Polymorphs of maleate of linaratone glutarate

Abstract

The present invention relates to a polymorphic form of a maleate of 5-{2-[({8-[(2, 6-dimethylbenzyl) amino]-2, 3-dimethylimidazo [1, 2-a] pyridin-6-yl} carbonyl)-amino] ethoxy}-5-oxovaleric acid (linaraben glutarate), and more particularly to Form 1 of a maleate of linaraben glutarate. The invention also relates to a pharmaceutical composition containing the polymorphic substance, and application of the polymorphic substance in treatment or prevention of gastrointestinal inflammatory diseases or gastric acid related diseases (especially erosive gastroesophageal reflux disease, eGERD).

Description

Technical Field

[0001] The present invention relates to a polymorph of the maleate salt of 5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid (linalaxen glutarate), and more specifically to Form 1 of the maleate salt of linalaxen glutarate. The present invention also relates to a pharmaceutical composition comprising the polymorph, and the use of the polymorph in treating or preventing gastrointestinal inflammatory diseases or gastric acid-related diseases, particularly erosive gastroesophageal reflux disease (eGERD). Background Art

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

[0003]

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

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

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

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

[0009] Figure 1 Shown is the X-ray powder diffraction pattern of linarasen glutarate maleate salt Form 1 prepared by the synthesis described in Example 1.

[0010] Figure 2 Thermogravimetric analysis (TGA) weight loss curve of Form 1 is shown.

[0011] Figure 3 A differential scanning calorimetry (DSC) thermogram of Form 1 is shown.

[0012] FIG4 shows a dynamic vapor sorption (DVS) weight change graph (A) and a DVS isotherm graph (B) of Form 1. Detailed Description of the Invention

[0014] It has been discovered that under certain conditions, linarasen glutarate maleate can form a stable crystalline form (polymorph) with high crystallinity and high chemical stability. Therefore, this new polymorph is promising for use in linarasen glutarate pharmaceutical compositions. Therefore, a first aspect of the present invention relates to crystalline linarasen glutarate maleate.

[0015] In one embodiment, the present invention provides crystalline linarasen glutarate maleate, wherein the crystalline maleate is stable at room temperature at a relative humidity (RH) of 94%. Such crystalline maleate can be stable under these conditions for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, or even longer.

[0016] In some embodiments, the crystalline maleate salt is an anhydrate. In one embodiment, the crystalline anhydrate is Form 1. This form can be prepared directly from linarasen glutarate free base, or using its maleate salt by certain crystallization techniques, for example, from a slurry in DMA or THF; by antisolvent crystallization from DMA or pyridine and certain antisolvents. In one embodiment, Form 1 has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation having at least two peaks at °2θ values selected from the following list: 5.4±0.2, 9.6±0.2, 12.1±0.2, 16.3±0.2, 17.4±0.2, 19.0±0.2, 20.2±0.2, 22.5±0.2, 23.2±0.2, and 26.0±0.2. In some embodiments, Form 1 has an XRPD pattern obtained by CuKa-radiation having at least four peaks at °2θ values selected from the group consisting of 5.4±0.2, 9.6±0.2, 12.1±0.2, 16.3±0.2, 17.4±0.2, 19.0±0.2, 20.2±0.2, 22.5±0.2, 23.2±0.2, and 26.0±0.2. In some embodiments, Form 1 has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 9.6±0.2, 17.4±0.2, 20.2±0.2, and 26.0±0.2. In some embodiments, Form 1 has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 9.6±0.2, 17.4±0.2, 20.2±0.2, and 26.0±0.2 and peaks at one or more of the following °2θ values: 5.4±0.2, 12.1±0.2, 16.0±0.2, 19.0±0.2, 22.5±0.2, and 23.2±0.2. In some embodiments, Form 1 has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 5.4±0.2, 9.6±0.2, 17.4±0.2, 19.0±0.2, 20.2±0.2, 23.2±0.2, and 26.0±0.2.In some embodiments, Form 1 has an XRPD pattern obtained by CuKα1-radiation having peaks at at least the following °2θ values: 5.4±0.2, 9.6±0.2, 12.1±0.2, 16.3±0.2, 17.4±0.2, 19.0±0.2, 20.2±0.2, 22.5±0.2, 23.2±0.2, and 26.0±0.2. In some embodiments, Form 1 has an XRPD pattern obtained by CuKα1-radiation having at least peaks at the following °2θ values: 5.4±0.2, 9.6±0.2, 12.1±0.2, 16.3±0.2, 17.4±0.2, 19.0±0.2, 20.2±0.2, 22.5±0.2, 23.2±0.2, and 26.0±0.2 and peaks at one or more of the following °2θ values: 5.6±0.2, 12.4±0.2, 23.5±0.2, 24.0±0.2, and 25.7±0.2. In a specific embodiment, the present invention relates to Form 1 having substantially the same. Figure 1 In another embodiment, the present invention relates to Form 1 having an XRPD pattern obtained by CuKα1-radiation, the XRPD pattern having the peaks shown in Table 6.

[0017] In some embodiments, the DSC curve of Form 1 comprises an endotherm between about 154°C and about 169°C, for example, at about 163°C. The DSC curve of Form 1 is as follows Figure 3 shown.

[0018] Dynamic vapor sorption analysis shows that Form 1 has low hygroscopicity, with a water absorption rate of approximately 0.45% at 80% relative humidity. This low hygroscopicity is considered advantageous because the water content of the crystals remains substantially constant even when humidity varies within the normal relative humidity range of about 30% to about 80% relative humidity. In some embodiments, Form 1 remains stable at 25°C and relative humidity up to 90%. A DVS plot of Form 1 is shown in Figure 4.

[0019] In one embodiment, the present invention is directed to crystalline linarasen glutarate maleate having a crystallinity greater than 99%.

[0020] In a second aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline linarasen glutarate maleate disclosed herein, and one or more pharmaceutically acceptable excipients. The excipients may include, for example, fillers, binders, surfactants, disintegrants, glidants, and lubricants. In some embodiments, the crystalline linarasen glutarate maleate is in Form 1.

[0021] In some embodiments, the pharmaceutical composition comprises crystalline linarasen glutarate maleate, such as Form 1, having a polymorph purity of at least about 90%. In some embodiments, the polymorph purity is at least about 95%. In some embodiments, the polymorph purity is at least about 98%. For example, the polymorph purity may be at least about 98.5%, such as at least about 99%, such as at least about 99.5%, such as at least about 99.8%, or such as at least about 99.9%. In some embodiments, the pharmaceutical composition comprising crystalline linarasen glutarate maleate is substantially free of other forms of linarasen glutarate. For example, in some embodiments, the pharmaceutical composition comprising Form 1 is substantially free of other forms of linarasen glutarate, such as the free base form or solvate form of linarasen glutarate. In some embodiments, Form 1 comprises less than about 15% by weight of any other polymorph of linarasen glutarate. For example, Form 1 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 any other polymorph of linarasen glutarate.

[0022] In some embodiments, the pharmaceutical composition may comprise from about 1% to about 100%, such as from about 1% to about 50%, or such as from about 1% to about 20% by weight of crystalline linalaxen glutarate maleate. For example, the composition may comprise from about 1% to about 15%, or from about 5% to about 20%, such as from about 1% to about 10%, from about 5% to about 15%, and from about 10% to about 20%, or such as from about 1% to about 5%, from about 5% to about 10%, from about 10% to about 15%, and from about 15% to about 20% by weight of crystalline linalaxen glutarate maleate. 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 crystalline linalaxen glutarate maleate.

[0023] In some embodiments, the composition comprises a unit dose of about 25 mg to about 150 mg of crystalline linarasen glutarate maleate. For example, the composition can comprise about 25 mg to about 50 mg, about 50 mg to about 75 mg, about 75 mg to about 100 mg, about 100 mg to about 125 mg, or about 125 mg to about 150 mg. In some embodiments, the composition comprises about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg of crystalline linapsen glutarate maleate. The daily dose can be administered as a single dose or divided into two, three, or more unit doses.

[0024] In some embodiments, the pharmaceutical composition comprises a surfactant. The surfactant can be a cationic surfactant, an anionic surfactant or a nonionic surfactant. Examples of cationic surfactants include, but are not limited to, cetyl trimethylammonium bromide (cetrimonium bromide) and cetyl pyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium lauryl sulfate (sodium lauryl sulfate) and lauryl ammonium sulfate (ammonium lauryl sulfate). Examples of nonionic surfactants include, but are not limited to, glyceryl monooleate, glyceryl monostearate, polyoxyethylene castor oil (Cremophor El), poloxamer (e.g., poloxamer 407 or 188), polysorbate 80 and sorbitan esters (Tween).

[0025] In some embodiments, the pharmaceutical composition comprises a filler. Examples of suitable fillers include, but are not limited to, dibasic calcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0026] In some embodiments, the pharmaceutical composition comprises a binder. Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as gum arabic and tragacanth, etc.), sodium alginate, cellulose derivatives (such as hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose and ethyl cellulose, etc.), and synthetic polymers (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers and polyvinyl pyrrolidone (povidone), etc.).

[0027] In some embodiments, the pharmaceutical composition comprises a disintegrant. Examples of suitable disintegrants include, but are not limited to, dry starch, modified starch (such as (partially) pregelatinized starch, sodium starch glycolate, and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose (L-HPC)), and cross-linked polymers (such as carboxymethyl ether cellulose, croscarmellose sodium, carboxymethyl ether cellulose calcium, and cross-linked PVP (crospovidone)).

[0028] In some embodiments, the pharmaceutical composition comprises a glidant or lubricant. Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, colloidal anhydrous silica, hydrous silica, synthetic magnesium silicate, fine-grained silica, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax, etc.), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0029] Typically, pharmaceutical compositions can be prepared in a conventional manner using conventional excipients. In some embodiments, the ingredients of the formulation are mixed into a uniform mixture and then formulated into tablets or capsules. Conventional techniques such as rotary tableting can be used to press the uniform mixture of ingredients into tablets. The mixture of ingredients can also be granulated. For example, the mixture of ingredients can be moistened by adding a liquid such as water and / or a suitable organic solvent (e.g., ethanol or isopropanol), then granulated and dried. Alternatively, particles can be prepared by dry granulation such as roller compaction. The resulting particles can be pressed into tablets using conventional techniques. Capsules can contain a powder mixture of ingredients or small multiparticulates (such as granules, extruded pellets, or tablets). If desired, any of the tablets, capsules, granules, extruded pellets, and tablets mentioned above can be coated with one or more coating layers. Such coating layers can be applied by methods known in the art, such as by film coating involving orifice plates and fluidized beds. In some embodiments, the formulation is in tablet form.

[0030] After being absorbed into the bloodstream, linarasen glutarate is rapidly metabolized to the active metabolite linarasen. Although the plasma concentration of linarasen glutarate is only very low and difficult to measure, the plasma concentration of linarasen, unlike this, can be measured. Phase I studies have shown that certain doses of linarasen glutarate should be able to maintain the intragastric pH at more than 4 for 24 hours after administration. It is estimated that this requires a minimum plasma concentration (C ) of linarasen after 22 hours. min ) is at least about 240 nmol / L. At such a dose, oral administration of the formulation once a day is sufficient. Thus, in some embodiments, a single unit dose of the linarasen glutarate pharmaceutical composition provides at least about 240 nmol / L of linarasen C in a human 22 hours after oral administration of the pharmaceutical composition. min In other embodiments, daily administration of two unit doses of the linarasen glutarate pharmaceutical composition provides at least about 240 nmol / L of linarasen C in the human 10 hours after oral administration of the last unit dose of the pharmaceutical composition. min .

[0031] In one aspect, the present invention relates to crystalline linarasen glutarate maleate for use in therapy.

[0032] The crystalline form of linarasen glutarate maleate disclosed herein can be used to treat or prevent diseases or conditions in which it is necessary or desirable to inhibit gastric acid secretion, such as in Helicobacter pylori (H. Pylori) eradication. Examples of such diseases and conditions include inflammatory diseases of the gastrointestinal tract and gastric acid-related diseases, such as gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), Helicobacter pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcer and duodenal ulcer), bleeding gastric ulcer, gastroesophageal reflux disease symptoms (including heartburn, regurgitation and nausea), gastrinoma and acute upper gastrointestinal bleeding.

[0033] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the crystalline linarasen glutarate maleate disclosed herein for use in treating or preventing gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0034] In another aspect, the present invention relates to a method for treating or preventing a gastrointestinal inflammatory disease or a gastric acid-related disease in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the maleate salt of linarasen glutarate disclosed herein. In some embodiments, the crystalline form of the maleate salt of linarasen glutarate is Form 1.

[0035] In some embodiments, the gastrointestinal inflammatory disease or gastric acid-related disease is erosive gastroesophageal reflux disease (eGERD).

[0036] In a further embodiment, the treatment of GERD is an on-demand treatment of GERD.

[0037] As used herein, the term "polymorph" refers to crystals of the same molecule that have different physical properties due to the molecular arrangement in the crystal lattice. Polymorphs of a single compound have one or more chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties that differ from each other. The differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rate (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water absorption, compactability, and particle morphology. Stability differences can be caused by changes in chemical reactivity (e.g., differential oxidation, causing a dosage form to change color more quickly when containing one polymorph than when containing another polymorph) or mechanical changes (e.g., changes in storage crystals as a kinetically favored polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). Due to differences in solubility / dissolution, some transformations can affect efficacy and / or toxicity. Additionally, the physical properties of the crystals may be important in processing; for example, one polymorph may more readily form solvates or may be difficult to filter and wash free of impurities (i.e., the particle shape and size distribution may differ from one polymorph to another). "Polymorphs" does not encompass amorphous forms of a compound.

[0038] As used herein, the term "amorphous" refers to a non-crystalline form of a compound, which may be a solid state form of the compound or a dissolved form of the compound. For example, "amorphous" means that the compound does not have a regularly repeating molecular arrangement or external surface planes.

[0039] As used herein, the term "anhydrate" or "anhydrous form" refers to a polymorph of linarasen glutarate having 0.5% or less by weight water, e.g., 0.4% or less, or 0.3% or less, or 0.2% or less, or 0.1% or less by weight water.

[0040] As used herein, the term "polymorphic purity," when used in reference to a composition comprising a polymorph of linarasen glutarate, refers to the percentage of one particular polymorph of linarasen glutarate relative to another polymorph or amorphous form in the composition. For example, a composition comprising Form 1 having a polymorphic purity of 90% would contain 90 parts by weight of Form 1 of linarasen glutarate and 10 parts by weight of other crystalline and / or amorphous forms of linarasen glutarate.

[0041] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of linaprenyl glutarate that, upon administration to a subject, is sufficient to provide some relief from one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs and symptoms, or any other desired alteration in a biological system. For example, an "effective amount" for therapeutic use is the amount of linaprenyl glutarate required to provide a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0042] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual before the onset of symptoms (e.g., in view of a history of symptoms and / or in view of genetic or other predisposing factors). Treatment can also be continued after symptoms have been alleviated, for example, to prevent or delay their recurrence.

[0043] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for human pharmaceutical use and that are generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0044] As used herein, if a compound or composition does not include a significant amount of one or more other components, the compound or composition is "substantially free of" such other components. Such components may include impurities such as starting materials, residual solvents, or any other impurities that may result from the preparation and / or separation of the compounds and compositions provided herein. In some embodiments, provided herein are polymorphs that 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).

[0045] In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of linarasen glutarate is "substantially free" of other polymorphs if the particular polymorph of linarasen glutarate comprises at least about 95% by weight of the linarasen glutarate present. In some embodiments, a particular polymorph of linarasen glutarate is "substantially free" of other polymorphs if the particular polymorph of linarasen glutarate comprises at least about 97%, about 98%, about 99%, or about 99.5% by weight of the linarasen glutarate present.

[0046] As used herein, a compound is "substantially" present as a given polymorph if at least about 50% by weight of the compound is in that polymorphic form, for example, if at least about 60%, at least about 70%, at least about 80%, or at least about 90% by weight of the compound is in that polymorphic form. In some embodiments, at least about 95%, such as at least about 96%, such as at least about 97%, such as at least about 98%, such as at least about 99%, or such as at least about 99.5% by weight of the compound is in that polymorphic form.

[0047] As used herein, the term "stable" means that a polymorph does not exhibit a change over time in one or more of the polymorphic form (e.g., an increase or decrease in a certain form), appearance, pH, percentage of impurities, activity (measured by an in vitro assay), or osmotic pressure. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, or 4 weeks. For example, the polymorph does not exhibit a change in one or more of the polymorphic form (e.g., an increase or decrease in a certain form), appearance, pH, percentage of impurities, activity (measured by an in vitro assay), or osmotic pressure for at least 1, 2, 3, or 4 weeks. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. For example, the polymorph does not exhibit a change in one or more of the polymorphic form (e.g., an increase or decrease in a certain form), appearance, pH, percentage of impurities, activity (measured by an in vitro assay), or osmotic pressure for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. As used hereinabove, the phrase "does not exhibit a change" means that any parameter changes by less than 5% (eg, less than 4%, less than 3%, less than 2%, less than 1%) when measured over the relevant time period.

[0048] The crystallinity of linarasen glutarate maleate polymorph can be measured, for example, by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). When referring to a crystalline compound in this article, it is preferred that the crystallinity is greater than about 70%, such as greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%. In some embodiments, the crystallinity is greater than about 98%. In some embodiments, the crystallinity is greater than about 99%. % crystallinity refers to the weight percentage of the total mass of the sample of crystallization.

[0049] As used herein, the term "about" refers to a value or parameter herein that includes (and describes) embodiments relating to the value or parameter itself. For example, a description relating to "about 20" includes a description of "20." Numerical ranges include numbers that define the range. In general, the term "about" refers to the variable value shown and all variable values within the experimental error of the shown value (e.g., for the mean value, within a 95% confidence interval) or ±10% of the shown value, whichever is greater.

[0050] The invention will now be described by the following examples, which do not limit the invention in any way.All citations and references mentioned herein are incorporated by reference in their entirety.

[0051] abbreviation

[0052] DMA dimethylacetamide

[0053] DMSO dimethyl sulfoxide

[0054] EtOAcEthyl acetate

[0055] EtOH

[0056] MeCNAcetonitrile

[0057] MeOH

[0058] MIBK methyl isobutyl ketone

[0059] MTBE methyl tert-butyl ether

[0060] RH relative humidity

[0061] THF Tetrahydrofuran

[0062] Experimental methods

[0063] General approach

[0064] The results were obtained on a Bruker 400 MHz instrument at 25 °C and with reference to the deuterated solvent used: DMSO-d6 ( 2.50 ppm) of residual protic solvent, record 1H-NMR spectrum.

[0065] Analytical HPLC-MS detection was performed using an Agilent 1100 series liquid chromatograph / mass selective detector (MSD) (single quadrupole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed using an ACE 3C8 (3.0 x 50 mm) column with a gradient of acetonitrile in 0.1% TFA in water over 3 minutes at a flow rate of 1 mL / min.

[0066] Unless otherwise stated, all solvents were dried by adding molecular sieves before preparing solutions.

[0067] X-ray powder diffraction (XRPD) analysis

[0068] The analysis was performed using a Cu anode (45 kV, 40 mA), a K -1 Johansson monochromator (1.54060 ) and PanAlytical of Pixcel detectors The diffractometer was used. The 2θ range was 2–35°, with a scan speed of 0.03° or 0.10° / s and a step size of 0.013°. A slowly rotating sample holder was used. The sample was smeared onto a zero-background Si wafer to create a flat powder surface. Measurements were performed using a programmable incident divergence slit.

[0069] It is known in the art that, depending on the measurement conditions (such as the equipment, sample preparation or the machine used), the obtained X-ray powder diffraction pattern may have one or more measurement errors. Specifically, it is generally known that, depending on the measurement conditions and sample preparation, the intensity of the XRPD pattern may fluctuate. For example, those skilled in the art of XRPD will understand that the relative intensity of the peaks may vary depending on the orientation of the sample during the test and the type and setting of the instrument used. Those skilled in the art will also understand that the position of the reflections may be affected by the exact height at which the sample is positioned in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Therefore, those skilled in the art will appreciate that the diffraction patterns presented herein should not be interpreted as absolute, and any crystalline form that provides a powder diffraction pattern substantially identical to the powder diffraction pattern disclosed herein falls within the scope of the present disclosure (for further information, see R. Jenkins and RL Snyder, "Introduction to X-ray powder diffractometry", John Wiley & Sons, 1996).

[0070] Thermogravimetric analysis (TGA)

[0071] Analyses were performed using a PerkinElmer TGA7 instrument. Several milligrams of sample were gently placed in an open platinum pan and gravimetric analysis was performed under a dry nitrogen flow (20 ml / min) to ensure an inert atmosphere. The sample was scanned from 25°C to 200°C at a continuous scan rate of 10°C / min. Weight loss was calculated from 25°C to 145°C.

[0072] Differential Scanning Calorimetry (DSC)

[0073] The analysis was performed on a Netzsch DSC 204F1 instrument. A few milligrams of sample were gently placed in an aluminum pan and weighed. A lid with a pre-formed pinhole was fitted and crimped onto the pan. Conventional DSC analysis was performed with a heating rate of 10°C / min. The minimum temperature (start) was 0°C, and the maximum temperature was 250°C.

[0074] Dynamic Vapor Sorption (DVS)

[0075] The analysis was performed on an SMS DVS 1 instrument. Several milligrams of material were placed in an aluminum pan and exposed to a RH step change of 20-80-0-90-0% in two consecutive cycles in 10% RH steps in open-loop mode. The experiment was conducted at 25°C with a gas flow rate of 200 mL / min. The applied dm / dt criterion was 0.001 wt-% / min, and the maximum allowed time for all steps within a 5-minute window was 360 minutes, with a minimum allowed time of 10 minutes. Example

[0076] Example 1

[0077] Preparation of Linarasen Glutarate Maleate

[0078] Linarasen glutarate (0.500 g, 1.04 mmol) and maleic acid (121 mg, 1.04 mmol) were suspended in 2-propanol (20 mL) and water (2 mL). The resulting mixture was heated to 80 °C to completely dissolve. After removing the mixture from heat, it was concentrated under reduced pressure to obtain a colorless solid product. Yield: 94% (0.586 g; colorless glass); purity determined by LCMS was 100%.

[0079] 1H NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 8.82 (s, 1H), 8.28 (s,1H), 7.35-7.02 (m, 3H), 6.11 (s, 2H), 5.82 (s, 1H), 4.41 (d, J = 4.1 MS: (ESI+) m / z 481 (M+H).

[0080] Example 2

[0081] Polymorph screening

[0082] Polymorph screening of the maleate salt of linarasen glutarate was performed to determine its solubility, polymorphic form, and thermodynamic stability.

[0083] X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) indicated that the drug used for screening was Form 1. Prior to crystallization experiments, the solubility of the drug in 25 solvents was determined. The solubility of the maleate salt in these solvents was found to be either less than 1 mg / mL or greater than 50 mg / mL.

[0084] Serum experiment:

[0085] Slurry experiments were conducted in various solvents. Sample slurry times varied depending on temperature. In the absence of solvents with moderate solubility (approximately 20 to 30 mg / mL), many slurry experiments were either performed at 40°C or with the addition of small amounts of DMA as a cosolvent to increase solubility and thus enhance the transition between solid and dissolved powder. Some experiments were also attempted at 60°C using solvents with very low solubility at room temperature. Aqueous slurry experiments were performed to investigate possible hydrate formation.

[0086] Details of all slurry experiments performed, including solvents used, total concentrations, and final form for XRPD analysis, are listed in Table 1 .

[0087] Unless otherwise noted, each experiment used approximately 30 mg of linarasen glutarate maleate and was conducted using 20 different solvents (pure and binary) at room temperature, 4°C, 40°C, and 60°C. All solvents were dried by adding molecular sieves before slurry preparation. The solid phase was separated and analyzed by XRPD. Table 1 summarizes the slurry experiments and indicates which solid form was obtained. Samples run at refrigerator temperature (approximately 4°C) were analyzed 26 and 53 days after slurry formation. Samples run at room temperature were analyzed 26 days after slurry formation. Samples run at 40°C were analyzed 6 and 12 days after slurry formation. Samples run at 60°C were analyzed 1 day after slurry formation.

[0088] Table 1. Results of slurry experiments at room temperature, analyzed after 26 days

[0089]

[0090] *Analysis also performed after 53 days

[0091] **Analysis performed after 21 days

[0092] Evaporation experiment:

[0093] Experiments were conducted in four solvents under high vapor pressure. Linarasen glutarate maleate had low solubility in all selected solvents. For each sample, 10–30 mg of the drug was suspended at room temperature to obtain a saturated solution phase. The solution was then filtered to remove any solid material and allowed to evaporate slowly over several days. The isolated solid was analyzed by XRPD, and the results are shown in Table 2. Evaporation experiments were performed at room temperature.

[0094] Table 2. Evaporation test results

[0095]

[0096] * Very small samples

[0097] Antisolvent crystallization experiments

[0098] Crystallization was performed using two solvents with high solubility for linarasen glutarate maleate and five antisolvents with low solubility. Stock solvent solutions were prepared with an estimated concentration of 100 mg / mL. In the forward sequence experiments, 100 µL aliquots of the antisolvent were added to 200 µL of each solution until precipitation occurred, after which the antisolvent was added to 1 mL. Reverse sequence experiments were performed by immediately adding 200 µL of the drug solution to 4 mL of the antisolvent. The isolated solid was analyzed by XRPD. The results are shown in Table 3 (reverse sequence) and Table 4 (forward sequence).

[0099] Table 3. Antisolvent crystallization results using "reverse order" addition

[0100]

[0101] Table 4. Antisolvent crystallization results using forward addition

[0102]

[0103] *Converted to Form 1 + Base Form 1 after 9 days.

[0104] Cooling experiment

[0105] Cooling experiments were conducted in 19 different solvents. Due to the low solubility of linarasen glutarate maleate in several common solvents, the saturation temperature was set at 70°C to increase the solution concentration. Approximately 5, 10, or 25 mg of solid sample was suspended in 4 mL of the selected solvent. The vial was heated to 70°C for at least 30 minutes, and in some experiments, a small aliquot of DMA was added to dissolve more powder. The sample was then filtered to remove any solid material. The resulting clear solution was placed in a refrigerator at 2–8°C. If no precipitation was observed after 20–27 days, or minimal powder formation occurred, the sample was placed in a freezer at -17 to -23°C.

[0106] Any precipitated solid phase was separated by vacuum filtration and analyzed by XRPD. The results are listed in Table 5.

[0107] Table 5. Cooling test results

[0108]

[0109] *Amount too small to be analyzed by XRPD

[0110] ** After several days of freezer storage

[0111] The XRPD peaks of Form 1 synthesized as described in Example 1 are listed in Table 6 below. Figure 1 shown.

[0112] Table 6. XRPD Peaks of Form 1

[0113]

[0114] *Relative intensity depends on particle orientation, grain size / shape, strain and sample thickness

[0115] The different solvates involved in the above experiments were considered not to be pharmaceutically viable and are therefore not described further.

[0116] Example 3

[0117] Thermogravimetric analysis

[0118] The Form 1 sample obtained according to the synthesis method of Example 1 showed a weight loss of 0.17% when heated to 145°C. This confirms that Form 1 is anhydrous. The TGA weight loss curve of Form 1 is as follows: Figure 2 shown.

[0119] Example 4

[0120] Differential Scanning Calorimetry (DSC) Analysis

[0121] The Form 1 sample (obtained by the synthesis method described in Example 1) exhibited an endothermic event at approximately 163°C with an onset temperature of approximately 159°C. The DSC thermogram of Form 1 is shown in FIG. Figure 3 shown.

[0122] Example 5

[0123] Gravimetric Vapor Sorption (GVS) Analysis

[0124] The hygroscopicity of Form 1 (obtained from the synthesis described in Example 1 below) was studied using GVS at 25°C. The weight change plots and adsorption isotherm plots ( Figure 4A and 4B ) showed a water absorption of only about 0.4% in the range of 0 to 80% relative humidity. Therefore, Form 1 can be classified as slightly hygroscopic.

Claims

1. Crystalline linarasen glutarate maleate.

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

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

4. The crystalline linarasen glutarate maleate according to any one of the preceding claims, having an XRPD pattern obtained using CuKα1-radiation having at least two peaks at °2θ values selected from the group consisting of 5.4±0.2, 9.6±0.2, 12.1±0.2, 16.3±0.2, 17.4±0.2, 19.0±0.2, 20.2±0.2, 22.5±0.2, 23.2±0.2 and 26.0±0.

2.

5. Crystalline linarasen glutarate maleate according to any one of the preceding claims, having an XRPD pattern obtained using CuK α-radiation, the XRPD pattern having peaks at at least the following °2θ values: 9.6±0.2, 17.4±0.2, 20.2±0.2 and 26.0±0.

2.

6. The crystalline linarasen glutarate maleate according to any one of the preceding claims, having an XRPD pattern obtained using CuK α-radiation, the XRPD pattern having peaks at at least the following °2θ values: 5.4±0.2, 9.6±0.2, 17.4±0.2, 19.0±0.2, 20.2±0.2, 23.2±0.2 and 26.0±0.

2.

7. Crystalline linarasen glutarate maleate according to any one of the preceding claims having an XRPD pattern substantially as shown in Figure 1, obtained using CuKα-radiation.

8. The crystalline linarasen glutarate maleate according to any one of the preceding claims, having a DSC curve comprising an endotherm at about 159°C to about 169°C, such as about 163°C.

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

10. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline linarasen glutarate maleate according to any one of the preceding claims, and one or more pharmaceutically acceptable excipients.

11. Crystalline linarasen glutarate maleate according to any one of claims 1 to 9 for use in therapy.

12. The crystalline linarasen glutarate maleate according to any one of claims 1 to 9, for use in treating or preventing gastrointestinal inflammatory diseases or gastric acid-related diseases.

13. The crystalline linarasen glutarate maleate for use according to claim 12, wherein the gastrointestinal inflammatory disease or gastric acid-related disease is gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), Helicobacter pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcer and duodenal ulcer), bleeding gastric ulcer, gastroesophageal reflux disease symptoms (including heartburn, regurgitation and nausea), gastrinoma or acute upper gastrointestinal bleeding.

14. The crystalline linarasen glutarate maleate for use according to claim 12, wherein the gastrointestinal inflammatory disease or gastric acid-related disease is erosive gastroesophageal reflux disease (eGERD).

Images