Polymorphs of metoprolol and its salts

Abstract

This invention relates to polymorphs of metoprolol and its salts. Crystal forms and combinations thereof of the free base of metoprolol selected from polymorphs A, B, C, D, E, F, and G are disclosed, as well as crystalline polymorphs of salts of metoprolol. Pharmaceutical compositions containing one or more of these polymorphs and methods for preparing such polymorphs are also disclosed. Metoprolol can be used to treat a variety of diseases associated with low intracellular BH4 levels, such as phenylketonuria.

Description

[0001] This application is a divisional application of PCT / US2017 / 063517, entitled “Polymorphs of metoprolol and its salts”, filed on November 28, 2017. The original application entered the Chinese national phase and was granted the national application number 201780084821.X.

[0002] This application claims the benefit and priority of U.S. Patent Application No. 62 / 427,686, filed November 29, 2016, and U.S. Patent Application No. 62 / 546,390, filed August 16, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to polymorphs of metoprolol and its salts. Background of the Invention

[0004] Metoprolol is a naturally occurring precursor of tetrahydrobiopterin (BH4), an essential cofactor for key intracellular enzymes, including but not limited to phenylalanine hydroxylase (PAH) (Kaufman, 1958), tyrosine hydroxylase (TH) (Nagatsu et al., 1964), tryptophan hydroxylase (TPH) (Ichiyama et al., 1970), nitric oxide synthase (NOS) (Kwon et al., 1989), (Mayer et al., 1991), and alkylglycerol monooxygenase (AGMO) (Tietz et al., 1964). The rapid conversion of metoprolol, which facilitates BH4 accumulation, to BH4 occurs via a two-step reduction in the salvage pathway of BH4 synthesis (Sawabe, 2008). Synthetic forms of BH4 (e.g., sapropterin hydrochloride) are used as therapeutic agents for diseases associated with high plasma phenylalanine levels, such as phenylketonuria (PKU). PKU is a congenital metabolic disorder primarily caused by mutations in the PAH gene. BH4 has also been tested as a therapeutic agent for various central nervous system symptoms associated with PKU and other diseases, but has shown limited efficacy, presumably because BH4 cannot effectively cross the blood-brain barrier (Klaiman et al., 2013; Grant et al., 2015).

[0005] Recent studies have shown that peripherally administered metoprolol has greater transmembrane permeability than BH4, and therefore can more easily enter liver, kidney, and brain cells. It has been reported that metoprolol is rapidly converted to BH4 intracellularly via the tetrahydrobiopterin-rescue pathway, thereby increasing BH4 levels in the liver, kidneys, and brain (Sawabe, 2008). Therefore, metoprolol could be used as a useful therapeutic agent for diseases associated with low intracellular BH4 levels or dysfunction of various BH4-dependent metabolic pathways.

[0006] In this paper, metoprolol is the S-enantiomer and has formula (I):

[0007]

[0008] Graphoprene is known to have limited stability in solution. Furthermore, certain forms of solid graphoprene degrade under oxidizing conditions, even at room temperature, and in the presence of light. Therefore, there is an unmet need for a stable solid form of graphoprene. Summary of the Invention

[0009] The present invention provides a solid form of maltodextrin free base, wherein the solid form includes an amorphous form of maltodextrin free base, a single polymorph of maltodextrin free base, a mixture of polymorphs of maltodextrin free base, a salt of maltodextrin or a mixture of maltodextrin salts, or a combination thereof, provided that the solid form is not a pure polymorph of maltodextrin free base of form A or form E.

[0010] The present invention also provides crystalline polymorphic forms of salts of metoprolol, or mixtures thereof. For example, the present invention provides crystalline polymorphic forms of metoprolol hydrochloride.

[0011] It has now been unexpectedly discovered that, under certain conditions, new crystalline forms of maltodextrin free base and its acid salt are formed, which possess advantageous applications and properties. Therefore, this invention provides a method for preparing various polymorphs.

[0012] The present invention also provides pharmaceutical compositions comprising one or more of these polymorphs.

[0013] In one aspect, the invention is characterized by a crystal form of maloptera, which, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) of 8.4°±0.5, 16.9°±0.5, or 25.4°±0.5. In some embodiments, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, the crystal form of maloptera has at least one peak at a diffraction angle 2θ (°) of 8.4°±0.5, 16.9°±0.5, and 25.4°±0.5. In some embodiments, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, the crystal form of maloptera has at least one peak at a diffraction angle 2θ (°) of 14.9°±0.5 or 34.1°±0.5. In some embodiments, such as by X-ray diffraction determination or calculation using Cu Kα X-ray irradiation, the crystal form of mepothalamic acid has at least one peak at diffraction angles 2θ (°) at 8.4°±0.5, 14.9°±0.5, 16.9°±0.5, 25.4°±0.5, and 34.1°±0.5.

[0014] In some implementations, the crystal form of metoprolol has the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is illustrated. In some embodiments, the crystal form of mepoteroin begins to absorb heat at approximately 195°C in differential scanning calorimetry (DSC) curves.

[0015] In one aspect, the invention is characterized by a crystal form of metoprolol that, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) of 5.7°±0.5, 7.8°±0.5, or 25.4°±0.5. In some embodiments, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, the crystal form of metoprolol has at least one peak at a diffraction angle 2θ (°) of 5.7°±0.5, 7.8°±0.5, and 25.4°±0.5. In some embodiments, such as by X-ray diffraction determination or calculation using Cu Kα X-ray irradiation, the crystal form of mepothalamic acid has at least one peak at a diffraction angle 2θ (°) of 9.1°±0.5, 11.5°±0.5, 15.3°±0.5, 16.0°±0.5, 20.1°±0.5, or 26.6°±0.5. In some embodiments, such as by X-ray diffraction determination or calculation using Cu Kα X-ray irradiation, the crystal form of mepothalamic acid has at least one peak at diffraction angles 2θ (°) at diffraction angles of 5.7°±0.5, 7.8°±0.5, 9.1°±0.5, 11.5°±0.5, 15.3°±0.5, 16.0°±0.5, 20.1°±0.5, 25.4°±0.5, and 26.6°±0.5.

[0016] In some implementations, the crystal form of metoprolol has the following characteristics: Figure 2 The X-ray powder diffraction pattern is shown. In some embodiments, the crystalline form of metoprolol begins to absorb heat at approximately 58°C, 102°C, 130°C, 156.5°C, or 168°C in differential scanning calorimetry (DSC) curves. In some embodiments, the crystalline form of metoprolol begins to absorb heat at approximately 58°C, 102°C, 130°C, 156.5°C, and 168°C in differential scanning calorimetry (DSC) curves.

[0017] In one aspect, the invention is characterized by a crystal form of metoprolol that, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) of 8.9°±0.5, 10.3°±0.5, or 26.0°±0.5. In some embodiments, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, the crystal form of metoprolol has at least one peak at a diffraction angle 2θ (°) of 8.9°±0.5, 10.3°±0.5, and 26.0°±0.5. In some embodiments, such as by X-ray diffraction determination or calculation using Cu Kα X-ray irradiation, the crystal form of mepothalamic acid has at least one peak at a diffraction angle 2θ (°) of 10.9°±0.5, 17.8°±0.5, 24.9°±0.5, 26.7°±0.5, 26.8°±0.5 or 28.3°±0.5. In some embodiments, such as by X-ray diffraction determination or calculation using Cu Kα X-ray irradiation, the crystal form of mepothalamic acid has at least one peak at diffraction angles 2θ (°) at 8.9°±0.5, 10.3°±0.5, 10.9°±0.5, 17.8°±0.5, 24.9°±0.5, 26.0°±0.5, 26.7°±0.5, 26.8°±0.5, and 28.3°±0.5.

[0018] In some implementations, the crystal form of metoprolol has the following characteristics: Figure 3 The X-ray powder diffraction pattern is shown. In some embodiments, the crystalline form of maltodextrin begins to absorb heat at approximately 43°C, 66°C, or 233°C in differential scanning calorimetry (DSC) curves. In some embodiments, the crystalline form of maltodextrin begins to absorb heat at approximately 43°C, 66°C, and 233°C in differential scanning calorimetry (DSC) curves.

[0019] In one aspect, the invention is characterized by a crystal form of metoprolol that, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) of 9.7°±0.5, 10.2°±0.5, or 11.3°±0.5. In some embodiments, as determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, the crystal form of metoprolol has at least one peak at a diffraction angle 2θ (°) of 9.7°±0.5, 10.2°±0.5, and 11.3°±0.5. In some embodiments, such as by X-ray diffraction determination or calculation using Cu Kα X-ray irradiation, the crystal form of mepothalamic acid has at least one peak at a diffraction angle 2θ (°) of 14.0°±0.5, 14.6°±0.5, 19.9°±0.5, 22.2°±0.5, 25.3°±0.5 or 32.4°±0.5. In some embodiments, such as by X-ray diffraction determination or calculation using Cu Kα X-ray irradiation, the crystal form of mepothalamic acid has at least one peak at diffraction angles 2θ (°) at diffraction angles of 9.7°±0.5, 10.2°±0.5, 11.3°±0.5, 14.0°±0.5, 14.6°±0.5, 19.9°±0.5, 22.2°±0.5, 25.3°±0.5, and 32.4°±0.5.

[0020] In some implementations, the crystal form of metoprolol has the following characteristics: Figure 4 The X-ray powder diffraction pattern is shown. In some embodiments, the crystalline form of metoprolol begins to absorb heat at approximately 113°C or 196°C in differential scanning calorimetry (DSC) curves. In some embodiments, the crystalline form of metoprolol begins to absorb heat at approximately 113°C and 196°C in differential scanning calorimetry (DSC) curves.

[0021] In one aspect, the invention is characterized by a composition comprising any of the aforementioned crystalline forms of metoprolol or combinations thereof. In some embodiments of the composition, the crystalline form of metoprolol of any one of claims 1 to 27 is present in an amount of at least 90% by weight of the composition.

[0022] In one aspect, the invention is characterized by pharmaceutical compositions comprising any of the aforementioned metoprolol crystal forms. In some embodiments, the metoprolol crystal form is formulated as particles with a size between 50 μm and 250 μm (e.g., less than 100 μm).

[0023] In one aspect, the present invention is characterized by a method for preparing crystalline forms of metoprolol, comprising preparing a slurry of a first crystalline form of metoprolol in water, acetone / water, isopropanol / isopropyl acetate, or tetrahydrofuran / n-hexane, separating a solid from the slurry, and drying the solid. In some embodiments, the slurry of the first crystalline form of metoprolol is stirred at 25-75°C for 6-72 hours. In some embodiments, the solid is dried at 20-30°C for 6-24 hours. In some embodiments, the solid is dried at 40-60°C for 5-10 hours. In some embodiments, the solid is dried at atmospheric pressure. In some embodiments, the solid is dried under vacuum.

[0024] In one aspect, the invention is characterized by salts of metoprolol. In some embodiments, the metoprolol salt is a methanesulfonate, nicotinate, p-toluenesulfonate, benzenesulfonate, phosphate, malonate, tartrate, gentianate, fumarate, glycolate, acetate, sulfate, or hydrochloride.

[0025] In one aspect, the present invention is characterized by the crystal form of a maltodextrin salt, wherein the crystal form of the maltodextrin salt is:

[0026] (a) The crystal form of metoprolol methanesulfonate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 7.8°±0.5, 23.5°±0.5 and / or 29.0°±0.5.

[0027] (b) The crystal form of metoprolol methanesulfonate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 21.7°±0.5, 26.0°±0.5 and / or 28.9°±0.5.

[0028] (c) The crystal form of metoprolol nicotinate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) of 9.5°±0.5, 9.9°±0.5 and / or 24.5°±0.5.

[0029] (d) The crystal form of metoprolol p-toluenesulfonate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 6.5°±0.5, 15.1°±0.5 and / or 23.4°±0.5.

[0030] (e) The crystal form of metoprolol benzenesulfonate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) of 6.5°±0.5, 14.8°±0.5 and / or 19.6°±0.5.

[0031] (f) The crystal form of metoprolol phosphate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 16.6°±0.5, 22.2°±0.5 and / or 25.6°±0.5.

[0032] (g) The crystal form of metoprolol malonate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 6.9°±0.5, 22.7°±0.5 and / or 23.8°±0.5.

[0033] (h) The crystal form of metoprolol tartrate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 7.3°±0.5, 14.2°±0.5 and / or 21.8°±0.5.

[0034] (i) The crystal form of metoprolol gentianate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 7.1°±0.5, 8.7°±0.5 and / or 26.7°±0.5.

[0035] (j) The crystal form of metoprolol fumarate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 11.3°±0.5, 24.0°±0.5 and / or 28.2°±0.5.

[0036] (k) The crystal form of metoprolol glycolate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 7.6°±0.5, 10.7°±0.5 and / or 24.0°±0.5.

[0037] (l) The crystal form of metoprolol acetate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 6.2°±0.5, 12.0°±0.5 and / or 18.1°±0.5.

[0038] (m) The crystal form of metoprolol sulfate, determined by X-ray diffraction using Cu Kα X-ray irradiation or calculated by X-ray diffraction, has at least one peak at diffraction angles 2θ (°) at 5.1°±0.5, 7.8°±0.5, and / or 23.0°±0.5; or

[0039] (n) The crystal form of metoprolol sulfate, as determined by X-ray diffraction by irradiation with Cu Kα X-rays or calculated by X-ray diffraction, has at least one peak at a diffraction angle 2θ (°) at 7.8°±0.5, 8.8°±0.5 and / or 24.1°±0.5.

[0040] In one aspect, the invention is characterized by the crystal form of metoprolol hydrochloride, which, as determined by X-ray diffraction or calculated by X-ray diffraction after irradiation with Cu Kα X-rays, has at least one peak at a diffraction angle 2θ (°) at 7.8°±0.5, 12.9°±0.5 and / or 26.2°±0.5.

[0041] In one aspect, the invention is characterized by compositions comprising any of the aforementioned crystalline forms of a metoprolol salt. In some embodiments, the crystalline form of the metoprolol salt is present in at least 90% by weight.

[0042] In one aspect, the present invention is characterized by a pharmaceutical composition comprising a crystalline form of any of the aforementioned metoprolol salts and a pharmaceutically acceptable carrier. In some embodiments, the crystalline form of metoprolol is formulated into particles with a size of less than 100 μm.

[0043] On another aspect, the present invention is characterized by a method for treating BH4-related disorders in patients requiring it, the method comprising administering to the patient an effective amount of any of the aforementioned metoprolol crystalline forms or pharmaceutical compositions. In some embodiments, BH4-related disorders are diseases associated with low intracellular BH4 levels or with dysfunction of various BH4-dependent metabolic pathways, including but not limited to primary tetrahydrobiopterin deficiency, GTPCH deficiency, 6-pyruvyl-tetrahydropterin synthase (PTPS) deficiency, DHPR deficiency, metoprolol reductase deficiency, dopamine-responsive dystonia, Segawa syndrome, tyrosine hydroxylase deficiency, phenylketonuria, DNAJC12 deficiency, Parkinson's disease, etc. Depression caused by Parkinson's disease, impulsive behavior in Parkinson's patients, major depressive disorder, autism spectrum disorder, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety disorder, aggressive behavior in Alzheimer's disease, cerebrovascular disease, gastroparesis, post-subarachnoid hemorrhage spasm, myocarditis, coronary artery spasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infectious diseases, endotoxic shock, cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, and hypoglycemia. Therefore, various forms of metoprolol according to the invention can be administered to patients in effective amounts to achieve treatment or improvement of disease or functional disorders.

[0044] In another aspect, the present invention is characterized by a method for increasing BH4, serotonin, and / or dopamine levels (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 1000%, or more) in a subject in need, said method comprising administering to the patient an effective amount of any of the aforementioned metoprolol crystalline form or pharmaceutical composition.

[0045] In another aspect, the invention is characterized by a method for reducing phenylalanine levels (e.g., at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 1000% or more) in a subject in need, said method comprising administering to the patient an effective amount of any of the aforementioned metoprolol crystalline form or pharmaceutical composition.

[0046] In another aspect, the present invention is characterized by a method for increasing the activity of phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, nitric oxide synthase and / or alkylglycerol monooxygenase in a subject (e.g., at least 55%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 1000% or more), said method comprising administering to the patient an effective amount of any of the aforementioned metoprolol crystalline form or pharmaceutical composition.

[0047] In another aspect, the present invention is characterized by a method for treating phenylketonuria in a subject in need, the method comprising administering to the patient an effective amount of any of the aforementioned metoprolol crystalline form or pharmaceutical composition.

[0048] definition

[0049] In this application, unless the context otherwise clearly indicates, (i) the term “a” is to be understood as “at least one”; (ii) the term “or” is to be understood as “and / or”; (iii) the terms “comprising” and “including” are to be understood as encompassing the listed components or steps, whether appearing alone or together with one or more other components or steps; and (iv) as would be understood by one of ordinary skill in the art, the terms “about” and “approximately” are to be understood as allowing for standard deviation; and (v) when providing a range, endpoints are included.

[0050] As used herein, the term "administration" means giving a composition (e.g., a compound as described herein or a formulation containing a compound) to a subject or body. Administration to animal subjects (e.g., humans) may be performed via any suitable route. For example, in some embodiments, administration may be performed via the bronchus (including bronchial infusion), buccal, enteral, intradermal, intra-arterial, intradermal, gastric, intraspinal, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intravenous, intraventricular, mucosal, nasal, oral cavity, rectum, subcutaneous, sublingual, local, trachea (including intratracheal infusion), percutaneous, vaginal, and vitreous.

[0051] As used herein, the term “BH4-related condition” refers to any disease or condition from which therapeutic benefits can be derived from regulation (e.g., inhibition) of BH4 levels, such as phenylketonuria.

[0052] "Determining protein levels" means the direct or indirect detection of a protein or the mRNA encoding the protein by methods known in the art. "Direct determination" means obtaining a physical entity or value by performing a method (e.g., analysis or testing on a sample, or "analyzing the sample," as defined herein). "Indirect determination" means obtaining a physical entity or value from another party or source (e.g., a third-party laboratory that directly obtains the physical entity or value). Methods for determining protein levels generally include, but are not limited to, Western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemistry, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometrics, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as analyses based on protein properties (including, but not limited to, enzyme activity or interactions with other protein chaperones). Methods for determining mRNA levels are known in the art.

[0053] The "effective amount" of a compound can vary depending on factors such as disease state, individual age, sex, weight, and the compound's ability to induce the desired response. A therapeutically effective amount includes the amount in which the compound's therapeutically beneficial effect outweighs any toxic or harmful effects. A therapeutically effective amount also includes an amount sufficient to impart benefit, such as clinical benefit.

[0054] "Increasing phenylalanine hydroxylase activity" means increasing the activity level associated with phenylalanine hydroxylase or its related downstream effects. A non-limiting example of increasing phenylalanine hydroxylase activity is decreasing phenylalanine levels. The activity level of phenylalanine hydroxylase can be determined using any method known in the art.

[0055] “Level” refers to the level of a protein or the mRNA encoding the protein compared to a reference. As defined herein, a reference can be any available reference. A “reduced level” or “increased level” of a protein means a decrease or increase in the protein level compared to a reference (e.g., a decrease or increase of approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, or more; greater than approximately 10% compared to a reference). A decrease or increase of approximately 15%, 20%, 50%, 75%, 100%, or 200%; less than approximately 0.01, 0.02, 0.1, 0.3, 0.5, or 0.8 times or less; or greater than approximately 1.2, 1.4, 1.5, 1.8, 2.0, 3.0, 3.5, 4.5, 5.0, 10, 15, 20, 30, 40, 50, 100, or 1000 times or more. Protein levels can be expressed as mass / volume (e.g., g / dL, mg / mL, μg / mL, ng / mL) or as a percentage of total protein or mRNA in the sample.

[0056] As used herein, the term "pharmaceutical composition" means a composition comprising the compounds described herein formulated with pharmaceutically acceptable excipients and permitted by a government regulatory authority to be manufactured or sold as part of a treatment regimen for treating diseases in mammals. Pharmaceutical compositions may be formulated for oral administration, for example, in unit dosage forms (e.g., tablets, capsules, capsule-shaped tablets, soft gelatin capsules, suspensions, solutions, or syrups); for topical administration (e.g., as creams, gels, lotions, or ointments); for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use, without granule suppositories); or in any other pharmaceutically acceptable formulation.

[0057] As used herein, “pharmaceuticalally acceptable excipient” means any component that is different from the compounds described herein and has substantially non-toxic and non-inflammatory properties in patients (e.g., a carrier capable of suspending or dissolving the active compound). Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and hydrated water. Exemplary excipients include, but are not limited to: ascorbic acid, butylated hydroxytoluene (BHT), calcium carbonate, calcium (hydrogen) phosphate, calcium stearate, colloidal silica, croscarmellose, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, citric acid, croscarmellose, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0058] As used herein, the term "pharmaceuticalally acceptable salt" means any pharmaceutically acceptable salt of a compound of formula (I). For example, a pharmaceutically acceptable salt of any compound described herein includes those that, to a reasonable medical judgment, are suitable for use in tissue contact with humans and animals without excessive toxicity, irritation, anaphylactic reactions, and in proportion to a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (edited by P.H. Stahl and C. G. Germuth), Wiley-VCH, 2008. The salt may be prepared in situ during the final isolation and purification of the compound described herein or solely by reacting the free base group with a suitable organic acid.

[0059] The compounds of the present invention may have ionizable groups, thereby enabling their preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or, in the case of the acidic form of the compounds of the present invention, the salts may be prepared from inorganic or organic bases. Typically, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable methods for preparing pharmaceutically acceptable acids and bases and suitable salts are well known in the art. Salts may be prepared from pharmaceutically acceptable, non-toxic acids and bases (including inorganic and organic acids and bases).

[0060] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheponicate, glyceryl phosphate, hemisulfate, heptasulfate, hexanoate, hydrobromide, hydrochloride, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, barmonate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0061] “Reference” means any available reference for comparing protein or mRNA levels. This reference can be any sample, standard, standard curve, or level used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, such as a predetermined negative control value like a “normal control” or a prior sample obtained from the same subject; a sample from a normal healthy subject, such as normal cells or normal tissue; a sample (e.g., cells or tissue) from a subject without disease; a sample from a subject diagnosed with a disease but not yet treated with the compounds of the present invention; a sample from a subject treated with the compounds of the present invention; or a sample of purified protein at a known normal concentration (e.g., any of those described herein). “Reference standard or level” means a value or number obtained from a reference sample. A “normal control value” is a predetermined value indicating a non-disease state, for example, a value expected in healthy control subjects. Typically, normal control values ​​are expressed as a range (“between X and Y”), a high threshold (“not higher than X”), or a low threshold (“not lower than X”). Subjects whose measured values ​​for a specific biomarker are within the normal control range are generally referred to as being “within the normal limits” for that biomarker. The normal reference standard or level may be a value or number obtained from a healthy subject without a disease or condition (e.g., cancer); or a subject who has been treated with the compounds of the present invention. In a preferred embodiment, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of purified protein (e.g., any of those described herein) levels within the normal reference range may also be used as a reference.

[0062] As used herein, the terms "subject" or "patient" refer to any organism to which the compositions according to the invention may be administered, for example, for experimental, diagnostic, preventive, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). Subjects may be seeking or needing treatment, requesting treatment, currently receiving treatment, or in the future receiving treatment, or may be persons or animals cared for by persons professionally trained to address a particular disease or condition.

[0063] As used herein, the term "treat" (treated or treating) refers to both therapeutic and prophylactic measures aimed at preventing or slowing (alleviating) an undesirable physical condition, symptom, or disease, or achieving a favorable or desired clinical outcome. Favorable or desired clinical outcomes include, but are not limited to, the reduction of symptoms; a decrease in the severity of the condition, symptom, or disease; a stable (i.e., non-worsening) state of the condition, symptom, or disease; a delay in the onset or slowing of the progression of the condition, symptom, or disease; an improvement or ablation of the condition, symptom, or disease state (whether partial or complete), whether detectable or undetectable; an improvement in at least one measurable physical parameter (not necessarily identifiable by the patient); or an enhancement or improvement of the condition, symptom, or disease. Treatment includes inducing a clinically important response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival without treatment.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Methods and materials used in this disclosure are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples described are exemplary only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of conflict, this specification (including definitions) shall prevail.

[0065] The following description sets forth details of one or more embodiments of the invention. Other features, objects, and advantages of the invention will be apparent from the specification and claims. Brief description of the attached diagram

[0066] Figure 1 The X-ray diffraction pattern of crystal form B of the free base of metoprolol is shown.

[0067] Figure 2 The X-ray diffraction pattern of crystal form C of maltodextrin free base is shown.

[0068] Figure 3 The X-ray diffraction pattern of crystal form D of the free base of metoprolol is shown.

[0069] Figure 4 The X-ray diffraction pattern of crystal form F of maltodextrin free base is shown.

[0070] Figure 5 The X-ray diffraction pattern of crystal form G of the free base of metoprolol is shown.

[0071] Figure 6The X-ray diffraction pattern of morphopterin hydrochloride 1 shows the overlap of the X-ray diffraction pattern of the starting free morphopterin base used in the preparation of the hydrochloride.

[0072] Figure 7 The image shows the overlap of X-ray diffraction patterns of metoprolol in crystal form 1, crystal form 2, crystal form 3, and the starting free base of metoprolol used in the preparation of the methanesulfonates.

[0073] Figure 8 The X-ray diffraction patterns of the crystalline nicotinate of metoprolol, nicotinic acid, and the starting free base of metoprolol used in the preparation of the nicotinate are shown to overlap.

[0074] Figure 9 The X-ray diffraction patterns of the crystallized p-toluenesulfonate of metoprolol, p-toluenesulfonic acid, and the starting free base of metoprolol used in the preparation of the p-toluenesulfonate are shown to overlap.

[0075] Figure 10 The X-ray diffraction patterns of the crystalline benzenesulfonate of metoprolol, benzenesulfonic acid, and the starting free base of metoprolol used in the preparation of the benzenesulfonate are shown to overlap.

[0076] Figure 11 The X-ray diffraction patterns of the crystalline phosphate of metoprolol and the initial free base of metoprolol used in the preparation of the phosphate are shown to overlap.

[0077] Figure 12 The X-ray diffraction patterns of crystalline malonate of metoprolol, malonic acid, and the starting free base of metoprolol used in the preparation of the malonate are shown to overlap.

[0078] Figure 13 The X-ray diffraction patterns of the crystallized L-tartrate of metoprolol, L-tartaric acid, and the starting free base of metoprolol used in the preparation of the L-tartrate are shown as overlapping.

[0079] Figure 14 The X-ray diffraction patterns of crystalline gentianate of metoprolol, gentic acid, and the starting free base of metoprolol used in the preparation of the gentianate are shown to overlap.

[0080] Figure 15 The X-ray diffraction patterns of the crystalline fumarate of metoprolol, fumaric acid, and the starting free base of metoprolol used in the preparation of the fumarate are shown to overlap.

[0081] Figure 16 The image shows the overlap of X-ray diffraction patterns of crystalline glycolate of metoprolol, glycolic acid, and the starting free base of metoprolol used in the preparation of the glycolate.

[0082] Figure 17The X-ray diffraction patterns of the crystalline acetate of metoprolol and the initial free metoprolol base used in the preparation of the acetate are shown to overlap.

[0083] Figure 18 The X-ray diffraction patterns of maltodrine crystalline form 1 sulfate, maltodrine crystalline form 2 sulfate, and the initial free maltodrine base used in the preparation of the sulfates are shown as overlapping.

[0084] Figure 19 The X-ray diffraction patterns of the crystal form of metophine A before and after the grinding and sieving process are shown to overlap and confirm its stability to the physical form after grinding and sieving.

[0085] Figure 20 The superposition of X-ray diffraction patterns of the crystal form of metoprolol F before and after the grinding and sieving process is shown, confirming its stability to grinding and sieving.

[0086] Figure 21 The image shows the crystal form of metopterin form D before and after the grinding and sieving process, as well as the overlay of X-ray diffraction patterns of metopterin forms D and F as references. This figure illustrates the potential instability of form D to grinding and sieving.

[0087] Figure 22 The X-ray diffraction pattern of crystal form E of the free base of metoprolol is shown. Invention Details

[0089] The present invention provides a solid form of maltodextrin, wherein the solid form includes an amorphous form of maltodextrin, a crystalline polymorphic form, a mixture of amorphous and / or crystalline polymorphic forms, a salt or a combination thereof, provided that the solid form of maltodextrin is not a pure polymorphic form A and / or a pure polymorphic form E.

[0090] In one embodiment, in the solid form of metoprolol, the mixture comprises at least one of the crystalline polymorphs of metoprolol, namely B, C, D, F, and G.

[0091] In one embodiment, the solid form comprises at least one crystalline metoprolol free base selected from polymorphic forms B, C, D, F, and G and crystalline polymorph A or E, or both crystalline polymorphs A and E.

[0092] Polymorphs of the free base of maltodextrin and polymorphs of maltodextrin salts can be used to characterize solid-state materials using any suitable method. In one embodiment, the polymorphs are characterized by X-ray powder diffraction (XRD). XRD peak positions are represented as 2θ°. In the X-ray pattern, the refraction angle 2θ is plotted on the horizontal axis (x-axis) and the relative peak intensities (background-corrected peak intensities) are plotted on the vertical axis (y-axis). X-ray powder diffraction patterns are determined on an instrument equivalent to a PANalytical Empyrean X-ray powder diffractometer or using an instrument equivalent to a PANalytical Empyrean X-ray powder diffractometer equipped with a Cu Kα radiation source (Kα1 radiation, wavelength λ = 1.54060 Å, Kα2 radiation, wavelength 1.544426 Å; Kα2 / Kα1 intensity ratio: 0.50). The optical density of the peaks on the film is proportional to the optical intensity. A peak scanner is used to scan the film.

[0093] When it refers to any X-ray powder diffraction peak listed throughout the application, “about” means a 2θ value expressed in “degrees” of ±0.1, particularly ±0.05, and more particularly ±0.02.

[0094] In one embodiment, the crystalline polymorph B of mepoteroin is characterized by having a peak denoted as 2θ at least at about 8.4, about 16.9 and about 25.4° in the X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0095] In one particular embodiment, the crystalline polymorph B of mepoteroin is characterized by having a peak denoted as 2θ at at least about 8.4, about 14.9, about 16.9, about 25.4 and about 34.1° in the X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0096] In one embodiment, the crystalline polymorphic form C of metoprolol is characterized by having a peak denoted as 2θ at at least about 5.7, about 7.8 and about 25.4° in the X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0097] In one particular embodiment, the polymorphic form C of crystalline metoprolol is characterized by having a peak denoted as 2θ at at least about 5.7, about 7.8, about 9.1, about 11.5, about 15.3, about 16.0, about 20.1, about 25.4 and about 26.6° in an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0098] In one embodiment, the polymorphic form D of crystalline metoprolol is characterized by having a peak denoted as 2θ at at least about 8.9, about 10.3 and about 26.0° in an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0099] In one particular embodiment, the polymorphic form D of crystalline metoprolol is characterized by having a peak denoted as 2θ at at least about 8.9, about 10.3, about 10.9, about 17.8, about 24.9, about 26.0, about 26.7, about 26.8 and about 28.3° in an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0100] In one embodiment, the polymorphic form F of crystalline metoprolol is characterized by having a peak denoted as 2θ at at least about 9.7, about 10.2, and about 11.3° in the X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0101] In one particular embodiment, the polymorphic form F of crystalline metoprolol is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays, the pattern having a peak represented as 2θ at at least about 9.7, about 10.2, about 11.3, about 14.0, about 14.6, about 19.9, about 22.2, about 25.3 and about 32.4°.

[0102] In one embodiment, the polymorphic form G of crystalline metoprolol is characterized by having a peak denoted as 2θ at at least about 10.0, about 10.6 and about 25.7° in the X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0103] In one particular embodiment, the polymorphic form G of crystalline metoprolol is characterized by having a peak denoted as 2θ at at least about 10.0, about 10.6, about 11.2, about 15.3, about 15.9, about 22.8, about 24.4, about 25.0, about 25.7 and about 26.6° in the X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0104] In one embodiment, the solid form comprises at least one crystalline maltodextrin free base selected from polymorphs B, C, D, F, and G; at least one crystalline maltodextrin free base selected from polymorphs B, C, and D; at least one crystalline maltodextrin free base selected from polymorphs B, C, and F; at least one crystalline maltodextrin free base selected from polymorphs D, F, and G; and any binary, ternary, or quaternary combination of the polymorphs. The solid form may further comprise polymorphs A and / or E.

[0105] In one embodiment, the polymorphic forms B, C, D, or G, or combinations thereof, are present in the solid form in an amount of at least 90% by weight.

[0106] In some embodiments, the crystalline metoprolol free base is present at at least 70% by weight or more, at least 80% by weight or more, preferably at least 90% by weight or more, based on the weight of the metoprolol free base.

[0107] The crystal form A of metoprolol free base is characterized by having a peak denoted as 2θ at at least about 4.7°, about 7.4°, about 9.5°, about 11.3°, about 15.6°, about 26.2° and about 27.2° in the X-ray powder diffraction pattern obtained by Cu Kα X-ray irradiation.

[0108] Figure 19 The X-ray diffraction pattern of form A of maltodextrin free base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of 2θ of approximately 7.4°. Crystalline form A is characterized by 2θ peak positions at at least approximately 4.7°, approximately 7.4°, approximately 9.5°, approximately 11.3°, approximately 15.6°, approximately 26.2°, and approximately 27.2°. In substantially pure materials of maltodextrin free base in crystalline form A, peaks are observed at refraction angles of 2θ as listed in Table 1.

[0109] Table 1

[0110] Position [2θ°] relative strength 4.7 47.76 7.4 100.00 9.5 33.54 11.3 19.31 12.4 8.49 13.4 3.60 14.2 8.24 15.6 15.08 16.4 11.97 17.6 8.35 18.4 5.03 19.8 9.18 21.5 5.44 24.4 5.56 26.2 35.37 27.2 19.11 28.9 5.93

[0111] The characteristic of crystal form B of metoprolol free base is the peaks observed in the X-ray diffraction patterns at refraction angles of at least about 8.4, about 16.9 and about 25.4.

[0112] Figure 1 The X-ray diffraction pattern of crystalline form B of maltodextrin free base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of 2θ of approximately 8.4°. Crystalline form B is characterized by refraction at at least approximately 8.4°, approximately 14.9°, approximately 16.9°, approximately 25.4°, and approximately 34.1°. In substantially pure crystalline form B of maltodextrin free base, peaks are observed at refraction angles of 2θ as listed in Table 2.

[0113] Table 2

[0114] Position [2θ°] relative strength 8.4 100.00 14.9 2.34 16.9 10.70 25.4 84.90 34.1 3.00

[0115] The characteristic of crystal form C of metoprolol free base is the peaks observed in X-ray diffraction patterns at refraction angles of at least 5.7°, 7.8°, and 25.4°.

[0116] Figure 2The X-ray diffraction pattern of crystalline form C of maltodextrin free base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 7.8° 2θ. Crystalline form C is characterized by refraction at refraction angles of at least about 5.7°, about 7.8°, about 9.1°, about 11.5°, about 15.3°, about 16.0°, about 20.1°, about 25.4°, and about 26.6°. In substantially pure materials of maltodextrin free base form C, peaks are observed at refraction angles of 2θ as listed in Table 3.

[0117] Table 3

[0118]

[0119]

[0120] The characteristic of crystal form D of metoprolol free base is the peaks observed in the X-ray diffraction patterns at refraction angles of at least 2θ of about 8.9°, about 10.3° and about 26.0°.

[0121] Figure 3 The X-ray diffraction pattern of crystal form D of maltodextrin free base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 8.9° (2θ). Crystal form D is characterized by refraction at refraction angles of at least about 8.9°, about 10.3°, about 10.9°, about 17.8°, about 24.9°, about 26.0°, about 26.7°, about 26.8°, and about 28.3°. In substantially pure material of maltodextrin free base form D, peaks are observed at refraction angles of 2θ as listed in Table 4.

[0122] Table 4

[0123]

[0124]

[0125] The crystal form E of metoprolol free base is characterized by X-ray powder diffraction patterns obtained by irradiation with Cu Kα X-rays having peaks denoted as 2θ at at least about 6.0°, about 10.6°, about 12.1°, about 15.9°, about 20.8° and about 24.6°.

[0126] Figure 22X-ray diffraction patterns of maltodextrin free base in form E are shown. The strongest peaks in the X-ray diffraction patterns are observed at refraction angles of at least about 6.0° (2θ). Crystalline form E is characterized by refraction at refraction angles of at least about 6.0°, about 10.6°, about 12.1°, about 15.9°, about 20.9°, and about 24.6°. In substantially pure materials of maltodextrin free base in form E, peaks are observed at refraction angles of 2θ as listed in Table 5.

[0127] Table 5

[0128]

[0129]

[0130] The characteristic of the crystal form F of metoprolol free base is the peaks observed in the X-ray diffraction patterns at refraction angles of at least about 9.7°, about 10.2° and about 11.3°.

[0131] Figure 4 The X-ray diffraction pattern of the F form of free malopterin base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 10.2° 2θ. The F form is characterized by refraction at refraction angles of at least about 9.7°, about 10.2°, about 11.3°, about 14.0°, about 14.6°, about 19.9°, about 22.2°, about 25.3°, and about 32.4° 2θ. In the F form of substantially pure free malopterin base, peaks are observed at refraction angles of 2θ as listed in Table 6.

[0132] Table 6

[0133] Position [2θ°] relative strength 9.7 98.27 10.2 100.00 11.3 22.47 14.0 5.01 14.6 12.36 19.9 5.63 21.1 3.72 22.2 5.37 22.7 4.04 24.5 2.99 25.3 17.65 27.2 3.10 32.4 5.29 36.7 2.72

[0134] The crystal form G of metoprolol free base is characterized by peaks in the X-ray diffraction patterns observed at refraction angles of at least about 10.0°, about 10.6°, and about 25.7°.

[0135] Figure 5 The X-ray diffraction pattern of crystalline form G of maltodextrin free base obtained at 120 °C is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 10.0° (2θ). More broadly, the G-crystalline form is characterized by refraction at refraction angles of at least about 10.0°, about 10.6°, about 11.2°, about 15.3°, about 15.9°, about 22.8°, about 24.4°, about 25.0°, about 25.7°, and about 26.6°. In substantially pure materials of the G-crystalline form of maltodextrin free base, peaks are observed at refraction angles of at 2θ as listed in Table 7.

[0136] Table 7

[0137] Position [2θ°] relative strength 5.3 8.30 6.9 4.54 10.0 100.00 10.6 69.64 11.2 6.59 13.5 7.52 15.3 26.59 15.9 26.43 16.0 23.41 16.9 4.28 18.6 13.02 19.3 11.90 20.1 7.22 20.8 11.01 22.8 16.77 23.5 19.60 24.4 41.45 25.0 23.99 25.7 65.40 26.6 39.64 27.6 13.04 28.7 6.55 30.8 14.76 32.2 9.63 33.7 5.16 37.5 5.80

[0138] The description of crystal form A of the free base of maltodextrin is basically as follows: Figure 19 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 19 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0139] Alternatively, or further, the crystal form A of metoprolol free base is characterized by DSC curves showing endothermic peaks at 82.8 °C and 179.8 °C.

[0140] The description of crystal form B of the free base of maltodextrin is basically as follows: Figure 1 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 1 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0141] Alternatively, or further, the crystal form B of the free base of metoprolol is characterized by a DSC curve showing a melting event at 195.2 °C.

[0142] In the preferred embodiment, the essentially pure crystalline form B of the metoprolol free base shows... Figure 1 The X-ray diffraction pattern shown is shown in the image.

[0143] In another preferred embodiment, crystal form B of the free base of metoprolol shows... Figure 1 The X-ray diffraction pattern shown in the image has the following characteristics: the relative peak intensities of each peak are... Figure 1 The relative peak intensity deviation shown in the figure does not exceed 10%, especially when showing the difference between the peak intensity and the peak intensity. Figure 1 The X-ray diffraction pattern shown is the same as the one shown.

[0144] The description of the crystal form C of the free base of maltodextrin is basically as follows: Figure 2 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 2 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0145] Alternatively, the crystalline form C of the free base of metoprolol is characterized by a DSC curve showing five endothermic peaks at 58.3 °C, 101.8 °C, 129.8 °C, 156.5 °C, and 168.3 °C.

[0146] In a preferred embodiment, the essentially pure crystalline form of the free base of metoprolol (C1) shows... Figure 2 The X-ray diffraction pattern shown is shown in the image.

[0147] In another preferred embodiment, the crystal form C of the free base of maltodextrin shows... Figure 2 The X-ray diffraction pattern shown in the image has the following characteristics: the relative peak intensities of each peak are... Figure 2 The relative peak intensity deviation shown in the figure does not exceed 10%, especially when showing the difference between the peak intensity and the peak intensity. Figure 2 The X-ray diffraction pattern shown is the same as the one shown.

[0148] The crystal form D of the free base of maltodextrin is basically as described. Figure 3 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 3 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0149] Alternatively, the crystal form D of the free base of metoprolol is characterized by a DSC curve showing three endothermic peaks at 42.7 °C, 66.3 °C, and 232.9 °C.

[0150] In a preferred embodiment, the essentially pure morphopterin free base crystal form D shows... Figure 3 The X-ray diffraction pattern shown is shown in the image.

[0151] In another preferred embodiment, the crystal form D of the free base of maltodextrin shows... Figure 3 The X-ray diffraction pattern shown in the image has the following characteristics: the relative peak intensities of each peak are... Figure 3 The relative peak intensity deviation shown in the figure does not exceed 10%, especially when showing the difference between the peak intensity and the peak intensity. Figure 3 The X-ray diffraction pattern shown is the same as the one shown.

[0152] The crystal form E of the description of the free base of maltodextrin is basically as follows: Figure 22 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 22 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0153] Alternatively, the crystal form E of the metoprolol free base is characterized by a DSC curve showing two endothermic peaks at 112.9 °C and 195.8 °C.

[0154] The description of the crystal form F of the free base of maltodextrin is basically as follows: Figure 4 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 4 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0155] Alternatively, the crystal form F of the free base of metoprolol is characterized by a DSC curve showing two endothermic peaks at 71.6 °C and 233.4 °C.

[0156] In a preferred embodiment, the essentially pure crystalline form F of the metoprolol free base is shown. Figure 4 The X-ray diffraction pattern shown is shown in the image.

[0157] In another preferred embodiment, the crystal form F of the free base of maltodextrin shows... Figure 4 The X-ray diffraction pattern shown in the image has the following characteristics: the relative peak intensities of each peak are... Figure 4 The relative peak intensity deviation shown in the figure does not exceed 10%, especially when showing the difference between the peak intensity and the peak intensity. Figure 4 The X-ray diffraction pattern shown is the same as the one shown.

[0158] The crystal form G of the free base of maltodextrin is basically as described. Figure 5 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 5 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0159] In a preferred embodiment, the essentially pure crystalline form G of the metoprolol free base is displayed. Figure 5 The X-ray diffraction pattern shown is shown in the image.

[0160] In another preferred embodiment, the crystal form G of the free base of maltodextrin shows... Figure 5 The X-ray diffraction pattern shown in the image has the following characteristics: the relative peak intensities of each peak are... Figure 5 The relative peak intensity deviation shown in the figure does not exceed 10%, especially when showing the difference between the peak intensity and the peak intensity. Figure 5 The X-ray diffraction pattern shown is the same as the one shown.

[0161] The present invention also provides crystal forms of metoprolol hydrochloride.

[0162] In one embodiment, the crystalline hydrochloride is characterized by having a peak denoted as 2θ at at least about 7.8°, about 12.9° and about 26.2° in an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays.

[0163] The present invention also provides crystalline polymorphic forms of salts of metoprolol. In some embodiments, the present invention provides crystalline polymorphic forms of salts of metoprolol, wherein the salt is a salt of metoprolol with sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid, tartaric acid (e.g., L-tartaric acid), phosphoric acid, gentian acid, fumaric acid, glycolic acid, acetic acid, or nicotinic acid.

[0164] In a particular embodiment, the crystalline polymorph salt is selected from:

[0165] Crystalline 1 methanesulfonate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 7.8°, about 23.5° and about 29.0°;

[0166] Crystalline 2-methanesulfonate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 7.9°, about 23.4° and about 28.9°;

[0167] Crystalline 3-methanesulfonate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 21.7°, about 26.0° and about 28.9°;

[0168] Crystalline nicotinate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 9.5°, about 9.9° and about 24.5°;

[0169] Crystalline p-toluenesulfonate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 6.5°, about 15.1° and about 23.4°;

[0170] Crystalline benzenesulfonate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 6.5°, about 14.8° and about 19.6°;

[0171] Crystalline phosphate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 16.6°, about 22.2° and about 25.6°;

[0172] Crystalline malonate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 6.9°, about 22.7° and about 23.8°;

[0173] Crystalline tartrate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 7.3°, about 14.2° and about 21.8°;

[0174] Crystalline gentianate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 7.1°, about 8.7° and about 26.7°;

[0175] Crystalline fumarate, characterized by X-ray powder diffraction patterns obtained by Cu Kα X-ray irradiation having peaks represented as 2θ at approximately 11.3°, approximately 24.0°, and approximately 28.2°;

[0176] Crystalline glycolate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 7.6°, about 10.7° and about 24.0°;

[0177] Crystalline acetate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 6.2°, about 12.0° and about 18.1°;

[0178] Crystalline sulfate 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks represented as 2θ at at least about 5.1°, about 7.8°, and about 23.0°; and

[0179] Crystalline 2-sulfate, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu Kα X-rays having peaks denoted as 2θ at at least about 7.8°, about 8.8° and about 24.1°.

[0180] The crystalline hydrochloride of metoprolol free base is characterized by peaks in the X-ray diffraction pattern observed at diffraction angles 2θ at least 7.8°, 12.9° and 26.2°.

[0181] Figure 6 The X-ray diffraction pattern of the crystalline hydrochloride of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 7.8° 2θ. In substantially pure materials of the crystalline hydrochloride of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 8.

[0182] Table 8

[0183]

[0184]

[0185] The crystalline form of metoprolol free base, 1-methanesulfonate, is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 7.8°, 23.5°, and 29.0°.

[0186] Figure 17 The X-ray diffraction pattern of the crystalline form 1-methanesulfonate of maltodextrin free base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 23.5° 2θ. In substantially pure materials of the crystalline form 1-methanesulfonate of maltodextrin free base, peaks are observed at refraction angles of 2θ as listed in Table 9.

[0187] Table 9

[0188]

[0189]

[0190] The crystalline form of metoprolol free base, 2-methanesulfonate, is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 7.9°, 23.4°, and 28.9°.

[0191] Figure 7 The X-ray diffraction pattern of the crystalline 2-methanesulfonate of free metoprolol is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 23.5° (2θ). In substantially pure materials of the crystalline 2-methanesulfonate of free metoprolol, peaks are observed at refraction angles of 2θ as listed in Table 10.

[0192] Table 10

[0193] Position [2θ°] relative strength 7.9 100.00 11.0 21.32 12.1 22.02 13.5 79.87 15.7 11.87 17.8 9.81 19.7 10.93 21.3 26.79 23.4 96.13 24.1 24.88 24.3 22.10 25.5 9.45 26.0 11.27 27.6 7.63 28.9 95.64 31.2 4.39 36.1 6.65

[0194] The crystalline form of metoprolol 3-methanesulfonate is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 2θ, about 21.7°, about 26.0°, and about 28.9°.

[0195] Figure 7 The X-ray diffraction pattern of the crystalline 3-methanesulfonate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 26.0° (2θ). In substantially pure materials of the crystalline 3-methanesulfonate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 11.

[0196] Table 11

[0197] Position [2θ°] relative strength 8.2 47.29 10.8 56.14 12.6 16.34 13.2 15.90 14.0 24.39 15.0 12.03 15.9 16.20 18.2 22.97 20.1 25.53 20.5 14.97 21.3 22.70 21.7 71.48 22.2 11.40 23.6 46.37 24.8 44.00 25.5 9.08 26.1 100.00 27.3 3.52 28.9 68.42 31.2 4.49 32.1 6.48 34.8 5.95 35.6 1.67 39.1 2.91

[0198] The crystalline nicotinate salt of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 2θ of about 9.5°, about 9.9°, and about 24.5°.

[0199] Figure 8 The X-ray diffraction pattern of the crystalline nicotinate of free metoprolol is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least 24.5° (2θ). In substantially pure materials of the crystalline nicotinate of free metoprolol, peaks are observed at refraction angles of 2θ as listed in Table 12.

[0200] Table 12

[0201] Position [2θ°] relative strength 9.5 10.29 9.9 53.95 11.5 9.31 12.0 11.76 14.7 14.20 15.9 17.61 17.5 7.53 19.0 5.37 20.8 5.88 21.3 6.12 21.7 7.20 23.2 34.05 24.5 100.00 25.2 12.90 28.0 8.51 31.1 5.39 32.3 4.52 33.4 8.02 35.1 5.05

[0202] The crystalline p-toluenesulfonate of metopterin free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 6.5°, 15.1°, and 23.4°.

[0203] Figure 9 The X-ray diffraction pattern of the crystalline p-toluenesulfonate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 6.5° 2θ. In substantially pure materials of p-toluenesulfonate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 13.

[0204] Table 13

[0205]

[0206]

[0207] The crystalline benzenesulfonate of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 2θ of about 6.5°, about 14.8°, and about 19.6°.

[0208] Figure 10 The X-ray diffraction pattern of the crystalline benzenesulfonate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 6.5° 2θ. In substantially pure materials of the benzenesulfonate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 14.

[0209] Table 14

[0210]

[0211]

[0212] The crystalline phosphate of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 16.6°, 22.2°, and 25.6°.

[0213] Figure 11 The X-ray diffraction pattern of the crystalline phosphate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 25.6° (2θ). In substantially pure materials of the crystalline phosphate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 15.

[0214] Table 15

[0215] Position [2θ°] relative strength 5.5 4.41 8.1 1.21 8.9 2.21 10.3 1.79 10.8 5.80 15.3 1.84 16.6 8.35 17.7 1.95 20.3 1.40 21.2 1.61 22.2 9.77 23.1 1.74 25.6 100.00 30.8 6.31 31.1 4.85 33.5 0.73 36.0 1.70

[0216] The crystalline malonate of metoprolol free base is characterized by peaks in the X-ray diffraction pattern observed at refraction angles of at least 2θ of about 6.9°, about 22.7°, and about 23.8°.

[0217] Figure 12 The X-ray diffraction pattern of crystalline malonate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 6.9° 2θ. In substantially pure materials of crystalline malonate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 16.

[0218] Table 16

[0219] Position [2θ°] relative strength 6.9 100.00 8.4 13.11 10.6 7.62 16.4 5.63 17.8 9.73 19.3 8.96 20.1 9.99 22.2 10.50 22.7 20.52 23.8 34.02 24.5 5.82 25.5 24.50 26.6 4.00 27.3 6.96 29.8 5.38 33.1 12.08

[0220] The crystalline L-tartrate of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 7.3°, 14.2°, and 21.8°.

[0221] Figure 13 The X-ray diffraction pattern of crystalline L-tartrate of free metoprolol is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 6.9° 2θ. In substantially pure materials of crystalline L-tartrate of free metoprolol, peaks are observed at refraction angles of 2θ as listed in Table 17.

[0222] Table 17

[0223]

[0224]

[0225] The crystalline gentianate of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 7.1°, 8.7°, and 26.7°.

[0226] Figure 14 The X-ray diffraction pattern of crystalline gentianate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 7.1° 2θ. In substantially pure materials of crystalline gentianate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 18.

[0227] Table 18

[0228]

[0229]

[0230] The crystalline fumarate of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 11.3°, 24.0°, and 28.2°.

[0231] Figure 15 The X-ray diffraction pattern of the crystalline fumarate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 24.0° (2θ). In substantially pure materials of the crystalline fumarate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 19.

[0232] Table 19

[0233]

[0234]

[0235] The crystalline glycolate of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 7.6°, 10.7°, and 24.0°.

[0236] Figure 16 The X-ray diffraction pattern of the crystalline glycolate of maltodextrin free base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 7.6° 2θ. In substantially pure materials of the crystalline glycolate of maltodextrin free base, peaks are observed at refraction angles of 2θ as listed in Table 20.

[0237] Table 20

[0238] Position [2θ°] relative strength 4.8 6.23 7.6 100.00 10.3 68.06 10.7 70.69 15.3 36.51 18.2 24.25 18.7 27.26 19.9 2.66 21.2 17.11 24.0 96.62 24.4 18.44 28.8 47.57 30.3 7.43 32.5 4.42 33.3 7.49 34.3 5.21 36.3 7.37

[0239] The crystalline acetate of metoprolol free base is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 2θ of about 6.2°, about 12.0°, and about 18.1°.

[0240] Figure 17 The X-ray diffraction pattern of the crystalline acetate of maltodextrin free base is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 6.2° 2θ. In substantially pure materials of the crystalline acetate of maltodextrin free base, peaks are observed at refraction angles of 2θ as listed in Table 21.

[0241] Table 21

[0242] Position [2θ°] relative strength 6.2 100.00 10.2 23.29 12.0 71.59 18.1 31.27 21.1 20.29 24.2 14.92 25.2 23.03 27.3 13.30 29.1 12.95

[0243] The crystalline form of metoprolol free base, sulfate, is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 5.1°, 7.8°, and 23.0°.

[0244] Figure 18 The X-ray diffraction pattern of crystalline form 1 sulfate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 5.1° 2θ. In substantially pure materials of crystalline form 1 sulfate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 22.

[0245] Table 22

[0246]

[0247]

[0248] The crystalline form of metoprolol free base, 2-sulfate, is characterized by peaks in X-ray diffraction patterns observed at refraction angles of at least 7.8°, 8.8°, and 24.1°.

[0249] Figure 18 The X-ray diffraction pattern of the crystalline form 2-sulfate of free maltodextrin is shown. The highest intensity peak in the X-ray diffraction pattern is observed at a refraction angle of at least about 8.8° 2θ. In substantially pure materials of the crystalline form 2-sulfate of free maltodextrin, peaks are observed at refraction angles of 2θ as listed in Table 23.

[0250] Table 23

[0251]

[0252]

[0253] The description of the crystalline hydrochloride of maltodextrin free base is basically as follows: Figure 6 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 6 The main peaks depicted in the figure, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the figure, must exist.

[0254] Alternatively, the crystalline hydrochloride of metoprolol free base is characterized by a DSC curve showing an endothermic peak at 225.9 °C.

[0255] In a preferred embodiment, the crystalline hydrochloride of essentially pure metoprolol free base shows... Figure 6 The X-ray diffraction pattern shown is shown in the image.

[0256] In another preferred embodiment, the crystalline hydrochloride of the free base of maltodextrin shows... Figure 6 The X-ray diffraction pattern shown in the image has the following characteristics: the relative peak intensities of each peak are... Figure 6 The relative peak intensity deviation shown in the figure does not exceed 10%, especially when showing the difference between the peak intensity and the peak intensity. Figure 6 The X-ray diffraction pattern shown is the same as the X-ray diffraction pattern.

[0257] The crystalline salt forms of metoprolol free base (such as crystalline form 1 methanesulfonate, crystalline form 2 methanesulfonate, crystalline form 3 methanesulfonate, crystalline nicotinate, crystalline p-toluenesulfonate, crystalline benzenesulfonate, crystalline phosphate, crystalline malonate, crystalline L-tartrate, crystalline gentianate, crystalline fumarate, crystalline glycolate, crystalline acetate, crystalline form 1 sulfate, and crystalline form 2 sulfate) are respectively shown as basically as follows. Figure 7-18 In the context of X-ray diffraction patterns, the term "substantially" means at least Figure 7-18 The main peaks depicted in the graph, that is, those peaks with a relative peak intensity greater than 20%, especially greater than 30%, compared to the highest intensity peak in the graph, must exist.

[0258] In a preferred embodiment, the crystalline hydrochloride of essentially pure metoprolol free base shows... Figure 6 The X-ray diffraction pattern shown is shown in the image.

[0259] In another preferred embodiment, the free base of metoprolol is expressed in crystalline forms 1 (methanesulfonate), crystalline form 2 (methanesulfonate), crystalline form 3 (methanesulfonate), crystalline nicotinate, crystalline p-toluenesulfonate, crystalline benzenesulfonate, crystalline phosphate, crystalline malonate, crystalline L-tartrate, crystalline gentianate, crystalline fumarate, crystalline glycolate, crystalline acetate, crystalline form 1 sulfate, and crystalline form 2 sulfate. Figure 7-18 The X-ray diffraction pattern shown in the image has the following characteristics: the relative peak intensities of each peak are... Figure 7-18 The relative peak intensity deviation shown in the figure does not exceed 10%, especially when showing the difference between the peak intensity and the peak intensity in the figure. Figure 7-18 The X-ray diffraction pattern shown is the same as the one shown.

[0260] Alternatively, the crystalline form of metoprolol 1-methanesulfonate, the free base of metoprolol, is characterized by a DSC curve showing two endothermic peaks at 186.0 °C and 229.1 °C.

[0261] The crystalline form of metoprolol 2-methanesulfonate is characterized by a DSC curve showing three endothermic peaks at 75.5 °C, 182.6 °C, and 234.9 °C.

[0262] The crystalline form of metoprolol 3-methanesulfonate is characterized by a DSC curve showing two endothermic peaks at 195.1 °C and 240.1 °C.

[0263] The crystalline nicotinate of metoprolol free base is characterized by a DSC curve showing an endothermic peak at 221.9 °C;

[0264] The crystalline p-toluenesulfonate of metoprolol free base is characterized by a DSC curve showing three endothermic peaks at 77.2 °C, 202.4 °C, and 260.2 °C.

[0265] The crystalline benzenesulfonate of metoprolol free base is characterized by a DSC curve showing two endothermic peaks at 202.3 °C and 265.5 °C.

[0266] The crystalline phosphate of metoprolol free base is characterized by a DSC curve showing three endothermic peaks at 125.9 °C, 152.1 °C, and 157.6 °C.

[0267] The characteristic of the crystalline malonate of the free base of metoprolol is that it exhibits melting at 115.8 °C according to the DSC curve.

[0268] The crystalline L-tartrate of metoprolol free base is characterized by a DSC curve showing two endothermic peaks at 97.2 °C and 160.6 °C.

[0269] The crystalline gentianate of metoprolol free base is characterized by a DSC curve showing three endothermic peaks at 70.5 °C, 128.2 °C, and 184.7 °C.

[0270] The crystalline fumarate of metoprolol free base is characterized by a DSC curve showing two endothermic peaks at 114.3 °C and 229.7 °C.

[0271] The crystalline glycolate of metoprolol free base is characterized by a DSC curve showing two endothermic peaks at 133.9 °C and 147.7 °C.

[0272] The crystalline acetate of metoprolol, the free base, is characterized by a DSC curve showing two endothermic peaks at 146.1 °C and 175.4 °C; and

[0273] The crystalline form of metoprolol free base, sulfate 1, is characterized by a DSC curve showing three endothermic peaks at 94.5 °C, 158.3 °C, and 209.9 °C.

[0274] In any of the above embodiments, the crystalline polymorph of the free base of cymopterin or a salt of cymopterin may appear as an anhydrous form (e.g., without any bound water or solvent, hydration, or solvation) or as a hydrate, partial hydrate (e.g., hemihydrate, sesquihydrate, etc.), dihydrate, trihydrate, or the like, wherein the crystal form is bound to hydrated water or solvent molecules associated with the crystal form of cymopterin or its salt. In one embodiment, crystalline cymopterin form B appears as an anhydrous form. In one embodiment, crystalline cymopterin form C appears as a monohydrate or as a sesquihydrate. In one embodiment, crystalline cymopterin form D appears as a monohydrate or as a sesquihydrate. In one embodiment, crystalline cymopterin form F appears as a monohydrate or as a hemihydrate. In one embodiment, crystalline cymopterin form G appears as anhydrous.

[0275] In one embodiment, the present invention provides a method for preparing cytopoline form D. The method includes preparing a slurry of cytopoline in a liquid, wherein the liquid is water, acetone / water, isopropanol / isopropyl acetate, or tetrahydrofuran / n-hexane, and separating cytopoline form D from the slurry. Preferably, the liquid is water. Cytopoline form D can be separated using any suitable separation method, such as by centrifugation or by filtration. Preferably, cytopoline form D is separated by filtration. Typically, cytopoline form D can be further released from a solvent (e.g., water) by drying at room temperature.

[0276] In one embodiment, the present invention provides a method for preparing cytopoline crystalline form F. The method includes preparing a slurry of cytopoline in a solvent, wherein the solvent is water, acetone / water, isopropanol / isopropyl acetate, or tetrahydrofuran / n-hexane, and separating cytopoline form D from the slurry. Preferably, the solvent is water. Cytopoline form D can be separated using any suitable separation method, such as by centrifugation or by filtration. Preferably, cytopoline form D is separated by filtration. Cytopoline form D is then converted to form F, typically by heating to 40-60°C and holding for 0.5-10 hours. Heating can be performed at atmospheric pressure or under vacuum. Preferably, heating is performed under vacuum.

[0277] Metoprolol can be used as a useful therapeutic agent for diseases associated with low intracellular BH4 levels or with dysfunction of various BH4-dependent metabolic pathways, including but not limited to primary tetrahydrobiopterin deficiency, GTPCH deficiency, 6-pyruvyl-tetrahydropterin synthase (PTPS) deficiency, DHPR deficiency, metoprolol reductase deficiency, dopamine-responsive dystonia, Segawa syndrome, tyrosine hydroxylase deficiency, phenylketonuria, DNAJC12 deficiency, and Parkinson's disease. Depression caused by Parkinson's disease, impulsive behavior in Parkinson's patients, major depressive disorder, autism spectrum disorder, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety disorder, aggressive behavior in Alzheimer's disease, cerebrovascular disease, post-subarachnoid hemorrhage spasm, myocarditis, coronary artery spasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infectious diseases, endotoxic shock, cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, and hypoglycemia. Therefore, various forms of metoprolol according to the invention can be administered to patients in effective amounts to achieve treatment or improvement of diseases, symptoms, or conditions.

[0278] The present invention also provides pharmaceutical compositions comprising a crystalline polymorphic form of a crystalline base of maltodextrin or a salt of maltodextrin as described above and a pharmaceutically acceptable carrier. The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount, such as a therapeutically effective amount (including a preventatively effective amount), of one or more of the aforementioned compounds of the present invention or salts thereof.

[0279] Pharmaceutically acceptable carriers may be any of those commonly used and are limited only by chemical-physical considerations such as solubility or lack of reactivity with the compound and route of administration. Those skilled in the art will understand that, in addition to the pharmaceutical compositions described below, the compounds of the present invention can be formulated into inclusion complexes such as cyclodextrin inclusion complexes or liposomes.

[0280] The pharmaceutically acceptable carriers, such as vehicles, adjuvants, excipients, or diluents, described herein are well known to those skilled in the art and are readily available to the public. Preferably, pharmaceutically acceptable carriers are those that are chemically inert to the active compound and have no harmful side effects or toxicity under the conditions of use.

[0281] The choice of carrier depends in part on the specific active agent and the specific method of administration of the composition. Therefore, a large number of suitable formulations of the pharmaceutical compositions of the present invention exist. The following formulations for oral, spray, parenteral, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and not limiting.

[0282] Crystalline bases of metoprolol or its salts in crystalline polymorphs can be used to prepare liquid formulations, such as solutions, suspensions, or emulsions. Formulations suitable for oral administration may consist of (a) capsules, sachets, tablets, lozenges, and sugar lozenges, each containing a predetermined amount of the active ingredient (as a solid or granule); (b) powders; (c) liquid solutions, such as an effective amount of the compound dissolved in a diluent such as water, saline, or orange juice; (d) suspensions in a suitable liquid; and (e) suitable emulsions. Solid oral dosage forms, such as capsules, tablets, and powders, are preferred. Capsules may be of the common hard or soft-shell gelatin type and contain, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch. Tablets may contain one or more of the following: lactose, sucrose, mannose, corn starch, potato starch, alginate, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silica, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenges may contain the active ingredient in a flavoring agent (usually sucrose and gum arabic or astragalus gum) or in an inert base such as gelatin and glycerin or sucrose and gum arabic; emulsions, gels, etc., containing carriers known in the art in addition to the active ingredient.

[0283] Preparations suitable for oral and / or parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions (which may contain antioxidants, buffers, bacteriostatic agents and solutes that make the preparation isotonic with the blood of the intended recipient) and aqueous and non-aqueous sterile suspensions (which may include suspending agents, solubilizers, thickeners, stabilizers and preservatives). The compound may be administered in a physiologically acceptable diluent in a drug carrier (such as a sterile liquid or liquid mixture including water, saline, aqueous glucose and related sugar solutions, alcohols such as ethanol, benzyl alcohol or cetyl alcohol, glycols such as propylene glycol or polyethylene glycol and other polyvinyl alcohols, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides), with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose, or emulsifiers and other drug adjuvants).

[0284] Oils suitable for use in parenteral preparations include mineral oils, animal oils, vegetable oils, or synthetic oils. Specific examples of oils include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum oil, and mineral oil. Suitable fatty acids for use in parenteral preparations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral preparations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as dimethyl dialkyl ammonium halides and alkylpyridines. Halides, (b) anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates, (c) nonionic detergents such as fatty amine oxides, fatty acid chain alkanolamides and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as alkyl-β-aminopropionates and 2-alkyl-imidazopeak quaternary ammonium salts, and (3) mixtures thereof.

[0285] Parenteral preparations typically contain, in solution, about 0.5% to about 25% by weight of crystalline metoprolol free base or a salt of metoprolol in a crystalline polymorph. Suitable preservatives and buffers may be used in such preparations. To minimize or eliminate irritation at the injection site, such compositions may contain one or more nonionic surfactants with a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such preparations ranges from about 5% by weight to about 15% by weight. Suitable surfactants include polyvinyl sorbitol fatty acid esters such as sorbitol monooleate and high molecular weight adducts of ethylene oxide with hydrophobic bases, and high molecular weight adducts formed by the condensation of propane and propylene glycol. Parenteral preparations may be presented in single-dose or multi-dose sealed containers such as ampoules and vials and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile injectable liquid carrier, such as water, just before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the types described above.

[0286] The crystalline base of metoprolol or the crystalline polymorph of a salt of metoprolol of the present invention can be formulated into injectable formulations. The requirements for an effective drug carrier for injectable compositions are well known to those skilled in the art. See Pharmaceutics and Pharmacy Practice, JBLippincott Co., Philadelphia, Pa., edited by Banker and Chalmers, pp. 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th edition, pp. 622-630 (1986).

[0287] Topical formulations (including those suitable for transdermal drug delivery) are well known to those skilled in the art and are suitable for application to the skin. Topically applied compositions are typically in the form of liquids, creams, pastes, lotions, and gels. Topical administration includes application to the oral mucosa, including the oral cavity, oral epithelium, hard palate, gingiva, and nasal mucosa. In some embodiments, the composition comprises at least one crystalline metoprolol free base or a crystalline polymorph of a metoprolol salt and a suitable vehicle or carrier. It may also contain other components such as anti-irritants. The carrier may be liquid, solid, or semi-solid. In some embodiments, the composition is an aqueous solution. Alternatively, the composition may be a dispersion, emulsion, gel, lotion, or cream carrier of various components. In one embodiment, the primary carrier is water or a substantially neutral or substantially neutralized biocompatible solvent. Liquid carriers may include other materials such as buffers, alcohols, glycerin, and mineral oils having various emulsifiers or dispersants known in the art to achieve the desired pH, consistency, and viscosity. The composition may be prepared as a solid such as powder or granules. The solid can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a substantially neutral or substantially neutral solution that can then be applied to the target site. In some embodiments of the invention, the carrier for topical application to the skin may include water, buffer solutions, various alcohols, glycols such as glycerol, lipid materials such as fatty acids, mineral oil, glycerol phosphate, collagen, gelatin, and siloxane materials.

[0288] The compounds of the present invention, alone or in combination with other suitable components, can be formulated into aerosol formulations for administration by inhalation. These aerosol formulations can be contained in pressurized, acceptable propellants such as dichlorodifluoromethane, propane, and nitrogen. They can also be formulated into pharmaceutical preparations for use in unpressurized formulations, such as those in nebulizers or atomizers.

[0289] Additionally, the crystalline polymorph of the free base of methopterin or a salt of methopterin of the present invention can be prepared into suppositories by mixing with various matrices such as emulsion matrices or water-soluble matrices. Formulations suitable for vaginal administration can be presented as vaginal suppositories, hemostatic suppositories, creams, gels, pastes, foams, or sprays containing, in addition to the active ingredient, suitable carriers known in the art.

[0290] Crystalline maltodextrin free base or crystalline polymorphic form of maltodextrin salts can be used at any suitable dose. Suitable dosage and dosing regimens can be determined using conventional range study techniques. Typically, treatment begins with a smaller dose (less than the optimal dose). The dose is then increased in small increments until the optimal effect is achieved in that setting. For convenience, the total daily dose can be divided and administered in several portions on that day if desired. With suitable dosage and appropriate administration of certain compounds, the present invention provides a broad response. Typically, the dose is in the range of about 0.001 to about 1000 mg / kg of the treated patient's body weight / day. For example, in some embodiments, crystalline maltodextrin free base or crystalline polymorphic form of maltodextrin salts can be administered once or more daily at about 100 mg / kg to about 300 mg / kg, about 120 mg / kg to about 280 mg / kg, about 140 mg / kg to about 260 mg / kg, about 150 mg / kg to about 250 mg / kg, about 160 mg / kg to about 240 mg / kg of the subject's body weight to obtain the desired therapeutic effect.

[0291] In some embodiments, the crystalline polymorph of crystalline metoprolol base or a salt of metoprolol can be formulated into unit solid oral dosage forms such as capsules or tablets. In these embodiments, each unit solid oral dosage form contains any suitable amount of the crystalline polymorph of crystalline metoprolol base or a salt of metoprolol. For example, each solid oral dosage form may contain about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about... 500mg, approximately 525mg, approximately 550mg, approximately 575mg, approximately 600mg, approximately 625mg, approximately 650mg, approximately 675mg, approximately 700mg, approximately 725mg, approximately 750mg, approximately 775mg, approximately 800mg, approximately 825mg, approximately 850mg, approximately 875mg, approximately 900mg, approximately 925mg, approximately 950mg, approximately 975mg, approximately 1000mg, approximately 2000mg, approximately 3000mg, approximately 4000mg, approximately 5000mg, etc.

[0292] The following examples further illustrate the invention, but should not be construed as limiting its scope in any way.

[0293] Abbreviations: MeOH - methanol; DMSO - dimethyl sulfoxide; EtOAc - ethyl acetate; DMAc - dimethylacetamide; THF - tetrahydrofuran; NMP - N-methylpyrrolidone.

[0294] For X-ray powder diffraction analysis, a PANalytical Empyrean X-ray powder diffractometer was used. The parameters are as follows:

[0295] XRD parameters

[0296]

[0297] DSC was performed using a TA Q200 / Q2000 DSC from TA Instruments. The parameters used are as follows:

[0298] parameter DSC method slope Sample tray Aluminum, corrugated temperature 25℃ – The Desired Temperature heating rate 10℃ / min purge gas N2 Detailed Implementation

[0299] Example

[0300] Although certain features of the invention have been described and illustrated herein, many modifications, substitutions, alterations, and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and alterations that fall within the true spirit of the invention. Similarly, the following embodiments are provided to teach various aspects of the invention. These embodiments represent individual implementations of various aspects of the invention, and those skilled in the art will recognize that other embodiments may arise to similarly teach various aspects of the invention.

[0301] Example 1

[0302] This embodiment demonstrates the preparation of crystal form B of maltopterin free base according to one embodiment of the present invention.

[0303] Weigh 73.2 mg of the starting material, metoprolol, into a 20 mL glass vial. Add 2.5 mL of N-methylpyrrolidone (NMP) to dissolve the starting material. Filter the solution into a new vial. Gradually add 17 mL of acetonitrile (ACN) while stirring the sample at ~1000 rpm at RT. Stir the suspension at RT for 2 hours. Separate the precipitate by centrifugation and vacuum dry at RT for 3 hours to obtain crystalline form B of the free base of metoprolol.

[0304] Example 2

[0305] This embodiment demonstrates the preparation of crystalline form C of malpteroin free base according to one embodiment of the present invention.

[0306] 100.4 mg of starting material metoprolol was weighed into a 20 mL glass vial. 2 mL of ACN was added to form a suspension, which was stirred at 50 °C at a rate of ~1000 rpm. The resulting solid was separated by centrifugation for 2 minutes through a 0.25 μm pore size centrifugal filter and dried at RT for approximately 12 hours to obtain crystalline form C of the free base of metoprolol.

[0307] Example 3

[0308] This embodiment demonstrates the preparation of crystal form D of malpteroin free base according to one embodiment of the present invention.

[0309] 200.1 mg of starting material malopterin was weighed into a 20 mL glass vial. 5 mL of H₂O was added to form a suspension, which was stirred at ~1000 rpm at 50 °C. The resulting solid was separated by centrifugation for 2 minutes through a 0.25 μm pore size centrifugal filter. Half of the collected solid was dried at RT under atmospheric pressure for approximately 12 hours to obtain crystalline form D of the free malopterin base.

[0310] Example 4

[0311] This embodiment demonstrates the preparation of crystalline form F of maltodextrin free base according to one embodiment of the present invention. The other half of the solid collected in Example 3 was vacuum dried at 50°C for 0.5 hours to obtain crystalline form F of maltodextrin free base.

[0312] Example 5

[0313] This embodiment demonstrates the preparation of crystalline form G of maltodextrin free base according to one embodiment of the present invention. Crystalline form G of maltodextrin free base is prepared by heating a sample of crystalline form F prepared as in Example 4 to 120°C under a flow of N2.

[0314] Example 6

[0315] This embodiment demonstrates the preparation of a crystalline hydrochloride of maltodextrin free base according to one embodiment of the present invention.

[0316] Weigh 120.4 mg of metoprolol free base into a 20 mL glass vial. Add 0.8 mL of acetone / H₂O (9:1, v / v) and 42 μL of concentrated HCl (37.5%). Stir the resulting suspension at ~1000 rpm for 5 days at RT. Separate the solid by vacuum filtration and vacuum dry at RT for 3 hours.

[0317] The solid obtained above was dispersed in 3 mL of acetone / H2O (9:1, v / v). 5.5 μL of concentrated HCl (37.5%) was added and the suspension was stirred at ~1000 rpm for 6 days at RT. Then, the solid was separated by vacuum filtration and vacuum dried overnight at RT to obtain crystalline hydrochloride of metoprolol free base.

[0318] Example 7

[0319] This embodiment demonstrates the preparation of crystalline 3-methanesulfonate of the free base of metoprolol according to one embodiment of the present invention.

[0320] Weigh 51.7 mg of methanesulfonic acid into a 20 mL glass vial. Add 5 mL of MeOH to the vial. Weigh 120.7 mg of free metoprolol base into the vial. Stir the resulting suspension at ~1000 rpm for 5 days at RT, then add 20 μL of methanesulfonic acid to the vial. Stir the resulting mixture at ~1000 rpm for 1 day at RT. Separate the solid by vacuum filtration and vacuum dry overnight at RT. Disperse the dried solid in 3 mL of MeOH and stir at ~1000 rpm for 1 day at RT. Separate the solid by vacuum filtration and vacuum dry overnight at RT to obtain the crystalline 3-methanesulfonate of free metoprolol base.

[0321] Example 8

[0322] This embodiment demonstrates the preparation of crystalline nicotinate salts of malpteroin free base according to one embodiment of the present invention.

[0323] 119.5 mg of free base was weighed into a 20 mL glass vial. 10 mL of MeOH was added to the vial. 100.1 mg of nicotinic acid was weighed into the vial. The resulting suspension was stirred at ~1000 rpm for 7 hours at RT, then the solid was separated by vacuum filtration and dried under vacuum at RT for 3 hours to obtain crystalline nicotinate of metoprolol free base.

[0324] Example 9

[0325] This embodiment demonstrates the preparation of a crystalline salt form of malpteroin free base according to one embodiment of the present invention.

[0326] Crystalline 1-sulfate was obtained by pulping equimolar amounts of starting material and H2SO4 in acetone / H2O (9:1, v / v).

[0327] Crystalline 2-sulfate was obtained by pulping equimolar amounts of starting material and H2SO4 in THF / DMAc (9:1, v / v).

[0328] Crystalline p-toluenesulfonate was obtained by slurry preparation of equimolar amounts of starting material and p-toluenesulfonic acid in methanol.

[0329] Crystalline 1-methanesulfonate was obtained by slurry preparation of equimolar amounts of starting material and methanesulfonic acid in methanol.

[0330] Crystalline 2-methanesulfonate was obtained by pulping equimolar amounts of starting material and methanesulfonic acid in acetone / H2O (9:1, v / v).

[0331] Crystalline benzenesulfonate was obtained by slurry preparation of equimolar amounts of starting material and benzenesulfonic acid in methanol.

[0332] Crystalline phosphates were obtained by pulping equimolar amounts of starting material and H3PO4 in acetone / H2O (9:1, v / v).

[0333] Crystalline malonate was obtained by pulping the starting material and malonic acid (molar ratio of acid to free base of about 5:1) in acetone / H2O (9:1, v / v).

[0334] Crystalline L-tartrate was obtained by pulping the starting material and gentian acid (acid / free base molar ratio of about 4:1) in acetone / H2O (9:1, v / v).

[0335] Crystalline gentianate was obtained by pulping the starting material and L-tartaric acid (acid / free base molar ratio of about 5:1) in acetone / H2O (9:1, v / v).

[0336] Crystalline fumarate was obtained by pulping the starting material and fumaric acid (acid / free base molar ratio of about 5:1) in acetone / H2O (9:1, v / v).

[0337] Crystalline glycolates were obtained by pulping the starting material and glycolic acid (acid / free base molar ratio of about 4:1) in acetone / H2O (9:1, v / v).

[0338] Crystalline acetate was obtained by pulping the starting material and acetic acid (acid / free base molar ratio of about 5:1) in acetone / H2O (9:1, v / v).

[0339] Example 10

[0340] This embodiment demonstrates the characterization of the starting maltodextrin used in the preparation of the crystalline polymorphs A, B, C, D, E, F, and G of the free maltodextrin base described herein and the crystalline polymorphs of maltodextrin salts.

[0341] The sample of free base malopterin was commercially available. DSC showed two endothermic peaks at 82.8 °C and 179.8 °C. The malopterin sample contained particles with an average particle size greater than 100 μm. XRD patterns were determined before and after milling to reduce the particle size so that it could pass through a 140-mesh sieve. XRD patterns before and after milling are shown on [image / data missing]. Figure 19 In this paper, this polymorph of the free base of metoprolol is referred to as form A.

[0342] Example 11

[0343] This embodiment demonstrates the results of stability studies conducted at room temperature (RT), 35°C, and 50°C on metophine starting material (form A), crystalline polymorph form D, and crystalline polymorph form F.

[0344] The purity of the initial sample was determined by HPLC and found to be as follows: Form A = 99.3% area, Form F = 99.7% area, Form D = 99.1% area, where area% refers to the area under the curve of the metoprine peak compared to the total area under all peaks.

[0345] Samples of forms A and F were placed in a chamber containing silica gel at different temperatures to remove water (relative humidity measured at ~10% RH). Sample of form D was placed in a chamber containing water at different temperatures (relative humidity estimated at ~100% RH).

[0346] HPLC purity and XRD patterns of each of the A / F / D samples stored at various temperatures were obtained. Results after 1 week and 4 weeks of storage are listed in Tables 22 and 23, respectively.

[0347] Table 24. After 1 week of storage

[0348]

[0349] Table 25. After 4 weeks of storage

[0350]

[0351] As is evident from the results listed in Tables 24 and 25, and as observed by XPD, no samples exhibited significant changes in crystal structure. As determined by HPLC, form A exhibited significantly lower stability. After storage at 50°C for 4 weeks, the purity of form A, as determined by HPLC peak area % compared to its initial purity, was 89.1%. The purities of forms F and D, compared to their initial purities, were 99.1% and 98.5%, respectively.

[0352] Example 12

[0353] This embodiment demonstrates the stability of the polymorphs D and F of the free base of metoprolol after storage.

[0354] Samples of maltopterin free base polymorphs D, F, and A were stored at room temperature (RT), 35°C, and 50°C. The samples were analyzed by HPLC at 1-week and 4-week intervals. HPLC parameters are as follows:

[0355]

[0356] The results for polymorphs A, F, and D of metoprolol free base are listed in Tables 26-28.

[0357] Table 26: Polymorph A

[0358]

[0359]

[0360] Table 27: Polymorphs F

[0361]

[0362] Table 28: Polymorph D

[0363]

[0364] *-Relative stay time

[0365] As clearly demonstrated by the results listed in Tables 26-28, polymorphs D and F of the malopterin free base exhibit significantly improved stability compared to polymorph A. After 4 weeks of storage at 50°C / 10% RH, the amount of malopterin in polymorph A decreased from 99.33% to 88.49%. After 4 weeks of storage at 50°C / 100% RH, the amount of malopterin in polymorph D decreased from 99.14% to 97.65%. After 4 weeks of storage at 50°C / 10% RH, the amount of malopterin in polymorph F decreased from 99.74% to 98.85%.

[0366] Example 13

[0367] This embodiment demonstrates the preparation of crystal form E of the free base of metoprolol.

[0368] Weigh 100.6 mg of starting material into a 3 mL glass vial. Add 1 mL of MeOH to form a suspension. Stir the sample at ~1000 rpm under RT. After 3 days, separate the solid by centrifugation and dry under RT overnight.

[0369] Other implementation plans

[0370] In the context of describing the invention (particularly in the context of the following claims), the terms “a” (“a” and “an”), “the”, and “at least one”, and similar designations, shall be interpreted to cover both the singular and the plural, unless otherwise indicated herein or obviously contradicted by the context. The term “at least one” (e.g., “at least one of A and B”) followed by a list of one or more items shall be interpreted to mean one item (A or B) selected from the list or any combination of two or more of the list items (A and B), unless otherwise indicated herein or obviously contradicted by the context. The terms “comprising,” “having,” “including,” and “containing” shall be interpreted as open-ended terms (i.e., meaning “including but not limited to”), unless otherwise indicated. The ranges of values ​​mentioned herein are intended only as a way of abbreviating the individual values ​​falling within that range, unless otherwise indicated herein, and each individual value is incorporated into the specification as if it were listed separately herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or obviously contradicted by the context. The use of any and all instances or exemplary language (e.g., “such”) provided herein is intended only to better illustrate the invention and not to limit its scope, unless otherwise stated. No language in the specification should be construed as indicating that any unclaimed element is necessary for the implementation of the invention.

[0371] Preferred embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments will become apparent to those skilled in the art after reading the foregoing description. The inventors intend that those skilled in the art may adopt such variations as appropriate, and the inventors intend to carry out the invention in a manner different from that specifically described herein. Therefore, as permitted by applicable law, the invention includes all modifications and equivalents of the subject matter described in the appended claims. Furthermore, any combination of the foregoing elements in all possible variations is covered by the invention unless otherwise indicated herein or otherwise clearly contradicted by the context.

[0372] 1. Crystalline metoprolol, having at least one peak at a diffraction angle of 2θ (°) of 8.4°±0.5, 16.9°±0.5 or 25.4°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0373] 2. The crystal form of metoprolol of Scheme 1, having at least one peak at diffraction angles 2θ (°) of 8.4°±0.5, 16.9°±0.5 and 25.4°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0374] 3. The crystal form of metoprolol of scheme 1 or 2, having at least one peak at a diffraction angle 2θ (°) of 14.9°±0.5 or 34.1°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0375] 4. The crystal form of mepothalamic acid of any one of Schemes 1 to 3, having at least one peak at a diffraction angle 2θ (°) of 8.4°±0.5, 14.9°±0.5, 16.9°±0.5, 25.4°±0.5 and 34.1°±0.5, as determined by X-ray diffraction of Cu Kα X-ray irradiation or calculated by X-ray diffraction.

[0376] 5. The crystal form of metoprolol from any of schemes 1 to 4, which has the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0377] 6. The crystal form of metoprolol from any of Schemes 1 to 5, which begins to absorb heat at approximately 195°C in the differential scanning calorimetry (DSC) curve.

[0378] 7. Crystalline metoprolol, having at least one peak at a diffraction angle of 2θ (°) of 5.7°±0.5, 7.8°±0.5 or 25.4°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0379] 8. The crystal form of metoprolol of Scheme 7, having at least one peak at diffraction angles 2θ (°) of 5.7°±0.5, 7.8°±0.5 and 25.4°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0380] 9. The crystal form of metoprolol of scheme 7 or 8, having at least one peak at a diffraction angle 2θ (°) of 9.1°±0.5, 11.5°±0.5, 15.3°±0.5, 16.0°±0.5, 20.1°±0.5 or 26.6°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0381] 10. The crystal form of mepothalamic acid of any one of Schemes 7 to 9, having at least one peak at diffraction angles 2θ (°) of 5.7°±0.5, 7.8°±0.5, 9.1°±0.5, 11.5°±0.5, 15.3°±0.5, 16.0°±0.5, 20.1°±0.5, 25.4°±0.5 and 26.6°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0382] 11. The crystal form of metoprolol from any of schemes 7 to 10, which has the following characteristics: Figure 2 The X-ray powder diffraction pattern shown is shown.

[0383] 12. The crystal form of metoprolol of any of Schemes 7 to 11, which begins to absorb heat at approximately 58°C, 102°C, 130°C, 156.5°C or 168°C in the differential scanning calorimetry (DSC) curve.

[0384] 13. The crystal form of metoprolol of any of Schemes 7 to 12, which begins to absorb heat at approximately 58°C, 102°C, 130°C, 156.5°C and 168°C in differential scanning calorimetry (DSC) curves.

[0385] 14. Crystalline metoprolol, having at least one peak at a diffraction angle of 2θ (°) of 8.9°±0.5, 10.3°±0.5 or 26.0°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0386] 15. The crystal form of metoprolol of Scheme 14, having at least one peak at diffraction angles 2θ (°) of 8.9°±0.5, 10.3°±0.5 and 26.0°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0387] 16. The crystal form of metoprolol of Scheme 14 or 15, having at least one peak at a diffraction angle 2θ (°) of 10.9°±0.5, 17.8°±0.5, 24.9°±0.5, 26.7°±0.5, 26.8°±0.5 or 28.3°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0388] 17. The crystal form of mepothalamic acid of any one of Schemes 14 to 16, having at least one peak at diffraction angles 2θ (°) of 8.9°±0.5, 10.3°±0.5, 10.9°±0.5, 17.8°±0.5, 24.9°±0.5, 26.0°±0.5, 26.7°±0.5, 26.8°±0.5 and 28.3°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0389] 18. The crystal form of metoprolol from any of schemes 14 to 17, having the following characteristics: Figure 3 The X-ray powder diffraction pattern shown is shown.

[0390] 19. The crystal form of metoprolol of any of Schemes 14 to 18, which begins to absorb heat at approximately 43°C, 66°C or 233°C in a differential scanning calorimetry (DSC) curve.

[0391] 20. The crystal form of metoprolol of any of Schemes 14 to 19, which begins to absorb heat at approximately 43°C, 66°C and 233°C in differential scanning calorimetry (DSC) curves.

[0392] 21. Crystalline metoprolol having at least one peak at a diffraction angle of 2θ (°) of 9.7°±0.5, 10.2°±0.5 or 11.3°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0393] 22. The crystal form of metoprolol of Scheme 21, having at least one peak at diffraction angles 2θ (°) of 9.7°±0.5, 10.2°±0.5 and 11.3°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0394] 23. The crystal form of mepothalamic acid of scheme 21 or 22, having at least one peak at a diffraction angle 2θ (°) of 14.0°±0.5, 14.6°±0.5, 19.9°±0.5, 22.2°±0.5, 25.3°±0.5 or 32.4°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0395] 24. The crystal form of mepothalamic acid of any one of schemes 21 to 23, having at least one peak at diffraction angles 2θ (°) of 9.7°±0.5, 10.2°±0.5, 11.3°±0.5, 14.0°±0.5, 14.6°±0.5, 19.9°±0.5, 22.2°±0.5, 25.3°±0.5 and 32.4°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0396] 25. The crystal form of metoprolol from any of schemes 21 to 24, which has the following characteristics: Figure 4 The X-ray powder diffraction pattern shown is shown.

[0397] 26. The crystal form of metoprolol of any of schemes 21 to 25, which begins to absorb heat at approximately 113°C or 196°C in a differential scanning calorimetry (DSC) curve.

[0398] 27. The crystal form of metoprolol of any of schemes 21 to 26, which begins to absorb heat at approximately 113 °C and 196 °C in differential scanning calorimetry (DSC) curves.

[0399] 28. Crystalline metoprolol having at least one peak at a diffraction angle of 2θ (°) of 10.0°±0.5, 10.6°±0.5 or 25.7°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0400] 29. The crystal form of metoprolol of Scheme 28, having at least one peak at diffraction angles 2θ (°) of 10.0°±0.5, 10.6°±0.5 and 25.7°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0401] 30. The crystal form of mepothalamic acid of scheme 28 or 29, having at least one peak at a diffraction angle 2θ (°) of 11.2°±0.5, 15.3°±0.5, 15.9°±0.5, 22.8°±0.5, 24.4°±0.5 or 25.0°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0402] 31. The crystal form of mepothalamic acid of any one of Schemes 28 to 30, having at least one peak at diffraction angles 2θ (°) of 10.0°±0.5, 10.6°±0.5, 11.2°±0.5, 15.3°±0.5, 15.9°±0.5, 22.8°±0.5, 24.4°±0.5, 25.0°±0.5 and 25.7°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0403] 32. The crystal form of metoprolol from any of schemes 28 to 31, which has the following characteristics: Figure 5 The X-ray powder diffraction pattern shown is shown.

[0404] 33. A composition comprising the crystalline form of metoprolol of any one of schemes 1 to 32.

[0405] 34. The composition of Scheme 33, wherein the crystalline form of metoprolol of any one of Schemes 1 to 27 is present in an amount of at least 90% by weight of the composition.

[0406] 35. A pharmaceutical composition comprising a crystalline form of metoprolol from any one of schemes 1 to 32 and a pharmaceutically acceptable carrier.

[0407] 36. The pharmaceutical composition of Scheme 35, wherein the metoprolol crystals are formulated as particles with a size of less than 100 μm.

[0408] 37. A method for preparing a crystalline form of metoprolol, comprising preparing a slurry of a first crystalline form of metoprolol in water, acetone / water, isopropanol / isopropyl acetate or tetrahydrofuran / n-hexane, separating a solid from the slurry and drying the solid.

[0409] 38. The method of Scheme 37, wherein the slurry of the first crystal form of metoprolol is stirred at 25-75°C for 6-72 hours.

[0410] 39. The method of scheme 37 or 38, wherein the solid is dried at 20-30°C for 6-24 hours.

[0411] 40. The method of scheme 37 or 38, wherein the solid is dried at 40-60°C for 5-10 hours.

[0412] 41. The method of any one of claims 37 to 40, wherein the solid is dried under atmospheric pressure.

[0413] 42. The method of any one of claims 37 to 40, wherein the solid is dried under vacuum.

[0414] 43. The crystal form of a salt of metoprolol, wherein the crystal form of the salt of metoprolol is:

[0415] (a) The crystal form of mesylate of metoprolol having at least one peak at diffraction angles 2θ (°) at 7.8°±0.5, 23.5°±0.5 and 29.0°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0416] (b) The crystal form of mesylate of metoprolol having at least one peak at diffraction angles 2θ (°) at 21.7°±0.5, 26.0°±0.5 and 28.9°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0417] (c) The crystal form of the nicotinate of metoprolol, having at least one peak at diffraction angles 2θ (°) at 9.5°±0.5, 9.9°±0.5 and 24.5°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0418] (d) The crystal form of p-toluenesulfonate of metoprolol, having at least one peak at diffraction angles 2θ (°) at 6.5°±0.5, 15.1°±0.5 and 23.4°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0419] (e) The crystal form of metoprolol benzenesulfonate having at least one peak at diffraction angles 2θ (°) of 6.5°±0.5, 14.8°±0.5 and 19.6°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0420] (f) The crystal form of metoprolol phosphate, having at least one peak at diffraction angles 2θ (°) at 16.6°±0.5, 22.2°±0.5 and 25.6°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0421] (g) The crystal form of metoprolol malonate, having at least one peak at diffraction angles 2θ (°) of 6.9°±0.5, 22.7°±0.5 and 23.8°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0422] (h) The crystal form of metoprolol tartrate, having at least one peak at diffraction angles 2θ (°) at 7.3°±0.5, 14.2°±0.5 and 21.8°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0423] (i) The crystal form of the gentian salt of metoprolol, having at least one peak at diffraction angles 2θ (°) of 7.1°±0.5, 8.7°±0.5 and 26.7°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0424] (j) The crystal form of the fumarate of metoprolol, having at least one peak at diffraction angles 2θ (°) at 11.3°±0.5, 24.0°±0.5 and 28.2°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0425] (k) The crystal form of metoprolol glycolate having at least one peak at diffraction angles 2θ (°) at 7.6°±0.5, 10.7°±0.5 and 24.0°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0426] (l) The crystal form of metoprolol acetate, having at least one peak at diffraction angles 2θ (°) at 6.2°±0.5, 12.0°±0.5 and 18.1°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0427] (m) The crystal form of metoprolol sulfate, having at least one peak at diffraction angles 2θ (°) of 5.1°±0.5, 7.8°±0.5, and 23.0°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction; or

[0428] (n) The crystal form of metopterin sulfate, having at least one peak at diffraction angles of 2θ (°) at 7.8°±0.5, 8.8°±0.5 and 24.1°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0429] 44. The crystal form of metoprolol hydrochloride having at least one peak at diffraction angles 2θ (°) at 7.8°±0.5, 12.9°±0.5 and 26.2°±0.5, as determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

[0430] 45. A composition comprising a crystalline form of a salt of metoprolol according to scheme 43 or 44, wherein the crystalline form of the salt of metoprolol is present in at least 90% by weight.

[0431] 46. ​​A pharmaceutical composition comprising a crystalline form of a salt of metoprolol of scheme 43 or 44 and a pharmaceutically acceptable carrier.

[0432] 47. The pharmaceutical composition of Scheme 46, wherein the metoprolol crystals are formulated as particles with a size of less than 100 μm.

[0433] 48. A method for treating BH4-related conditions in patients in need, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-32, 43 or 44, or a pharmaceutical composition from any of schemes 35, 36, 46 or 47.

[0434] 49. A method for increasing BH4 levels in a subject in need, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-32, 43 or 44, or a pharmaceutical composition from any of schemes 35, 36, 46 or 47.

[0435] 50. A method for reducing phenylalanine levels in a subject in need, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-32, 43 or 44, or a pharmaceutical composition from any of schemes 35, 36, 46 or 47.

[0436] 51. A method for increasing phenylalanine hydroxylase activity in a subject, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any one of schemes 1-32, 43 or 44, or a pharmaceutical composition from any one of schemes 35, 36, 46 or 47.

[0437] 52. A method for treating phenylketonuria in a subject in need, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-32, 43 or 44, or a pharmaceutical composition from any of schemes 35, 36, 46 or 47.

[0438] 53. A method for increasing serotonin levels in a subject in need, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of regimens 1-27, 38 or 39, or a pharmaceutical composition from any of regimens 30, 31, 41 or 42.

[0439] 54. A method for increasing tryptophan hydroxylase activity in a subject, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-27, 38 or 39, or a pharmaceutical composition from any of schemes 30, 31, 41 or 42.

[0440] 55. A method for increasing dopamine levels in a subject in need, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of regimens 1-27, 38 or 39, or a pharmaceutical composition from any of regimens 30, 31, 41 or 42.

[0441] 56. A method for increasing tyrosine hydroxylase activity in a subject, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-27, 38 or 39, or a pharmaceutical composition from any of schemes 30, 31, 41 or 42.

[0442] 57. A method for increasing nitric oxide synthase activity in a subject, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-27, 38 or 39, or a pharmaceutical composition from any of schemes 30, 31, 41 or 42.

[0443] 58. A method for increasing alkylglycerol monooxygenase activity in a subject, the method comprising administering to the patient an effective amount of a crystalline form of metoprolol from any of schemes 1-27, 38 or 39, or a pharmaceutical composition from any of schemes 30, 31, 41 or 42.

Claims

1. The crystal form D of the free base of metoprolol, which has peaks at diffraction angles of 2θ (°) at 8.9°±0.5, 10.3°±0.5, 10.9°±0.5, 17.8°±0.5, 24.9°±0.5, 26.0°±0.5, 26.7°±0.5, 26.8°±0.5 and 28.3°±0.5, determined by X-ray diffraction with Cu Kα X-rays or calculated by X-ray diffraction.

2. The crystal form D of the metopterin free base of claim 1, having the X-ray powder diffraction pattern shown in FIG3.

3. The crystal form D of the metoprolol free base of claim 1 or 2, which is endothermic at about 43°C, 66°C or 233°C in a differential scanning calorimetry (DSC) curve.

4. The crystal form D of the metoprolol free base according to any one of claims 1 to 2, which is endothermic at about 43°C, 66°C and 233°C in differential scanning calorimetry (DSC) curves.

5. A composition comprising crystal form D of the metoprolol free base of any one of claims 1 to 2.

6. The composition of claim 5, wherein the crystal form D of the free base of metoprolol is present in an amount of at least 90% by weight of the composition.

7. A pharmaceutical composition comprising the crystal form D of the metoprolol free base of any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7, wherein the crystal form D of the metoprolol free base is formulated as particles with a size of less than 100 μm.

9. Use of the crystal form D of the metoprolol free base of any one of claims 1 to 2 in the preparation of a medicament for treating BH4-related conditions in patients in need, wherein the BH4-related conditions are primary tetrahydrobiopterin deficiency, dopamine-responsive dystonia, phenylketonuria, DNAJC12 deficiency, Parkinson's disease, depression caused by Parkinson's disease, major depressive disorder, autism spectrum disorder, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety disorder, cerebrovascular disease, gastroparesis, post-subarachnoid hemorrhage spasm, myocarditis, coronary artery spasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infectious diseases, endotoxic shock, cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, or hypoglycemia.

10. The use of claim 9, wherein the BH4-related condition is primary tetrahydrobiopterin deficiency.

11. The use of claim 9, wherein the BH4-related condition is phenylketonuria.

12. The use of claim 9, wherein the BH4-related condition is gastroparesis.

13. The use of claim 9, wherein the BH4-related condition is GTPCH deficiency, 6-pyruvyl-tetrahydropterin synthase (PTPS) deficiency, DHPR deficiency, or metopterin reductase deficiency.

14. The use of claim 9, wherein the BH4-related condition is Segawa syndrome or tyrosine hydroxylase deficiency.

15. Use of the crystal form D of the metoprolol free base of any one of claims 1 to 2 in the preparation of a medicament for increasing BH4 levels, decreasing phenylalanine levels, increasing phenylalanine hydroxylase activity, increasing serotonin levels, increasing tryptophan hydroxylase activity, increasing dopamine levels, increasing tyrosine hydroxylase activity, increasing nitric oxide synthase activity, or increasing alkylglycerol monooxygenase activity in subjects of need.

16. A method for preparing a liquid formulation, comprising dispersing the crystal form D of the metoprolol free base of any one of claims 1 to 2 in a liquid.

17. The method of claim 16, wherein the liquid formulation is a suspension.

18. A method for preparing crystal form D of the free base of metoprolol according to any one of claims 1 to 2, comprising preparing a slurry of metoprolol in water, acetone / water, isopropanol / isopropyl acetate or tetrahydrofuran / n-hexane, and separating crystal form D of the free base of metoprolol from the slurry.

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