phase II clinical trials. These trials demonstrated that linaprazan was well tolerated, had a rapid onset of action, and was sufficiently effective with a single dose. However, linaprazan was rapidly eliminated from the body, and its duration of acid inhibition was too short. In comparison, linaprazanurate has a longer half-life in the body and completely controls gastric acid production for a longer period than linaprazan. Phase I clinical trials demonstrated that a single dose of linaprazan could maintain intragastric acidity above pH 4 for 24 hours. Therefore, linaprazan is indicated for patients with severe erosive gastroesophageal reflux disease (eGERD).

[0005] For use in pharmaceutical formulations, it is desirable for active pharmaceutical ingredients (APIs) to be in a highly crystalline form. Non-crystalline (i.e., amorphous) materials may contain higher levels of residual solvent, which is undesirable. Also, due to lower chemical and physical stability compared to crystalline materials, amorphous materials may exhibit faster degradation and may spontaneously form crystals of varying degrees of crystallinity. This can result in unreproducible dissolution rates and make storage and handling of the material difficult.

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

[0007] [Patent Document 1] WO 2010 / 063876 [Patent Document 2] WO 99 / 55706 [Patent Document 3] CN 10627915 [Non-patent literature]

[0008] [Non-Patent Document 1] R. Jenkins and R.L. Snyder, "Introduction to X-ray powder diffractometry", John Wiley & Sons, 1996 Summary of the Invention

[0009] Therefore, there is a need for additional crystalline forms of linaprazangrate that have better properties than amorphous linaprazangrate and its previously disclosed crystalline forms. In particular, it is an object of the present invention to provide a stable crystalline form of linaprazangrate that has good solubility, contains low levels of residual solvent, has high chemical stability and low hygroscopicity, and can be obtained with a high level of crystallinity. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of Form A of the HBr salt of linaprazanglelate obtained from the synthesis described in Example 1. [Figure 2] FIG. 1 shows the X-ray powder diffraction pattern of Form B of the HBr salt of linaprazancleate (“Sample 1”) obtained from a slurry in methanol / toluene 4:1. [Figure 3] FIG. 1 shows the X-ray powder diffractogram of Form B of the HBr salt of linaprazancleate ("Sample 2") obtained from a slurry in 4:1 methanol / water, showing additional peaks of the putative channel solvate. [Figure 4]FIG. 1 shows the X-ray powder diffraction pattern of Form C of the HBr salt of linaprazancleate obtained from a slurry in DMF / toluene 1:1. [Figure 5] FIG. 1 shows the thermogravimetric analysis (TGA) mass loss curve of Form A (obtained in Example 1). [Figure 6] FIG. 1 shows the TGA mass loss curve of Form B (Sample 1). [Figure 7] FIG. 1 shows the TGA mass loss curve of Form C. [Figure 8] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram of Form A. [Figure 9] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram of Form B. [Figure 10] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram of Form C. [Figure 11A] FIG. 1 shows the dynamic vapor sorption (DVS) mass change plot of Form A. [Figure 11B] FIG. 1 shows a DVS isotherm plot of Form A. [Figure 12A] FIG. 1 shows the DVS mass change plot of Form B. [Figure 12B] FIG. 1 shows a DVS isotherm plot of Form B. [Figure 13A] FIG. 1 shows the DVS mass change plot of Form C. [Figure 13B] FIG. 1 shows a DVS isotherm plot of Form C. DETAILED DESCRIPTION OF THE INVENTION

[0011] It has been discovered that the hydrobromide salt of linaprazanurate can form a stable crystalline form (polymorph) under certain conditions, and has high crystallinity and high chemical stability.Therefore, this new polymorph is expected to be useful in pharmaceutical compositions of linaprazanurate.Therefore, in a first aspect, the present invention relates to a crystalline HBr salt of linaprazanurate.

[0012] In one embodiment, the present invention provides a crystalline HBr salt of linaprazanglete that is stable at room temperature and 94% relative humidity (RH). Such a crystalline HBr salt may 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.

[0013] In some embodiments, the crystalline HBr salt is anhydrous. In one embodiment, the crystalline anhydrous is Form A. This form can be prepared directly from the free base of linaprazangrate or by specific crystallization techniques using its hydrobromide salt, such as from a slurry in 1,4-dioxane; by antisolvent crystallization from MeOH, pyridine, or DMF and a specific antisolvent; or by reversed crystallization from DMF and MTBE. In one embodiment, Form A has an X-ray powder diffraction (XRPD) pattern obtained using CuKα1 radiation with at least two peaks at °2θ values ​​selected from the list 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 using CuKα1 radiation with at least peaks at °2θ values ​​of 5.4±0.2 and 19.4±0.2, or 5.4±0.2 and 22.4±0.2, or 5.4±0.2 and 25.4±0.2, or 19.4±0.2 and 22.4±0.2, or 19.4±0.2 and 25.4±0.2, or 22.4±0.2 and 25.4±0.2, °2θ values. In some embodiments, Form A has an XRPD pattern obtained using CuKα1 radiation with at least four peaks at °2θ values ​​selected from the list 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 using CuKα1 radiation with at least peaks at °2θ values ​​of 5.4±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 using CuKα1 radiation with peaks at one or more of the following °2θ values: 5.4±0.2, 19.4±0.2, 22.4±0.2, and 25.4±0.2, and 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 using CuKα1 radiation with peaks at one or more of 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 using CuKα1 radiation with at least peaks at °2θ values ​​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 using CuKα1 radiation with peaks at one or more of 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 13.5±0.2, 14.4±0.2, 20.6±0.2, 25.8±0.2, and 26.8±0.2. In certain embodiments, the present invention relates to Form A having an XRPD pattern obtained using CuKα1 radiation substantially as shown in Figure 1. In further embodiments, the present invention relates to Form A having an XRPD pattern obtained using CuKα1 radiation with peaks as shown in Table 8.

[0014] In some embodiments, Form A has a DSC curve comprising an endotherm between about 194° C. and about 198° C., e.g., at about 196° C. In certain embodiments, Form A has a DSC curve comprising an endotherm between about 194° C. and about 198° C., e.g., at about 196° C., followed by an additional endotherm between about 220° C. and about 224° C., e.g., at about 222° C. The DSC curve for Form A is shown in FIG. 8.

[0015] Dynamic vapor sorption analysis has shown that Form A has very low hygroscopicity, with a water uptake of about 0.15% at 80% RH. This low hygroscopicity is believed to be advantageous because the crystalline water content remains substantially constant with humidity changes within the typical relative humidity range of about 30% to about 80% RH. In some embodiments, Form A is stable at temperatures up to 90% relative humidity at 25° C. A DVS plot for Form A is shown in FIG. 11.

[0016] In another embodiment, the crystalline HBr salt is Form B. This form can be prepared from specific crystallization techniques using the hydrobromide salt of X842, such as from a slurry in MeOH or a mixture of methanol and toluene; by evaporation from ethanol; by reversed anti-solvent crystallization from benzyl alcohol and isopropyl acetate or MTBE, or from pyridine and MTBE; or by cooling from methanol. In one embodiment, Form B has an X-ray powder diffraction (XRPD) pattern obtained using CuKα1 radiation with at least two peaks at °2θ values ​​selected from the list 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 using CuKα1 radiation with at least peaks at °2θ values ​​of 23.6±0.2 and 24.8±0.2, or 24.8±0.2 and 25.8±0.2. In some embodiments, Form B has an XRPD pattern obtained using CuKα1 radiation with at least four peaks at °2θ values ​​selected from the list 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 using CuKα1 radiation with peaks at least at °2θ values ​​of 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 using CuKα1 radiation with peaks at least at °2θ values ​​of one or more of 14.5±0.2, 23.6±0.2, 24.8±0.2, and 25.8±0.2, and 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 using CuKα1 radiation with peaks at least at °2θ values ​​of 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 using CuKα1 radiation with peaks at least at °2θ values ​​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 using CuKα1 radiation with peaks at one or more of 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 7.6±0.2, 20.4±0.2, 27.8±0.2, 29.6±0.2, and 30.9±0.2. In certain embodiments, the present invention relates to Form B having an XRPD pattern obtained using CuKα1 radiation substantially as shown in Figure 2. In further embodiments, the present invention relates to Form B having an XRPD pattern obtained using CuKα1 radiation with peaks as shown in Table 9.

[0017] For example, in experiments in which Form B was formed in methanol or methanol mixtures, in acetonitrile, or by evaporation from ethanol, it was found that the X-ray diffraction pattern of Form B sometimes contained a few additional peaks. The additional peaks are believed to belong to small amounts of putative channel solvates. Thus, in some embodiments, the present invention relates to Form B having an XRPD pattern, obtained using CuKα1 radiation, substantially as shown in Figure 3. The channel solvates appear to convert to Form B upon drying.

[0018] In some embodiments, Form B has a DSC curve comprising an endotherm between about 115° C. and about 121° C., e.g., about 118° C. In certain embodiments, Form B has a DSC curve comprising an endotherm between about 115° C. and about 121° C., e.g., about 118° C., followed by an additional endotherm between about 202° C. and about 206° C., e.g., about 204° C. The DSC curve for Form B is shown in FIG.

[0019] It has been found that the water content of Form B can vary between about 0 and 3% depending on the relative humidity, as shown in Figure 12. The significant moisture interaction of Form B indicates that it forms a hydrate at high humidity (about 3% corresponds to the monohydrate) and reverts to the anhydrous form upon drying.

[0020] In a further embodiment, the crystalline anhydrate is Form C. This form can also be prepared by certain crystallization techniques using the hydrobromide salt, such as from a slurry in EtOH, or a mixture of DMF / toluene, benzyl alcohol / toluene, DMF / isopropyl acetate, or EtOH / water; by anti-solvent crystallization from DMF or benzyl alcohol in conjunction with certain anti-solvents; or by anti-solvent anti-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 list 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 using CuKα1 radiation with at least peaks at °2θ values ​​of 19.9±0.2 and 23.4±0.2, or 19.9±0.2 and 26.6±0.2. In some embodiments, Form C has an XRPD pattern obtained using CuKα1 radiation with at least four peaks at °2θ values ​​selected from the list 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 using CuKα1 radiation with peaks at least at °2θ values ​​of 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 using CuKα1 radiation with peaks at least at °2θ values ​​of one or more of 19.9±0.2, 23.4±0.2, 24.5±0.2, and 26.6±0.2, and 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 using CuKα1 radiation with peaks at least at °2θ values ​​of 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 using CuKα1 radiation with peaks at least at °2θ values ​​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 using CuKα1 radiation having peaks at one or more of 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 23.1±0.2, 24.8±0.2, 25.3±0.2, 26.9±0.2, and 27.7±0.2. In certain embodiments, the present invention relates to Form C having an XRPD pattern obtained using CuKα1 radiation substantially as shown in Figure 4. In further embodiments, the present invention relates to Form C having an XRPD pattern obtained using CuKα1 radiation having peaks as shown in Table 10.

[0021] In some embodiments, Form C has a DSC curve between about 214° C. and about 230° C., for example, including an endotherm at about 226° C. as shown in FIG.

[0022] Dynamic vapor sorption analysis showed that Form C has very low humidity interaction, with a water content of about 0.05% or less at 90% RH. A DVS plot of Form C is shown in Figure 13.

[0023] In one embodiment, the present invention relates to a crystalline HBr salt of linaprazanglete having a crystallinity of greater than 99%.

[0024] In a second aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline HBr salt of linaprazangrate disclosed herein in association with one or more pharmaceutically acceptable excipients. The excipients may include, for example, fillers, binders, surfactants, disintegrants, glidants, and lubricants. In some embodiments, the crystalline HBr salt of linaprazangrate is Form A. In some embodiments, the crystalline HBr salt of linaprazangrate is Form B. In some embodiments, the crystalline HBr salt of linaprazangrate is Form C.

[0025] In some embodiments, a pharmaceutical composition comprises a crystalline HBr salt of linaprazanurate, such as Form A, Form B, or Form C, having a polymorphic purity of at least about 90%. In some embodiments, the polymorphic purity is at least about 95%. In some embodiments, the polymorphic purity is at least about 98%. For example, the polymorphic purity can 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, a pharmaceutical composition comprising the crystalline HBr salt of linaprazanurate is substantially free of other forms of linaprazanurate. For example, in some embodiments, a pharmaceutical composition comprising Form A is substantially free of other forms of linaprazanurate, such as Form B or Form C of linaprazanurate. In some embodiments, Form A contains less than about 15% by weight of Form B, Form C, or any other polymorph of linaprazanurate. For example, Form A 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 linaprazangrate Form B, Form C, or any other polymorph. In some embodiments, Form B contains less than about 15% by weight of linaprazangrate Form A, Form C, or any other polymorph. For example, Form B 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 linaprazangrate Form A, Form C, or any other polymorph. In some embodiments, Form C contains less than about 15% by weight of linaprazanurate Form A, Form B, or any other polymorphic form. 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 linaprazanurate Form A, Form B, or any other polymorphic form.

[0026] In some embodiments, the pharmaceutical composition may contain between about 1% and about 100% by weight, e.g., between about 1% and about 50% by weight, or between about 1% and about 20% by weight, of the crystalline HBr salt of linaprazangrate. For example, the composition may contain between about 1% and about 15% by weight, or between about 5% and about 20% by weight, e.g., between about 1% and about 10% by weight, between about 5% and about 15% by weight, and between about 10% and about 20% by weight, or for example, between about 1% and about 5% by weight, between about 5% and about 10% by weight, between about 10% and about 15% by weight, and between about 15% and about 20% by weight of the crystalline HBr salt of linaprazangrate. 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 HBr salt of linaprazangleate.

[0027] In some embodiments, the composition comprises a unit dose of about 25 mg to about 150 mg of the crystalline HBr salt of linaprazangleate. For example, the composition may contain between about 25 mg and about 50 mg, between about 50 mg and about 75 mg, between about 75 mg and about 100 mg, between about 100 mg and about 125 mg, or between about 125 mg and about 150 mg. In some embodiments, the composition contains 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 the crystalline HBr salt of linaprazanglerate. The daily dose can be administered as a single dose or divided into two, three, or more unit doses.

[0028] In some embodiments, the pharmaceutical composition includes 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, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate). Examples of nonionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophor EL), poloxamer (e.g., poloxamer 407 or 188), polysorbate 80, and sorbitan esters (Tween).

[0029] In some embodiments, the pharmaceutical composition comprises a filler. Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0030] 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., acacia gum and tragacanth gum), sodium alginate, cellulose derivatives (e.g., hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, and ethylcellulose), 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 polyvinylpyrrolidone (povidone)).

[0031] 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 carboxymethylcellulose, hydroxypropylcellulose, and low-substituted hydroxypropylcellulose (L-HPC)), and cross-linked polymers (e.g., carmellose, croscarmellose sodium, carmellose calcium, and cross-linked PVP (crospovidone)).

[0032] 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, aqueous silicon dioxide, synthetic magnesium silicate, microgranular silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (e.g., carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0033] In general, pharmaceutical compositions can be prepared by conventional methods using conventional excipients. In some embodiments, the ingredients of the formulation are mixed into a homogeneous mixture and then formulated as tablets or capsules. The homogeneous mixture of ingredients can be compressed into tablets using conventional techniques, such as a rotary tablet press. The mixture of ingredients may also be granulated. For example, the mixture of ingredients can be moistened by adding a liquid such as water and / or a suitable organic solvent (e.g., ethanol or isopropanol), then granulated and dried. Alternatively, granules can be prepared by dry granulation, such as roller compaction. The resulting granules can be compressed into tablets using conventional techniques. Capsules can contain a powder mixture of ingredients or small multiparticulates (e.g., granules, extruded pellets, or minitablets). If desired, any of the tablets, capsules, granules, extruded pellets, and minitablets described above can be coated with one or more coating layers. Such coating layers can be applied by methods known in the art, such as film coating, including perforated pans and fluidized beds. In some embodiments, the formulation is in the form of a tablet.

[0034] After absorption into the bloodstream, linaprazanurate is rapidly metabolized to its active metabolite, linaprazan. While the plasma concentration of linaprazanurate is extremely low and difficult to determine, the plasma concentration of linaprazan can be determined instead. Phase I studies have shown that a specific dose of linaprazanurate should be able to maintain intragastric pH above 4 for 24 hours after administration. This includes the minimum plasma concentration of linaprazan (C ) at 22 hours. min It is estimated that a C of linaprazan of at least about 240 nmol / L is required. At such a dose, once-daily oral administration of the formulation would be sufficient. Thus, in some embodiments, a single unit dose of a pharmaceutical composition of linaprazan provides a C of linaprazan of at least about 240 nmol / L in a human 22 hours after oral administration of the pharmaceutical composition to the human. minIn another embodiment, daily administration of two unit doses of a pharmaceutical composition of linaprazan results in a C of linaprazan of at least about 240 nmol / L in a human 10 hours after oral administration of the last unit dose of the pharmaceutical composition to the human. min results.

[0035] In one aspect, the present invention relates to a crystalline HBr salt of linaprazanglerate for use in therapy.

[0036] The crystalline forms of the HBr salt of linaprazanurate disclosed herein can be used to treat or prevent diseases or conditions in which inhibition of gastric acid secretion is necessary or desirable, such as eradication of Helicobacter pylori (H. pylori). Examples of such diseases and conditions include gastrointestinal inflammatory 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 and duodenal ulcers), bleeding gastric ulcers, symptoms of gastroesophageal reflux disease (including heartburn, reflux, and nausea), gastrinoma, and acute upper gastrointestinal bleeding.

[0037] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline HBr salt of linaprazanglerate disclosed herein for use in treating or preventing a gastrointestinal inflammatory disorder or a gastric acid-related disorder.

[0038] 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 therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of the HBr salt of linaprazangrate, as disclosed herein. In some embodiments, the crystalline form of the HBr salt of linaprazangrate is Form A. In other embodiments, the crystalline form of the HBr salt of linaprazangrate is Form B. In a further embodiment, the crystalline form of the HBr salt of linaprazangrate is Form C.

[0039] In some embodiments, the gastrointestinal inflammatory or gastric acid-related disease is erosive gastroesophageal reflux disease (eGERD).

[0040] In a further embodiment, the treatment for GERD is an on-demand treatment for GERD.

[0041] As used herein, the term "polymorph" refers to crystals of the same molecule that have different physical properties as a result of the molecular order in the crystal lattice. Polymorphs of a single compound have one or more distinct chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water sorption, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., oxidation differences, such as a dosage form discoloring more rapidly when composed of one polymorph than when composed of another), mechanical changes (e.g., crystalline changes during storage when a kinetically favorable polymorph converts to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, some transitions affect efficacy and / or toxicity. Furthermore, the physical properties of the crystals may be important in processing, for example, some polymorphs may be prone to forming 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). "Polymorph" does not include amorphous forms of a compound.

[0042] 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 solubilized form of the compound. For example, "amorphous" refers to a compound that does not have a regular repeating arrangement of molecules or external face planes.

[0043] As used herein, the term "anhydrate" or "anhydrous form" refers to a polymorph of linaprazanglete having 0.5% or less water by weight, e.g., 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less water by weight.

[0044] As used herein, the term "anhydrous" refers to a polymorph of linaprazanglete having 0.5% or less water by weight, e.g., 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less water by weight.

[0045] As used herein, the term "polymorphic purity," when used in reference to a composition containing a polymorph of linaprazanurate, refers to the proportion of a particular polymorph relative to another polymorph or amorphous form of linaprazanurate in a reference compound. For example, a composition containing Form A with 90% polymorphic purity contains 90 parts by weight of Form A and 10 parts by weight of another crystalline and / or amorphous form of linaprazanurate, such as Form B or Form C.

[0046] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of linapraglangurate sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated after administration to a subject. The results include reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of linapraglangurate required to produce a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0047] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of 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 prior to the onset of symptoms (e.g., taking into account a history of the condition and / or genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0048] As used herein, the term "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable for human pharmaceutical use and are generally safe, non-toxic, and not biologically or otherwise undesirable.

[0049] As used herein, a compound or composition is "substantially free" of one or more other components if it does not contain significant amounts of such other components. Such components may include starting materials, residual solvent, or any other impurities that may result from the preparation and / or isolation 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), e.g., greater than about 95% (w / w), e.g., greater than about 97% (w / w), or e.g., 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), e.g., less than about 0.5% (w / w), or e.g., less than about 0.1% (w / w). The total amount of impurities can be determined, for example, by high-performance liquid chromatography (HPLC) methods.

[0050] In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of linaprazanurate is "substantially free" of other polymorphs when it constitutes at least about 95% by weight of the linaprazanurate present. In some embodiments, a particular polymorph of linaprazanurate is "substantially free" of other polymorphs when it constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the linaprazanurate present.

[0051] As used herein, a compound is "substantially present" as a given polymorph when at least about 50% by weight of the compound is in that polymorphic form, e.g., 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%, for example at least about 97%, for example at least about 98%, for example at least about 99%, or for example at least about 99.5% by weight of the compound is in that polymorphic form.

[0052] As used herein, the term "stable" means that a polymorph does not exhibit a change over time in one or more of the following: polymorphic form (e.g., an increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (as measured by in vitro assay), or osmolality. 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 over at least 1, 2, 3, or 4 weeks in one or more of the following: polymorphic form (e.g., an increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (as measured by in vitro assay), or osmolality. 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, a polymorph exhibits no change in one or more polymorphic forms (e.g., an increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (as measured by in vitro assay), or osmolality over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In the above, the phrase "no change" refers to a measured change of less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%) for any parameter over the relevant period of time.

[0053] The crystallinity of the polymorph of the HBr salt of linaprazanglete can be measured, for example, by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). When referring to a crystalline compound herein, the crystallinity is preferably greater than about 70%, for example greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%. In some embodiments, the degree of crystallinity is greater than about 98%. In some embodiments, the degree of crystallinity is greater than about 99%. Crystallinity % refers to the mass percentage of the total sample mass that is crystalline.

[0054] As used herein, the term "about" refers to a value or parameter herein, including (and describing) embodiments directed to the value or parameter itself. For example, a statement referring to "about 20" includes the statement "20." Numerical ranges include the numbers defining the range. In general, the term "about" refers to the indicated value of the variable and all values ​​of the variable within experimental error of the indicated value (e.g., within a 95% confidence interval of the mean) or within 10 percent of the indicated value, whichever is greater.

[0055] The present invention will now be illustrated 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.

[0056] Abbreviation DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol MeCN acetonitrile MeOH Methanol MTBE Methyl tert-butyl ether RH Relative Humidity

[0057] Experimental Method General method 1 H-NMR spectra were recorded on a Bruker 400 MHz instrument at 25 °C and were referenced to residual protic solvent in the deuterated solvent used: DMSO-d6 (δ H 2.50 ppm).

[0058] Analytical HPLC-MS was performed using an Agilent 1100 Series Liquid Chromatography / Mass Selective Detector (MSD) (single quadrupole) equipped with an electrospray interface and a UV diode array detector. The analysis was performed using an ACE 3 C8 (3.0 × 50 mm) column with a 3 min gradient of acetonitrile in 0.1% TFA in water and a flow rate of 1 mL / min.

[0059] All solvents were dried by adding molecular sieves before preparing the slurries unless otherwise indicated.

[0060] X-ray powder diffraction (XRPD) analysis Analyses were performed on a PanAlytical X'Pert Pro diffractometer equipped with a Cu anode (45 kV, 40 mA), a Kα-1 Johansson monochromator (1.540598 Å), and a Pixcel detector. The 2θ range was 2–35°, using a scan rate of 0.03° / s or 0.10° / s and a step size of 0.013°. A slow-rotating sample holder was used. The sample was smeared onto a zero-background silicon wafer to obtain a flat powder surface. For one measurement, the sample was covered with plastic film to prevent evaporation of the solvate. Measurements were performed using a programmable entrance and divergence slit.

[0061] It is known in the art that X-ray powder diffraction patterns may be obtained with one or more measurement errors depending on the measurement conditions (such as the instrument, sample preparation, or machine used). In particular, it is generally known that the intensities of an XRPD pattern may vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of XRPD will understand that the relative intensities of peaks may vary depending on the orientation of the sample under test and the type and settings of the instrument used. Those skilled in the art will also understand that the exact height at which the sample is placed in the diffractometer and the zero calibration of the diffractometer may affect the position of reflections. The surface planarity of the sample may also have a slight effect. Therefore, those skilled in the art will understand that the diffraction patterns presented herein should not be construed as absolute, and that any crystalline form that provides a powder diffraction pattern substantially identical to that disclosed herein falls within the scope of the present disclosure (for further information, see R. Jenkins and R.L. Snyder, "Introduction to X-ray Powder Diffractometry," John Wiley & Sons, 1996).

[0062] Thermogravimetric analysis (TGA) The analysis was performed on a PerkinElmer TGA8000 instrument. A few milligrams of sample were gently placed in an open Pt pan and subjected to mass analysis in a flow of dry nitrogen gas (40 mL / min) to ensure an inert atmosphere. Samples were scanned from 25 to 200 °C using a continuous scan rate of 10 °C / min.

[0063] Differential scanning calorimetry (DSC) The analysis was carried out on a Netzsch DSC 204F1 instrument. A few mg of sample was gently placed into an Al pan and weighed. A pre-made lid with a pinhole was fitted to the pan and crimped. A conventional DSC with a heating rate of 10°C / min was used. The minimum temperature (onset) was 0°C and the maximum temperature was 230°C.

[0064] Gravimetric vapor sorption (GVS) Analyses were performed on an SMS DVS Advantage instrument. A few milligrams of material were added to an aluminum pan and subjected to a stepwise RH change from 0 to 90 to 20% in 10% RH steps using open-loop mode. Experiments were performed at 25 °C using a gas flow rate of 200 mL / min. The applied dm / dt criterion was 0.001 mass% / min over a 5-minute window, with a maximum allowed time of 150 minutes and a minimum allowed time of 50 minutes for all steps except the step at 0% RH, which had no criterion but was set to 6 hours. [Example]

[0065] Example 1 Preparation of linaprazangrates hydrobromides. Linaprazancleate (0.500 g, 1.04 mmol) was suspended in 2-propanol (25 mL) at 22 °C. 48% aqueous HBr (0.175 g, 1.04 mmol) was added, resulting in a slurry followed by complete dissolution. The solution was cooled in an ice bath for 10 min, after which it was filtered through a P3 fritted glass filter funnel. The resulting solid was dried under vacuum. Yield: 92% (0.539 g, colorless powder), 100% pure by LCMS. 1 H NMR (400 MHz, DMSO-d6): δ 13.65 (s, 1H), 12.05 (s, 1H), 8.98 (t, J = 5.6 Hz, 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).

[0066] Example 2 Polymorphic selection Polymorph screening was performed on the HBr salt of linaprazangulate to determine solubility, polymorphism, and thermodynamic stability.

[0067] X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) indicated that the drug substance used in screening was Form A. Prior to the crystallization experiments, the solubility of the drug substance was determined in over 20 solvents and solvent mixtures.

[0068] Slurry Experiments: Slurry experiments were performed in various solvents, and the HBr salt of linaprazangrates was found to have intermediate solubility. Approximately 10 to 220 mg of drug substance was slurried in 14 different solvents (pure and binary) at room temperature and 40°C for 2 weeks, unless otherwise indicated. The solid phase was isolated and analyzed by XRPD. Table 1 summarizes the slurry experiments and indicates which solid forms were obtained.

[0069] [Table 1A]

[0070] [Table 1B]

[0071] Evaporation experiment: Experiments were conducted in seven different solvents, and the HBr salt of linapragluturate was found to have sufficiently high solubility. Approximately 10 mg of the drug substance was dissolved and allowed to evaporate slowly in a vial at room temperature, 10°C, or 50°C. The results are shown in Table 2 below.

[0072] [Table 2]

[0073] Antisolvent crystallization experiments at RT: Crystallization was performed from five solvents, where the HBr salt of linaprazanurate was found to have high solubility, and from five antisolvents, where the HBr salt of linaprazanurate had low solubility. The drug substance was dissolved in solvent 1 at room temperature. The solution was then heated to 40°C and cooled back to room temperature. Then, 0.5 mL of solvent 2 was added. Samples were analyzed after 6 days. The solid phase was isolated by vacuum filtration and analyzed by XRPD. The crystalline solid forms obtained in the experiment are shown in Table 3.

[0074] [Table 3]

[0075] Cold antisolvent crystallization experiments at 5°C: Cooling experiments were performed using five solvents in which the X842 HBr salt has high solubility, as well as five solvents in which the X842 HBr salt has low solubility. Samples were prepared by dissolving the drug substance in solvent 1, after which the solutions were placed in a refrigerator at 5°C. All solutions were then filtered through a 0.2 μm syringe filter, after which solution 2 was added, pre-cooled to 5°C. Samples were analyzed after two weeks unless otherwise indicated. 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.

[0076] [Table 4A]

[0077] [Table 4B]

[0078] Antisolvent anticrystallization experiments: Five solvents in which the X842 HBr salt has high solubility were used in conjunction with six anti-solvents in which it has low solubility. Saturated solutions were prepared by adding 100 μL of solvent increments until the solution became clear. The solutions were placed in an 18°C ​​cooling block. They were then filtered through a 0.2 μm syringe filter and allowed to cool to room temperature (see Table 5). Finally, the solution was added to the anti-solvent (solvent 2) (see Table 6). Samples were analyzed after 3–5 days unless otherwise indicated.

[0079] [Table 5]

[0080] [Table 6A]

[0081] [Table 6B]

[0082] Cooling experiment Cooling experiments were performed in five solvents in which the solubility of the drug substance was high enough to dissolve a reasonable amount. The solutions were then cooled to form a solid phase. Saturated solutions were prepared at room temperature. The temperature was then raised to 40°C, after which the solutions were filtered through 0.2 μm syringe filters and heated again to 40°C, after which they were placed in a refrigerator at 5°C. After 5 days, a piece of metal wire was inserted into the solution. Samples were analyzed after 1.5 weeks. The results are shown in Table 7 below.

[0083] [Table 7]

[0084] The XRPD peaks of Form A obtained from the synthesis described in Example 1 are listed below in Table 8. The diffractogram of Form A is shown in Figure 1.

[0085] [Table 8A]

[0086] [Table 8B]

[0087] The XRPD peaks of Form B ("Sample 1") obtained from a slurry in 4:1 methanol / toluene are listed below in Table 9. The diffractogram of Form B, Sample 1, is shown in Figure 2. The diffractogram of Form B ("Sample 2") obtained from a slurry in 4:1 methanol / water is shown in Figure 3.

[0088] [Table 9A]

[0089] [Table 9B]

[0090] The XRPD peaks of Form C obtained from a slurry in DMF / toluene 1:1 are listed below in Table 10. The diffractogram of Form C is shown in FIG.

[0091] [Table 10A]

[0092] [Table 10B]

[0093] The different solvates are not considered to be pharmaceutically viable and therefore will not be further described in this disclosure.

[0094] Example 3 thermogravimetric analysis A sample of Form A obtained from the synthesis described in Example 1 exhibited a mass loss of 0.3% upon heating to 175° C., confirming that Form A is anhydrous. The TGA mass loss curve for Form A is shown in FIG. 5.

[0095] A sample of Form B (obtained from a slurry in 4:1 methanol / toluene) showed a mass loss of 0.3% when heated to 175° C., confirming that Form B is also anhydrous. The TGA mass loss curve of Form A is shown in FIG. 6.

[0096] A sample of Form C (obtained from a slurry in 1:1 DMF / toluene) showed a 0.2% mass loss when heated to 175° C., confirming that Form C is also anhydrous. The TGA mass loss curve for Form A is shown in FIG. 7.

[0097] Example 4 Differential scanning calorimetry (DSC) analysis A sample of Form A (obtained from the synthesis described in Example 1) exhibited an endothermic event with an onset of approximately 195° C., followed directly (overlapping) by an exothermic event that was interpreted as crystallization into another form. The new unknown form then melted in a second endothermic event with an onset of approximately 220° C. The DSC thermogram of Form A is shown in FIG.

[0098] A sample of Form B (obtained from a slurry in 4:1 methanol / water) showed two endothermic events. First, a small endothermic event was observed at about 118°C (onset: about 116°C), which was interpreted as a solid-state transition to another form. Then, the new (unknown) form began to melt at about 205°C (onset: about 202°C). The DSC thermogram of Form B is shown in Figure 9.

[0099] A sample of Form C (obtained from a slurry in ethanol) showed one thermal event at about 223° C. with an onset temperature of about 214° C. The DSC thermogram is shown in FIG.

[0100] Example 5 Dynamic Vapor Sorption (DVS) Analysis The hygroscopicity of Form A (obtained from the synthesis described in Example 1), Form B (obtained from a slurry in methanol / water 4:1), and Form C (obtained from a slurry in ethanol) was investigated using GVS at 25°C. The mass change plot and sorption isotherm plot of Form A showed an uptake of approximately 0.22% water in the humidity range of 0-90%; see Figures 11A and 11B, respectively. Therefore, Form A can be classified as non-hygroscopic.

[0101] For Form B, the mass change plot and sorption isotherm plot showed significant water uptake with increasing humidity. A hydrate form appears to form, with a mass increase of approximately 3% at increasing humidity. Upon drying, Form B reverted to the anhydrous form; see Figures 12A and 12B, respectively.

[0102] For Form C, the mass change plot and sorption isotherm plot showed only about 0.05% water uptake over the humidity range of 0-90%; see Figures 13A and 13B, respectively. Therefore, Form C is classified as non-hygroscopic.

Claims

1. Crystalline HBr salt of linaprazanglete.

2. 2. The crystalline HBr salt of linaprazanglete of claim 1, which is stable at room temperature and 94% relative humidity.

3. 3. The crystalline HBr salt of linaprazanglete according to claim 1 or 2, which is anhydrous.

4. 4. The crystalline HBr salt of linaprazanglete of claim 1, wherein the crystalline HBr salt is Form A and has an XRPD pattern having at least two peaks at °2θ values ​​selected from the list 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, obtained using CuKα1 radiation.

5. 5. The crystalline HBr salt of linaprazangle of any one of claims 1 to 4, wherein the crystalline HBr salt is Form A and has an XRPD pattern obtained using CuKα radiation with at least peaks at °2θ values ​​of 5.4±0.2, 19.4±0.2, 22.4±0.2, and 25.4±0.

2.

6. 6. The crystalline HBr salt of linaprazangle of any one of claims 1 to 5, wherein the crystalline HBr salt is Form A having an XRPD pattern obtained using CuKα radiation with at least peaks at °2θ values ​​of 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. 7. The crystalline HBr salt of linaprazanglete according to any one of claims 1 to 6, which is Form A having an XRPD pattern obtained using CuKα radiation substantially as shown in Figure 1.

8. 8. The crystalline HBr salt of linaprazanglete according to any one of claims 1 to 7, wherein the crystalline HBr salt is Form A having a DSC curve comprising an endotherm between about 194°C and about 198°C, for example at about 196°C.

9. 9. The crystalline HBr salt of linaprazanglete of claim 8, wherein Form A has a DSC curve comprising an endotherm between about 194°C and about 198°C, e.g., about 196°C, and an additional endotherm between about 220°C and about 224°C, e.g., about 222°C.

10. 4. The crystalline HBr salt of linaprazanglete according to claim 1, wherein the crystalline HBr salt is Form B, having an XRPD pattern having at least two peaks at °2θ values ​​selected from the list 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, obtained using CuKα1 radiation.

11. 11. The crystalline HBr salt of linaprazanglete of claim 10, wherein Form B has an XRPD pattern obtained using CuKα1 radiation with at least peaks at °2θ values ​​of 14.5±0.2, 23.6±0.2, 24.8±0.2, and 25.8±0.

2.

12. 12. The crystalline HBr salt of linaprazanglete of claim 10 or 11, wherein Form B has an XRPD pattern obtained using CuKα1 radiation with at least peaks at °2θ values ​​of 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. 13. The crystalline HBr salt of linaprazanglete according to any one of claims 10 to 12, wherein Form B has an XRPD pattern obtained using CuKα radiation substantially as shown in Figure 2 or Figure 3.

14. 14. The crystalline HBr salt of linaprazanglete of any one of claims 10 to 13, wherein Form B has a DSC curve comprising an endotherm between about 115°C and about 121°C, for example, at about 118°C.

15. 15. The crystalline HBr salt of linaprazanglete of any one of claims 10 to 14, wherein Form B has a DSC curve comprising an endotherm between about 115°C and about 121°C, e.g., about 118°C, and an additional endotherm between about 202°C and about 206°C, e.g., about 204°C.

16. 4. The crystalline HBr salt of linaprazanglete of any one of claims 1 to 3, wherein the crystalline HBr salt is Form C having an XRPD pattern having at least two peaks at °2θ values ​​selected from the list 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 using CuKα1 radiation.

17. 17. The crystalline HBr salt of linaprazanglete of claim 16, wherein Form C has an XRPD pattern obtained using CuKα1 radiation with at least peaks at °2θ values ​​of 19.9±0.2, 23.4±0.2, 24.5±0.2, and 26.6±0.

2.

18. 18. The crystalline HBr salt of linaprazanglete of claim 16 or 17, wherein Form C has an XRPD pattern obtained using CuKα1 radiation with at least peaks at °2θ values ​​of 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. 19. The crystalline HBr salt of linaprazanglete of any one of claims 16 to 18, wherein Form C has an XRPD pattern obtained using CuKα radiation substantially as shown in Figure 4.

20. 20. The crystalline HBr salt of linaprazanglete of any one of claims 16 to 19, wherein Form C has a DSC curve comprising an endotherm between about 214°C and about 230°C, for example, at about 226°C.

21. 21. The crystalline HBr salt of linaprazanglete according to any one of claims 1 to 20, having a crystallinity of greater than 99%.

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

23. 22. The crystalline HBr salt of linapraanglete according to any one of claims 1 to 21 for use in therapy.

24. 22. The crystalline HBr salt of linaprazanglerate according to any one of claims 1 to 21 for use in the treatment or prevention of gastrointestinal inflammatory diseases or gastric acid related diseases.

25. 25. The crystalline HBr salt of linaprazanurate 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 ulcers and duodenal ulcers), bleeding gastric ulcers, symptoms of gastroesophageal reflux disease (including heartburn, reflux, and nausea), gastrinoma, or acute upper gastrointestinal bleeding.

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

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