Polymorphs of hydrochloride salt of linaprazan glurate

Abstract

To provide a stable crystalline form of linaprazan glurate.SOLUTION: Provided are polymorphs of the hydrochloride salt of 5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}carbonyl)amino]ethoxy}-5-oxopentanoic acid (linaprazan glurate).SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications This application claims the priority of International Patent Application No. PCT / CN2021 / 128918, filed on November 5, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to polymorphs of the hydrochloride salt of 5 - {2 - [({8 - [(2,6 - dimethylbenzyl)amino]-2,3 - dimethylimidazo[1,2 - a]pyridin - 6 - yl}carbonyl)-amino]ethoxy}-5 - oxopentanoic acid (linaprazan gulrate), more specifically, Forms 1 and 2 of the HCl salt of linaprazan gulrate. The present invention also relates to methods for preparing such polymorphs, pharmaceutical compositions containing such polymorphs, and the use of these polymorphs in the treatment or prevention of gastrointestinal inflammatory diseases or gastric acid - related diseases, particularly erosive gastroesophageal reflux disease (eGERD).

Background Art

[0003] The compound linaprazan gulrate (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 linaprazan gulrate is shown below. Linaprazan gulrate is a potassium - competitive acid blocker (P - CAB) that competitively inhibits the gastric hydrogen - potassium pump (H+ / K+ ATPase) in parietal cells. Therefore, linaprazan gulrate can be used to control gastric acid secretion in the stomach.

[0004]

Chemical formula

[0005] Rinaprazan guruleate is a prodrug of rinaprazan, disclosed in WO 99 / 55706 and previously studied in Phase I and Phase II trials. These trials showed that rinaprazan has high tolerability, rapid onset of action, and sufficient efficacy with a single dose. However, rinaprazan was rapidly excreted from the body and the duration of acid inhibition was too short. In comparison, rinaprazan guruleate has a longer half-life in the body and completely controls gastric acid production for a longer time compared to rinaprazan. Clinical Phase I trials showed that administration of a single dose of rinaprazan guruleate can maintain intragastric acidity above pH 4 for 24 hours. Therefore, rinaprazan guruleate is tailored for patients with severe erosive gastroesophageal reflux disease (eGERD).

[0006] For use in pharmaceutical formulations, the active pharmaceutical ingredient (API) is desirably in a highly crystallized form. Amorphous (i.e., non-crystalline) substances may contain higher levels of residual solvents and are undesirable. Also, amorphous substances may exhibit faster degradation due to lower chemical and physical stability compared to crystalline substances and may naturally form crystals with varying degrees of crystallinity. This results in a non-reproducible dissolution rate and can make the storage and handling of the substance difficult.

[0007] Two crystalline forms of the free base of rinaprazan guruleate are disclosed in CN 106279151. 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 high crystallinity, is substantially insoluble in water at pH 6.8, and is only slightly soluble at pH 1. The low solubility limits the development of formulations with desired properties.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

[0009] [Non-Patent Document 1] R. Jenkins and R.L. Snyder, "Introduction to X-ray powder diffractometry", John Wiley & Sons, 1996 [Summary of the Invention]

[0010] Therefore, there is a need for a further crystalline form of linaprazan gluleate that has better properties than the amorphous linaprazan gluleate and its previously disclosed crystalline forms. In particular, it is an object of the present invention to provide a stable crystalline form of linaprazan gluleate that 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]

[0011]

Figure 1

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Figure 10B

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Figure 13A

Figure 13B

Embodiments for Carrying out the Invention

[0012] It has been discovered that linaprazan gulrate hydrochloride may form stable crystalline forms (polymorphs) under certain conditions. In addition to high crystallinity and high chemical stability, these polymorphs have significantly higher solubility than forms A and B of the free base of linaprazan gulrate. Therefore, this new polymorph is expected to be useful in pharmaceutical compositions of linaprazan gulrate. Accordingly, in a first aspect, the present invention relates to the crystalline HCl salt of linaprazan gulrate.

[0013] In some embodiments, the present invention provides a crystalline HCl salt of linaprazan gulrate that is stable at room temperature and 94% relative humidity (RH). Such a crystalline HCl salt can be stable for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, or even longer under these conditions.

[0014] In some embodiments, the crystalline HCl salt is the anhydrate. In certain embodiments, the crystalline anhydrate is Form 1. This form can be prepared directly from the free base of linaprazan gluleate or using its hydrochloride salt by certain crystallization techniques, for example, from a slurry in DMF, pyridine, benzyl alcohol, or ethanol; by anti-solvent crystallization from DMF or pyridine and a specific anti-solvent; or by cooling from DMF or pyridine. In one embodiment, Form 1 has an X-ray powder diffraction (XRPD) pattern having at least two peaks at °2θ values selected from the list consisting of 3.8±0.2, 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα1 radiation. In some embodiments, Form 1 has an XRPD pattern having at least peaks at °2θ values of 20.0±0.2 and 26.7±0.2 obtained using CuKα1 radiation. In some embodiments, Form 1 has an XRPD pattern having at least four peaks at °2θ values selected from the list consisting of 3.8±0.2, 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα1 radiation. In some embodiments, Form 1 has an XRPD pattern having at least peaks at °2θ values of 20.0±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα1 radiation. In some embodiments, Form 1 has an XRPD pattern having at least peaks at °2θ values of 20.0±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2, and at least one or more of the °2θ values of 3.8±0.2, 9.1±0.2, 13.8±0.2, 14.0±0.2, 22.9±0.2, and 23.4±0.2 obtained using CuKα1 radiation.In some embodiments, Form 1 has an XRPD pattern having at least peaks at 2θ values of 9.1±0.2, 13.8±0.2, 20.0±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα1 radiation. In some embodiments, Form 1 has an XRPD pattern having at least peaks at 2θ values of 3.8±0.2, 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα1 radiation. In some embodiments, Form 1 has an XRPD pattern having at least peaks at one or more 2θ values of 3.8±0.2, 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2, as well as 16.2±0.2, 18.6±0.2, 22.2±0.2, 25.6±0.2, and 27.9±0.2 obtained using CuKα1 radiation. In certain embodiments, the present invention relates to Form 1 having an XRPD pattern obtained using CuKα1 radiation that is substantially as shown in FIG. 1. In further embodiments, the present invention relates to Form 1 having an XRPD pattern obtained using CuKα1 radiation that is substantially as shown in Table 5 (Table 6).

[0015] In some embodiments, Form 1 has a DSC curve that includes an endotherm between about 230 °C and about 240 °C. In certain embodiments, Form 1 has a DSC curve that includes an endotherm at approximately 233 °C.

[0016] Dynamic vapor sorption analysis showed that Form 1 has very low hygroscopicity, with water uptake of only about 0.2% at 90% RH. This low hygroscopicity is considered advantageous because the water content of the crystal remains substantially constant even when the humidity changes within the normal relative humidity range of about 30% to about 80% RH. In some embodiments, Form 1 is stable at relative humidities up to 90% at a temperature of 25 °C.

[0017] In some embodiments, the crystalline HCl salt is a hydrate such as a non-stoichiometric hydrate. In certain embodiments, the crystalline hydrate is Form 2. This form can be prepared directly from the free base of linaprazan gluleate or using its hydrochloride salt by specific crystallization techniques, for example, from a slurry in acetic acid, methanol, or a mixture of methanol and water; by evaporation from methanol; by anti-solvent crystallization from methanol and a specific anti-solvent; or by cooling from methanol or a mixture of methanol and water. In one embodiment, Form 2 has an X-ray powder diffraction (XRPD) pattern having at least two peaks at °2θ values selected from the list consisting of 7.1±0.2, 9.9±0.2, 10.2±0.2, 15.0±0.2, 15.7±0.2, 22.6±0.2, 22.8±0.2, and 25.0±0.2 obtained using CuKα1 radiation. In some embodiments, Form 2 has an XRPD pattern having at least peaks at °2θ values of 7.1±0.2 and 15.0±0.2, or 7.1±0.2 and 25.0±0.2 obtained using CuKα1 radiation. In some embodiments, Form 2 has an XRPD pattern having at least four peaks at °2θ values selected from the list consisting of 7.1±0.2, 9.9±0.2, 10.2±0.2, 15.0±0.2, 15.7±0.2, 22.6±0.2, 22.8±0.2, and 25.0±0.2 obtained using CuKα1 radiation. In some embodiments, Form 2 has an XRPD pattern having at least peaks at °2θ values of 7.1±0.2, 15.0±0.2, 22.6±0.2, and 25.0±0.2 obtained using CuKα1 radiation. In some embodiments, Form 2 has an XRPD pattern having at least six peaks at °2θ values selected from the list consisting of 7.1±0.2, 9.9±0.2, 10.2±0.2, 15.0±0.2, 15.7±0.2, 22.6±0.2, 22.8±0.2, and 25.0±0.2 obtained using CuKα1 radiation.In some embodiments, Form 2 has an XRPD pattern having at least peaks at °2θ values of 7.1±0.2, 9.9±0.2, 10.2±0.2, 15.0±0.2, 15.7±0.2, 22.6±0.2, 22.8±0.2, and 25.0±0.2 obtained using CuKα1 radiation. In certain embodiments, the invention relates to Form 2 having an XRPD pattern obtained using CuKα1 radiation that is substantially as shown in FIG. 2 or FIG. 3. In further embodiments, the invention relates to Form 2 having an XRPD pattern obtained using CuKα1 radiation that is substantially as shown in Table 6 (Table 7) or Table 7 (Table 8).

[0018] In some embodiments, Form 2 has a DSC curve that includes an endotherm between about 175 °C and about 185 °C. In certain embodiments, Form 2 has a DSC curve that includes an endotherm at approximately 180 °C.

[0019] The water content of Form 2 has been found to vary between about 0 to 5% depending on the relative humidity. Between about 20 - 90% RH, the uptake of water by Form 2 increases almost linearly with increasing relative humidity. Thus, the crystalline non-stoichiometric hydrate is characterized as a channel hydrate. In some embodiments, Form 2 is stable at 25 °C at relative humidities up to 90%.

[0020] As described in the experimental section, solubility experiments showed that the crystalline free base and the crystalline HCl salt behave differently at low and medium - low pH (see FIG. 12). In a medium (FaSSGF; pH 1.6) mimicking fasting gastric juice, the solubility of the free base was approximately 1.4 - fold higher than that of the HCl salt after 1 hour of incubation. However, surprisingly, in a medium (FeDSGA; pH 5.0) mimicking fed gastric juice, the relative solubility of the two crystalline substances was reversed, and the HCl salt was more than 6.5 - fold more soluble than the free base after 1 hour of incubation. The increased solubility of the crystalline HCl salt at high pH is considered useful, especially since the gastric pH rises during ongoing treatment with linaprazan gululate.

[0021] It has also been found that the solubility of the two crystalline HCl salts in gastric juice (fed state) is higher than their solubility in intestinal juice (fed or fasting state); see Figures 13A and 13B.

[0022] In another aspect, the present invention relates to a method for the preparation of Form 1 of the HCl salt of linaprazan gulrate. Form 1 can be prepared directly from the free base of linaprazan gulrate or by using an amorphous or partially crystalline hydrochloride salt of linaprazan gulrate and specific crystallization techniques as described in the appended examples. Alternatively, Form 1 can be prepared via Form 2 as an intermediate. This route has been found to be more suitable for large-scale preparation of Form 1 and enables the preparation of the product at significantly lower residual solvent levels than when Form 1 is prepared directly from the free base of linaprazan gulrate.

[0023] Thus, in some embodiments, the method for the preparation of Form 1 of the HCl salt of linaprazan gulrate comprises a) preparing a suspension of Form 2 of the HCl salt in a suitable solvent such as ethyl acetate; b) slurrying the suspension of step a) until the conversion of Form 2 to Form 1 of the HCl salt is complete; c) recovering the solid obtained in step b); d) drying the solid of step c) under vacuum and / or at an elevated temperature such as about 50 °C, about 55 °C, about 60 °C, about 65 °C, or about 70 °C.

[0024] Step b) is preferably carried out at a temperature between about 25 and about 40 °C, more preferably about 30 °C. The suspension is preferably slurried for at least 6 hours, more preferably at least 12 hours, more preferably at least 18 hours, and even more preferably at least 24 hours. The drying step c) is preferably carried out under vacuum at an elevated temperature such as about 50 °C, about 55 °C, about 60 °C, about 65 °C, or about 70 °C.

[0025] The crystalline form 2 of the HCl salt can be prepared directly from an amorphous or partially crystalline hydrochloride or from the free base of linaprazan gulrate as described in the attached examples. Thus, in a further embodiment, the method for the preparation of form 1 of the HCl salt of linaprazan gulrate is a) preparing a solution of the free base of linaprazan gulrate in acetic acid; b) adding ethyl acetate; c) adding concentrated hydrochloric acid and maintaining stirring until form 2 of the HCl salt is obtained; d) recovering the solid obtained in step c); e) adding ethyl acetate to the solid of step d); f) slurrying the suspension of step e) until the conversion of form 2 of the HCl salt to form 1 is complete; g) recovering the solid obtained in step f); h) drying the solid of step g) under vacuum and / or at an elevated temperature such as about 50 °C, about 55 °C, about 60 °C, about 65 °C, or about 70 °C.

[0026] One or more in-line filtration steps can be optionally carried out after steps a) and / or b) to remove any insoluble substances or fine particles from the solution of linaprazan gulrate. Seed crystals can be optionally used to induce crystallization in step f). Step f) is preferably carried out at a temperature between about 25 °C and about 40 °C, more preferably at about 30 °C. The suspension is preferably slurried for at least 6 hours, more preferably at least 12 hours, more preferably at least 18 hours, and even more preferably at least 24 hours. The drying step h) is preferably carried out under vacuum at an elevated temperature such as about 50 °C, about 55 °C, about 60 °C, about 65 °C, or about 70 °C.

[0027] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline HCl salt of linaprazan gulrate, in association with one or more pharmaceutically acceptable excipients, disclosed herein. Excipients can include, for example, fillers, binders, surfactants, disintegrants, glidants, and lubricants. In some embodiments, the crystalline HCl salt of linaprazan gulrate is Form 1. In some embodiments, the crystalline HCl salt of linaprazan gulrate is Form 2.

[0028] In some embodiments, the pharmaceutical composition comprises the crystalline HCl salt of linaprazan gulrate, such as Form 1 or Form 2, 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 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, the pharmaceutical composition comprising the crystalline HCl salt of linaprazan gulrate is substantially free of other forms of linaprazan gulrate. For example, in some embodiments, the pharmaceutical composition comprising Form 1 is substantially free of other forms of linaprazan gulrate, such as Form 2 of linaprazan gulrate. In some embodiments, Form 1 comprises less than about 15% by mass of Form 2 or any other polymorph of linaprazan gulrate. For example, Form 1 comprises about 14% by mass, about 13% by mass, about 12% by mass, about 11% by mass, about 10% by mass, about 9% by mass, about 8% by mass, about 7% by mass, about 6% by mass, about 5% by mass, about 4% by mass, about 3% by mass, about 2% by mass, less than about 1% by mass, or less than that of Form 2 or any other polymorph of linaprazan gulrate. In other embodiments, Form 2 comprises less than about 15% by mass of Form 1 or any other polymorph of linaprazan gulrate. For example, Form 2 comprises about 14% by mass, about 13% by mass, about 12% by mass, about 11% by mass, about 10% by mass, about 9% by mass, about 8% by mass, about 7% by mass, about 6% by mass, about 5% by mass, about 4% by mass, about 3% by mass, about 2% by mass, less than about 1% by mass, or less than that of Form 1 or any other polymorph of linaprazan gulrate.

[0029] In some embodiments, the pharmaceutical composition may contain the crystalline HCl salt of linaprazan gulrate in an amount between about 1% and about 100% by weight, such as between about 1% and about 50% by weight, or for example between about 1% and about 20% by weight. For example, the composition may contain the crystalline HCl salt of linaprazan gulrate in an amount between about 1% and about 15% by weight, or between about 5% and about 20% by weight, such as 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. In some embodiments, the composition contains the crystalline HCl salt of linaprazan gulrate in an amount of about 20% by weight, about 19% by weight, about 18% by weight, about 17% by weight, about 16% by weight, about 15% by weight, about 14% by weight, about 13% by weight, about 12% by weight, about 11% by weight, about 10% by weight, about 9% by weight, about 8% by weight, about 7% by weight, about 6% by weight, about 5% by weight, about 4% by weight, about 3% by weight, about 2% by weight or about 1% by weight.

[0030] In some embodiments, the composition contains the crystalline HCl salt of linaprazan gulrate in a unit dose of about 25 mg to about 150 mg. 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 the crystalline HCl salt of linaprazan gulrate in an amount of 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. The daily dose can be administered as a single dose or divided into two, three, or more unit doses.

[0031] 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).

[0032] In some embodiments, the pharmaceutical composition includes 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, dried starch, hydrolyzed starch, and pregelatinized starch.

[0033] In some embodiments, the pharmaceutical composition includes 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 rubbers (e.g., acacia gum and tragacanth gum), sodium alginate, cellulose derivatives (e.g., hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, and ethylcellulose), and synthetic polymers (e.g., copolymers of acrylic acid and methacrylic acid, copolymers of methacrylic acid, copolymers of methyl methacrylate, copolymers of aminoalkyl methacrylate, copolymers of polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone (povidone)).

[0034] In some embodiments, the pharmaceutical composition includes a disintegrant. Examples of suitable disintegrants include, but are not limited to, dried starch, modified starch (e.g., (partial) 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., carmellose, croscarmellose sodium, carmellose calcium, and cross-linked PVP (crospovidone)).

[0035] In some embodiments, the pharmaceutical composition includes a glidant or a 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, fine particulate silicon dioxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, wax (e.g., carnauba wax), hardened oil, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0036] Generally, the pharmaceutical composition can be prepared by conventional methods using conventional excipients. In some embodiments, the components of the formulation are mixed into a homogeneous mixture and then formulated into tablets or capsules. The homogeneous mixture of components can be compressed into tablets using conventional techniques such as rotary tablet presses. The mixture of components may be granulated. For example, the mixture of components can be wetted by the addition of a liquid such as water and / or a suitable organic solvent (e.g., ethanol or isopropanol), and then granulated and dried. Alternatively, the 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 the components or small multiparticulates (e.g., granules, extruded pellets, or mini tablets). If desired, any of the above tablets, capsules, granules, extruded pellets, and mini tablets 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.

[0037] After absorption into the bloodstream, linaprazan gulrate is rapidly metabolized to linaprazan, the active metabolite. The plasma concentration of linaprazan gulrate is extremely low and difficult to determine, whereas the plasma concentration of linaprazan can be determined instead. Phase I studies have shown that a specific dose of linaprazan gulrate should be able to maintain the gastric pH above 4 for 24 hours after administration. This is estimated to require that the minimum plasma concentration (C min ) of linaprazan be at least about 240 nmol / L at 22 hours. At such a dose, once-daily oral administration of the formulation would be sufficient. Thus, in some embodiments, the single unit dose of the pharmaceutical composition of linaprazan gulrate, in a human, at 22 hours after oral administration of the pharmaceutical composition to the human, is at least about 240 nmol / L of the C minresults in. In other embodiments, administration of two unit doses of a linaprazan gluleate pharmaceutical composition results in at least about 240 nmol / L of linaprazan C in a human 10 hours after oral administration of the last unit dose of the pharmaceutical composition to the human. min results in.

[0038] In one aspect, the present invention relates to a crystalline form of the HCl salt of linaprazan gluleate as disclosed herein for use in therapy.

[0039] The crystalline form of the HCl salt of linaprazan gluleate as disclosed herein can be used for the treatment or prevention of diseases or conditions where inhibition of gastric acid secretion is essential or desirable, such as the eradication of Helicobacter pylori (H. pylori). Examples of such diseases and conditions include gastrointestinal inflammatory diseases 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), hemorrhagic gastric ulcer, symptoms of gastroesophageal reflux disease (including heartburn, regurgitation, and nausea), gastrinoma, and acute upper gastrointestinal bleeding.

[0040] Accordingly, in one 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 the step of administering a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the HCl salt of linaprazan gluleate as disclosed herein. In some embodiments, the crystalline form of the HCl salt of linaprazan gluleate is Form 1. In some embodiments, the crystalline form of the HCl salt of linaprazan gluleate is Form 2.

[0041] In some embodiments, the treatment of GERD is on-demand treatment of GERD.

[0042] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline HCl salt of linaprazan gluleate as disclosed herein for use in the treatment or prevention of a gastrointestinal inflammatory disease or a gastric acid-related disease.

[0043] As used herein, the term "polymorph" refers to crystals of the same molecule having different physical properties as a result of the order of molecules in the crystal lattice. Polymorphs of a single compound have one or more different 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 (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water sorption, compression, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differences in oxidation such that a dosage form discolors more rapidly when composed of one polymorph than when composed of another), or mechanical changes (e.g., crystal changes during storage when a kinetically favored polymorph converts to a more thermodynamically stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, some transitions can affect efficacy and / or toxicity. Furthermore, the physical properties of crystals can be important in processing; for example, one polymorph may be prone to forming solvates or may be difficult to filter and wash to be free of impurities (i.e., particle shape and size distribution can differ between one polymorph and another). "Polymorph" does not include the amorphous form of a compound.

[0044] As used herein, the term "amorphous" refers to the amorphous form of a compound, which can be the solid state form of the compound or the 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.

[0045] As used herein, the term "anhydrate" or "anhydrous form" refers to a polymorph of linaprazan gulrate having 0.5% by mass or less of water, such as 0.4% by mass or less, 0.3% by mass or less, 0.2% by mass or less, or 0.1% by mass or less of water.

[0046] As used herein, the term "polymorphic purity", when used in connection with a composition containing a polymorph of linaprazan gluleate, refers to the proportion of a particular polymorph relative to another polymorph or amorphous form of linaprazan gluleate in a reference compound. For example, a composition containing Form 1 with a polymorphic purity of 90% contains 90 parts by weight of Form 1 and 10 parts by weight of other crystalline and / or amorphous forms of linaprazan gluleate.

[0047] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of linaprazan gluleate sufficient to, to some extent, alleviate one or more symptoms of a disease or condition being treated after administration to a subject. The results include alleviation and / or mitigation of the signs, symptoms, or causes of the disease, and / or any other desirable changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of linaprazan gluleate necessary to bring about a clinically significant decrease in disease symptoms. The appropriate "effective" amount in any individual case is determined using any appropriate technique, such as a dose escalation study.

[0048] 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 of their symptoms. In some embodiments, treatment can be performed after one or more symptoms have developed. In other embodiments, treatment can be performed when no symptoms are present. For example, treatment can be performed on a susceptible individual before the onset of symptoms (e.g., taking into account a history of symptoms and / or genetic or other susceptibility factors). Treatment can also continue after symptoms have resolved, for example, to prevent or delay their recurrence.

[0049] As used herein, the term "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable for human pharmaceutical use, generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0050] As used herein, a compound or composition is "substantially free" of one or more other components if it contains no appreciable amount of such other components. Such components can include impurities such as starting materials, residual solvents, or any other impurities that may result from the preparation and / or isolation of the compounds and compositions provided herein. In some embodiments, the polymorphs provided herein are "substantially free" of impurities. The purity of a particular polymorph is preferably greater than about 90% (w / w), such as greater than about 95% (w / w), such as greater than about 97% (w / w), or such as 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), such as less than about 0.5% (w / w), or such as less than about 0.1% (w / w). The total amount of impurities can be determined, for example, by high performance liquid chromatography (HPLC) methods.

[0051] In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of linaprazan glulepidate is "substantially free" of other polymorphs if it constitutes at least about 95% by weight of the linaprazan glulepidate in which it is present. In some embodiments, a particular polymorph of linaprazan glulepidate is "substantially free" of other polymorphs if it constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the linaprazan glulepidate in which it is present.

[0052] As used herein, a compound is "substantially present" as a given polymorph when at least about 50% by weight of the compound is in its polymorphic form, for example when at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, or at least about 90% by weight of the compound is in its polymorphic form. In some embodiments, at least about 95% by weight, for example at least about 96% by weight, for example at least about 97% by weight, for example at least about 98% by weight, for example at least about 99% by weight, or for example at least about 99.5% by weight of the compound is in its polymorphic form.

[0053] As used herein, the term "stable" means that a polymorph does not exhibit a change over time in one or more of polymorphic form (e.g., an increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (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 show a change in one or more of polymorphic form (e.g., an increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (measured by in vitro assay), or osmolality 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 show a change in one or more of polymorphic form (e.g., an increase or decrease in a particular form), appearance, pH, percentage of impurities, activity (measured by in vitro assay), or osmolality for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. As used above, the phrase "does not show a change" refers to a change of less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%) in any parameter measured over the relevant period.

[0054] The crystallinity of the polymorph of linaprazan hydrochloride can be measured, for example, by X-ray powder diffraction (XRPD) method or by differential scanning calorimetry (DSC) method. When referring to a crystalline compound herein, preferably the crystallinity is 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%. The % crystallinity refers to the mass percentage of the total sample mass that is crystalline.

[0055] As used herein, the term "about" refers to a value or parameter in this specification that includes (and describes) embodiments that target the value or parameter itself. For example, a description referring to "about 20" includes a description of "20". Numerical ranges include the numbers that define the range. Generally, the term "about" refers to all values of the variable that are either within the experimental error of the indicated value (e.g., within the 95% confidence interval of the mean value) or within 10 percent of the indicated value, whichever is greater.

[0056] The present invention will now be described by the following examples, which do not limit the present invention in any way. All cited documents and references mentioned herein are incorporated by reference in their entirety.

[0057] Abbreviations DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol MeOH Methanol RH Relative humidity

[0058] Experimental methods General method 1 1H-NMR spectra were recorded at 25 °C on a Bruker 400 MHz instrument, with the residual protic solvent in the deuterated solvent used as a reference: DMSO-d6 (δ H 2.50 ppm).

[0059] The HPLC-MS analysis was performed using an Agilent 1100 series liquid chromatography / mass selective detector (MSD) (single quadrupole type) equipped with an electrospray interface and a UV diode array detector. The analysis was carried out using an ACE 3 C8 (3.0×50 mm) column with a gradient of acetonitrile in 0.1% TFA aqueous solution over 3 minutes and a flow rate of 1 mL / min.

[0060] For the solubility study, HPLC was performed using an Agilent 1100 series liquid chromatography system equipped with a DAD spectrometer. The analysis was carried out at 30 °C using a Waters X Bridge BEH C18 column (4.6×100 mm, 2.5 μm). Mobile phase: A = 0.1% formic acid in water, B = 0.1% formic acid in acetonitrile. Flow rate 0.8 mL / min. Mobile phase program:

[0061] [Table 1]

[0062] X-ray powder diffraction (XRPD) analysis The analysis was performed using a PanAlytical X'Pert Pro diffractometer equipped with a Cu anode (45 kV, 40 mA), a Kα-1 Johannson monochromator (1.54060 Å), and a Pixcel detector. Using a scanning speed of 0.10° / s and a step size of 0.013°, the 2-theta range was 2 - 35°. A low-speed rotating sample holder was used. The sample was coated on a Si zero-background wafer to obtain a flat powder surface. The measurement was carried out using a programmable incident divergence slit.

[0063] In the art, it is known that X-ray powder diffraction patterns can be obtained with one or more measurement errors depending on measurement conditions (apparatus, sample preparation, or machinery used, etc.). In particular, it is generally known that the intensity of XRPD patterns can vary depending on measurement conditions and sample preparation. For example, one skilled in the art of XRPD will understand that the relative intensity of peaks can vary depending on the orientation of the sample under test as well as the type and settings of the equipment used. One skilled in the art will also understand that the position of reflections can be affected by the exact height at which the sample is placed in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample can also have a slight effect. Thus, one skilled in the art will understand that the diffraction patterns presented herein are not to be interpreted as absolute, and that any crystalline form that provides a powder diffraction pattern substantially identical to that disclosed herein falls within the scope of this disclosure (for further information, see R. Jenkins and R.L. Snyder, "Introduction to X-ray powder diffractometry", John Wiley & Sons, 1996).

[0064] Thermogravimetric analysis (TGA) The analysis was carried out on a PerkinElmer TGA7 instrument. A few milligrams of the sample were gently placed into an open Pt pan and mass analyzed in a stream of dry nitrogen gas (20 mL / min) to ensure an inert atmosphere. The sample was scanned from 25 to 200 °C using a continuous scanning rate of 10 °C / min.

[0065] Differential scanning calorimetry (DSC) The analysis was carried out on a Netzsch DSC 204F1 instrument. A few milligrams of the sample were 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 (start) was 0 °C and the maximum temperature was 250 °C.

[0066] Dynamic vapor sorption (DVS) The analysis was carried out on the SMS DVS-1 equipment. A few milligrams of the substance were added to an Al pan and exposed to a stepwise RH change between two identical consecutive cycles according to 0-10-20-30-40-50-60-70-80-90-80-70-60-50-40-30-20-10-0%RH using the open-loop mode. The experiment was carried out at 25 °C using a gas flow rate of 200 mL / min. The applied dm / dt criterion was 0.001 mass% / min during a 5-minute window, with a maximum allowable time of 360 minutes and a minimum allowable time of 10 minutes in all steps.

Example

[0067] (Example 1) Preparation of the hydrochloride salt of linaprazan gluleate Linaprazan gluleate (8.12 g, 16.9 mmol) was suspended in 2-propanol (200 mL) at 22 °C and the suspension was stirred. When HCl aqueous solution (12 M; 1.67 g, 16.9 mmol) was added, a slurry was formed. Stirring was continued for 2.5 hours. Then, the suspension was filtered through a P3 frit glass filter funnel and the solid was dried under vacuum. Yield: 94% (8.20 g, colorless powder), 100% purity according to LCMS. 1 H NMR (400 MHz, DMSO-d6): δ 12.07 (s, 1H), 9.10 (t, J = 5.6 Hz, 1H), 8.43 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 7.27 - 7.03 (m, 3H), 6.48 (s, 1H), 4.44 (d, J = 3.9 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 3.58 (q, J = 5.7 Hz, 2H), 2.45 - 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).

[0068] (Example 2) Polymorph discrimination Polymorph screening was performed on the HCl salt of linaprazan guruleate to determine solubility, polymorphism, and thermodynamic stability.

[0069] X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) showed that the drug substance used for screening was a mixture of Form 1 and Form 2. The TGA scan showed a gradual mass loss of about 1% when heated to 140 °C. (Data not shown). Prior to the crystallization experiments, the solubility of the drug substance was determined in more than 20 solvents and solvent mixtures.

[0070] Slurry experiments: Slurry experiments were performed in various solvents, and the HCl salt of linaprazan guruleate was found to have intermediate solubility. Approximately 50 - 200 mg of the drug substance was slurried in 11 solvents (pure solvents and binary solvents) at room temperature and 40 °C for 3 weeks, unless otherwise indicated. All solvents were dried by adding molecular sieves prior to preparing the slurry, unless otherwise indicated. The solid phase was isolated and analyzed by XRPD. Crystalline solid forms were obtained in the experiments shown in Table 1 (Table 2).

[0071] [Table 2]

[0072] Evaporation experiments: Experiments were performed in 6 solvents, and the HCl salt of linaprazan guruleate was found to have sufficiently high solubility. All solvents were dried by adding molecular sieves prior to preparing the solution, unless otherwise indicated. Approximately 10 or 20 mg of the drug substance was dissolved and left to evaporate at room temperature and ambient relative humidity for 10 days in a vial or directly on an XRPD zero-background plate. The results are shown in Table 2 (Table 3).

[0073] [Table 3]

[0074] Anti-solvent crystallization: Crystallization was carried out from specific solvents, and it was found that the HCl salt of linaprazan gulrate had high solubility. Also, when carried out from specific anti-solvents, the HCl salt of linaprazan gulrate was substantially insoluble. All solvents were dried by adding molecular sieves before conducting the experiments.

[0075] The drug substance was dissolved in Solvent 1, and then Solvent 2 was added in 0.5 mL portions. In all experiments, since precipitation did not occur promptly, the vial was placed at 5 °C to induce precipitation. If crystals had not formed after 4 days, a piece of metal wire was added to induce crystallization, and the vial was left for an additional 7 days. The solid phase was separated by vacuum filtration and analyzed by XRPD. The crystalline solid forms were obtained in the experiments shown in Table 3 (Table 4).

[0076] [Table 4]

[0077] Cooling experiment: The cooling experiment was carried out in solvents and solvent mixtures, and it was found that the solubility of the HCl salt of linaprazan gulrate was high enough for a reasonable amount to dissolve. All solvents were dried by adding molecular sieves before preparing the solution, unless otherwise instructed. Samples were prepared and most of the drug substance was dissolved at room temperature. Then, the temperature was raised to 40 °C to completely dissolve the drug substance. Except for the DMSO solution placed at room temperature, the vials were placed in a 5 °C refrigerator. The solid phase was separated by vacuum filtration and analyzed by XRPD. The crystalline solid forms were obtained in the experiments shown in Table 4 (Table 5).

[0078] [Table 5]

[0079] The XRPD peaks of Form 1 obtained from the slurry in DMF at 40 °C are listed in Table 5 (Table 6) below. The diffraction pattern of Form 1 is shown in Figure 1.

[0080] [Table 6]

[0081] The XRPD peaks of Form 2 ("Sample 1") obtained by cooling from MeOH / water 9:1 are listed in Table 6 (Table 7) below. The diffraction pattern of Form 2, Sample 1, is shown in Figure 2.

[0082] [Table 7]

[0083] The XRPD peaks of Form 2 ("Sample 2") obtained by cooling from MeOH are listed in Table 7 (Table 8) below. The diffraction pattern of Form 2, Sample 2, is shown in Figure 3.

[0084] [Table 8A]

[0085] [Table 8B]

[0086] The DMSO solvate obtained in a particular experiment was a highly crystalline solid form but was not considered pharmaceutically feasible. TGA experiments confirmed that this form contained approximately 1 mole of DMSO per mole of the HCl salt of linaprazan gulrate. After heating the sample in the TGA experiment, the X-ray powder diffraction pattern of the dried sample was found to be identical to that of Form 1 (data not shown).

[0087] (Example 3) Thermogravimetric analysis The sample of Form 1 (obtained by crystallization from DMF using EtOAc as the antisolvent) showed a mass loss of 0.1% when heated from 30 to 140 °C. This confirmed that Form 1 is an anhydrate. The TGA mass loss curve of Form 1 is shown in Figure 4.

[0088] Samples 1 and 2 of Form 2 showed mass losses of 1.8 and 3.1%, respectively, when heated from 30 to 140 °C. This mass loss is due to the release of water. The difference between these two samples is probably due to the difference in relative humidity during the analysis of the samples. The mass loss at higher temperatures is thought to be due to the decomposition of the samples. The TGA mass loss curves of Samples 1 and 2 of Form 2 are shown in Figures 5 and 6, respectively.

[0089] After the TGA experiment, Sample 2 of Form 2 was analyzed by XRPD. The diffraction pattern of the dried sample was found to be the same as the diffraction pattern obtained for Form 1 (data not shown).

[0090] (Example 4) Differential Scanning Calorimetry (DSC) Analysis The sample of Form 1 (obtained by crystallization from DMF using EtOAc as the antisolvent) showed a single endothermic event at approximately 233 °C (onset 230.7 °C) due to the melting of the anhydrous HCl salt. The DSC thermogram is shown in Figure 7.

[0091] In Form 2, Samples 1 and 2 were investigated. The DSC thermograms are shown in Figures 8 and 9, respectively. Sample 1 showed only one endothermic event due to the melting of Form 2. This event was broad, suggesting that some water remained when melting started and was released during the melting process. This event had a peak at approximately 171 - 172 °C (starting at 163.0 °C). Sample 2 showed more complex thermal behavior. The first small endotherm at about 150 °C could be due to the release of water. The second event starting at approximately 180 °C is interpreted as the melting of Form 2 (endothermic) overlapping with the recrystallization to Form 1 (exothermic). The last endothermic event is the melting of Form 1. The melting temperature of approximately 232 °C (starting at 229.3 °C) is consistent with that found in Form 1 (see Figure 7).

[0092] (Example 5) Dynamic vapor sorption (DVS) analysis The hygroscopicity of Form 1 (obtained by crystallization from DMF using EtOAc as the anti-solvent) and Form 2 (obtained from a slurry in MeOH) was investigated at 25 °C using DVS. The mass change plots and sorption isotherm plots of Form 1 showed only a small uptake of water at elevated humidity; see Figures 10A and 10B, respectively. Since the water uptake at 90% RH is 0.2%, Form 1 can be classified as non-hygroscopic.

[0093] In Form 2, the mass change plots and sorption isotherm plots (Figures 11A and 11B, respectively) showed significant uptake of water at elevated humidity. The uptake of water increased rapidly with increasing relative humidity and the loss of water was similarly rapid with decreasing relative humidity. The sorption behavior is typical of channel hydrates, where the crystal structure adapts to accommodate different amounts of water depending on the ambient humidity. The uptake of 4.7% water at 90% RH corresponds to 1.3 water molecules per unit of linaprazan gulonate HCl.

[0094] (Example 6) Large-scale preparation of Form 1 Step 1: Into a 250 L reactor, acetic acid (142.75 kg) and linaprazan gulrate (crude product, 28.50 kg) were charged. Further acetic acid was added (28.55 kg), the mixture was heated to 30 °C and stirred at that temperature until a clear solution was obtained. The solution was filtered and the filtrate was transferred to a 500 L reactor. The first reactor was rinsed with additional acetic acid (14.17 kg). Then, ethyl acetate (199.40 kg) was charged to the reactor. Then, a solution of HCl in acetic acid (10.9% w / w, 19.44 kg) was added dropwise to the reactor over 2 hours. The mixture was then stirred at 30 °C for 2 hours. The mixture was filtered by centrifugation and the wet cake was washed with ethyl acetate (28.44 kg).

[0095] Step 2: Ethyl acetate (285 kg) and the wet cake from Step 1 (37.98 kg) were charged to a reactor, and seed crystals of Form 1 (0. kg / kg) were added. Further ethyl acetate (28.49 kg) was added. Then, the suspension was slurried at 30 °C for 16 hours. Since the material became sticky, additional ethyl acetate (85.5 kg) was added. The suspension was filtered by centrifugation and the wet cake was washed with ethyl acetate (28.56 kg). The wet cake was dried under vacuum at 65 °C. A white solid was obtained (28.5 kg, 93.1% yield, Form 1).

[0096] (Example 7) Solubility Study I. Solubility of the free base and HCl salt of linaprazan gulrate in media mimicking gastric juice The solubility of the crystalline free base (Form A) and crystalline HCl salt (mixture of Forms 1 and 2) of linaprazan gulrate was studied in Fasted State Simulated Gastric Fluid (FaSSGF, Biorelevant, batch FFF-0119-B; pH 1.6) and Fed State Gastric Acid (FeDSGA, Biorelevant, batch FEDGAS-120-A; pH 5.0).

[0097] Sample Preparation, Analysis, and Results In a 4 mL vial, a saturated solution was prepared by adding a fixed mass of the crystalline base or crystalline HCl salt to 2 mL each of different buffers. The vial was sonicated for 10 minutes and then stirred with a magnetic stirrer on a water bath (37 °C) for 24 hours. Samples were taken repeatedly after 1, 4, and 24 hours and analyzed by HPLC-UV. Concentrations were calculated from a calibration curve prepared using eight calibration standards (serial dilutions of stock solutions of the free base and HCl salt of linaprazan gulrate).

[0098] It was found that the free base had higher solubility in FaSSGF, while the HCl salt had higher solubility in FeDSGA. The difference was most prominent after 1 hour. In FaSSGF, the solubility of the free base was 1.4 times higher than that of the HCl salt, while in FeDSGA, the solubility of the HCl salt was 6.5 times higher than that of the free base. The results are shown in Figure 12.

[0099] II. Solubility in Media Mimicking Gastric and Intestinal Fluids of Forms 1 and 2 The solubility of two crystalline HCl salts of linaprazan gulrate in Fed State Simulated Gastric Fluid (FEDGAS) medium, the second version of Fasted State Simulated Intestinal Fluid (FaSSIF-V2), and the second version of Fed State Simulated Intestinal Fluid (FeSSIF-V2) was studied.

[0100] Preparation of Buffer FaSSIF-V2: 139 mg of NaOH, 222 mg of maleic acid, and 401 mg of NaCl were added to 90 mL of Milli-Q water, and the resulting mixture was stirred until completely dissolved. The pH was adjusted to 6.5 with 1 M HCl and 1 M NaOH and made up to 100 mL with Milli-Q water. 179 mg of FaSSIF-V2 (Biorelevant, batch V2FAS-1020-A) was mixed with 100 mL of the prepared buffer, stirred until completely dissolved, and equilibrated at RT for 1 hour before use.

[0101] FeSSIF-V2: 90 mL of Milli-Q water was added with 327 mg of NaOH, 639 mg of maleic acid, and 733 mg of NaCl, and the resulting mixture was stirred until completely dissolved. The pH was adjusted to 5.8 with 1 M HCl and 1 M NaOH, and made up to 100 mL with Milli-Q water. 976 mg of FeSSIF-V2 (Biorelevant, batch V2FES-1020-A) was mixed with 100 mL of the prepared buffer solution, stirred until completely dissolved, and equilibrated at RT for 1 hour before use.

[0102] FEDGAS (mid-term, pH 4.5): 3.68 g of FEDGAS buffer concentrate (Biorelevant, batch FEDBUF45-0122-A), 73.1 g of Milli-Q water, and 15.3 g of FEDGAS gel (Biorelevant, batch FEDGAS-0322-A) were thoroughly mixed. This medium was stored at 37 °C before use.

[0103] Sample preparation, analysis, and results In 4 mL vials, saturated solutions were prepared by adding a fixed mass (excess) of Form 1 or Form 2 to 2 mL of each of the different buffer solutions. Each experiment was performed in duplicate. The solutions were stirred with a magnetic stir bar at 37 °C for 24 hours. Samples were taken after 1, 3, 6, and 24 hours. At each sampling time point, 200 μL of the sample solution was filtered using a 0.2 μm PP syringe-less filter. The filtered sample solution was diluted 2- or 5-fold with DMA and then analyzed by HPLC-UV to determine the concentration of linaprazan gululate. Concentrations were calculated from a calibration curve based on seven calibration standards (stock solutions of 100 and 250 μg / mL and their serial dilutions).

[0104] The solubility of each of Form 1 and Form 2 in FEDGAS was found to be approximately 20 - 25 times higher than that in FaSSIF-V2 and approximately 7 - 8 times higher than that in FeSSIF-V2. The results are shown in Figure 13A (Form 1) and Figure 13B (Form 2).

Claims

1. The crystalline HCl salt of linaprazan gluleate.

2. The crystalline HCl salt of linaprazan gluleate according to Claim 1, which is stable at room temperature and 94% relative humidity.

3. The crystalline HCl salt of linaprazan gluleate according to Claim 1, which is an anhydrate.

4. Form 1 having an XRPD pattern having at least two peaks at °2θ values selected from the list consisting of 3.8±0.2, 9.1±0.2, 13.8±0.2, 14.0±0.2, 20.0±0.2, 22.9±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα1 radiation, of the crystalline HCl salt of linaprazan gluleate according to Claim 3.

5. The crystalline HCl salt of linaprazan gluleate according to Claim 4, wherein Form 1 has an XRPD pattern having at least peaks at °2θ values of 20.0±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα radiation.

6. The crystalline HCl salt of linaprazan gluleate according to Claim 4, wherein Form 1 has an XRPD pattern having at least peaks at °2θ values of 9.1±0.2, 13.8±0.2, 20.0±0.2, 23.4±0.2, 24.4±0.2, 24.6±0.2, and 26.7±0.2 obtained using CuKα radiation.

7. Form 1 having an XRPD pattern substantially as shown in Figure 1 obtained using CuKα1 radiation, of the crystalline HCl salt of linaprazan gluleate according to Claim 3.

8. The crystalline HCl salt of linaprazan gluleate according to Claim 4, wherein Form 1 has a DSC curve including an endotherm between about 230°C and about 240°C, for example at approximately 233°C.

9. The crystalline HCl salt of linaprazan gluleate according to Claim 1, which is a non-stoichiometric hydrate.

10. Form 2 having an XRPD pattern having at least two peaks at °2θ values selected from the list consisting of 7.1±0.2, 9.9±0.2, 10.2±0.2, 15.0±0.2, 15.7±0.2, 22.6±0.2, 22.8±0.2, and 25.0±0.2 obtained using CuKα1 radiation, of the crystalline HCl salt of linaprazan gluleate according to Claim 9.

11. The crystalline HCl salt of linaprazan gluco rate according to claim 10, wherein Form 2 has an XRPD pattern having at least peaks at 2θ values of 7.1 ± 0.2, 15.0 ± 0.2, 22.6 ± 0.2, and 25.0 ± 0.2 obtained using CuKα1 radiation.

12. The crystalline HCl salt of linaprazan gluco rate according to claim 10, wherein Form 2 has an XRPD pattern having at least peaks at 2θ values of 7.1 ± 0.2, 9.9 ± 0.2, 10.2 ± 0.2, 15.0 ± 0.2, 15.7 ± 0.2, 22.6 ± 0.2, 22.8 ± 0.2, and 25.0 ± 0.2 obtained using CuKα1 radiation.

13. The crystalline HCl salt of linaprazan gluco rate according to claim 9, which is Form 2 having an XRPD pattern substantially shown in FIG. 2 or FIG. 3 obtained using CuKα1 radiation.

14. The crystalline HCl salt of linaprazan gluco rate according to claim 10, wherein Form 2 has a DSC curve including an endotherm between about 175 °C and about 185 °C, for example, at approximately 180 °C.

15. The crystalline HCl salt of linaprazan gluco rate according to claim 1, having a crystallinity of more than 99%.

16. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline HCl salt of linaprazan gluco rate according to any one of claims 1 to 15, in combination with one or more pharmaceutically acceptable excipients.

17. A medicament comprising the crystalline HCl salt of linaprazan gluco rate according to any one of claims 1 to 15.

18. A medicament comprising the crystalline HCl salt of linaprazan gluco rate according to any one of claims 1 to 15 for use in the treatment or prevention of gastrointestinal inflammatory diseases or gastric acid-related diseases.

19. The medicament comprising the crystalline HCl salt of linaprazan gluco rate according to claim 18, 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), hemorrhagic gastric ulcer, symptoms of gastroesophageal reflux disease (including heartburn, reflux, and nausea), gastrinoma, or acute upper gastrointestinal bleeding.

20. The medicament comprising the crystalline HCl salt of linaprazan gluco rate according to claim 18, wherein the gastrointestinal inflammatory disease or gastric acid-related disease is erosive gastroesophageal reflux disease (eGERD).

21. A method for the preparation of form 1 of the HCl salt of linaprazan gurule rate, comprising: a) preparing a solution of the free base of linaprazan gurule rate in acetic acid; b) adding ethyl acetate; c) adding concentrated hydrochloric acid and maintaining stirring until form 2 of the HCl salt is obtained; d) recovering the solid obtained in step c); e) adding ethyl acetate to the solid of step d); f) slurrying the suspension of step e) until the conversion of form 2 of the HCl salt to form 1 is complete; g) recovering the solid obtained in step f); h) drying the solid of step g) under vacuum and / or at an elevated temperature, etc. A method.

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