Salts of pharmaceutical compounds

Abstract

The present invention relates to pharmaceutically acceptable acid addition salts of (i) S-oxprenolol and (ii) phosphoric acid. The medical uses of the salts and compositions comprising the salts are also described.

Description

[Technical Field]

[0001] This invention relates to salts of S-oxprenolol and pharmaceutical compositions containing the salts. Medical uses of the salts are also described. [Background technology]

[0002] S-oxprenolol is a β-adrenergic receptor antagonist and is also known as (-)-oxprenolol. The systematic name of S-oxprenolol is (S)-1-(2-(allyloxy)phenoxy)-3-(isopropylamino)propan-2-ol, and the structure of this compound is shown below.

[0003] [ka]

[0004] S-oxprenolol has affinity for both β-adrenergic receptors and 5-HT1a receptors and is useful in treating many diseases. WO 2014 / 138806 A1 describes the treatment of cachexia with S-oxprenolol, and WO 2014 / 138814 A1 describes the treatment of amyotrophic lateral sclerosis with S-oxprenolol.

[0005] Oxprenolol is approved in racemic form as a treatment for symptoms such as angina pectoris. For certain symptoms, S-oxprenolol has been found to be a more pharmacologically active enantiomer. However, the present invention has found that free S-oxprenolol base has properties that make it difficult to formulate into oral pharmaceuticals such as tablets. In particular, S-oxprenolol has a low melting point.

[0006] There is a need to develop a solid form of S-oxprenolol that is well-suited for use in clinical settings. In particular, it is desirable to develop a solid form of S-oxprenolol that is pharmaceutically acceptable, crystalline, and has a higher melting point compared to the free base. [Overview of the project]

[0007] The inventors have found that a salt of S-oxprenolol formed with phosphoric acid is well-suited for pharmaceutical formulations. In particular, this salt is found to be crystalline and has a higher melting point compared to the free base of S-oxprenolol. This salt is also pharmaceutically acceptable and has good hygroscopic properties.

[0008] The present invention provides a pharmaceutically acceptable acid addition salt of (a) S-oxprenolol and (b) phosphoric acid.

[0009] The present invention also provides a composition comprising at least 60% by weight of the pharmaceutically acceptable acid addition salt.

[0010] The present invention further provides a pharmaceutical composition comprising (i) a pharmaceutically acceptable acid addition salt and (ii) a pharmaceutically acceptable excipient, carrier, or diluent.

[0011] The present invention also provides pharmaceutically acceptable acid addition salts for use in the treatment of the human or animal body. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 shows the XRPD diffractograms of pattern 1 for S-oxprenolol free base and S-oxprenolol dihydrogen phosphate. [Figure 2] Figure 2 shows patterns 1 and 2 for S-oxprenolol free base, S-oxprenolol oxalate, and the XRPD diffractogram of oxalate. [Figure 3] Figure 3 shows the XRPD diffractogram of pattern 2 for S-oxprenolol dihydrogen phosphate. [Figure 4] Figure 4 shows the XRPD diffractogram of pattern 3 for S-oxprenolol dihydrogen phosphate.

Mode for Carrying Out the Invention

[0013] The pharmaceutically acceptable acid addition salt is a salt of S-oxprenolol and thus contains a cation formed from S-oxprenolol. The cation formed from S-oxprenolol typically has the following structure.

[0014]

Chemical Formula

[0015] The enantiomeric excess of the S-enantiomer of the cation of oxprenolol in the pharmaceutically acceptable salt is typically at least 80% or at least 90%. The enantiomeric excess is typically at least 95%. The cation of S-oxprenolol in the pharmaceutically acceptable acid addition salt is typically substantially in the S-configuration and thus can have an enantiomeric excess of at least 99%. The enantiomeric excess can be measured by any standard technique, such as measurement of optical rotation or use of chiral high performance liquid chromatography (HPLC).

[0016] [[ID=二十一]]Thus, typically at least 80 mol% of the cations in the salt are in the S-configuration. For example, at least 90 mol% or at least 95 mol% of the oxprenolol cations in the salt may be in the S-configuration. Preferably, at least 99 mol% of the oxprenolol cations in the salt are in the S-configuration.

[0017] Therefore, the pharmaceutically acceptable acid addition salt typically does not contain more than 10 mol% of a salt containing a cation that is the R-enantiomer of oxprenolol or a protonated R-oxprenolol molecule. The pharmaceutically acceptable acid addition salt typically contains less than 5.0 mol% of a salt containing a cation that is the R-enantiomer of oxprenolol or a protonated R-oxprenolol molecule. For example, the pharmaceutically acceptable acid addition salt typically does not contain substantially any salt containing a cation that is the R-enantiomer of oxprenolol or a protonated R-oxprenolol molecule.

[0018] The pharmaceutically acceptable acid addition salts are typically crystalline. Therefore, the salts may have a three-dimensional crystalline structure containing repeating unit cells. The pharmaceutically acceptable acid addition salts may be in solid form, for example, a solid form containing crystals or microcrystals of the pharmaceutically acceptable acid addition salt.

[0019] The pharmaceutically acceptable acid addition salt may be in the form of a solvate. A solvate of a salt is the solid form of the salt containing molecules of the solvent. For example, the salt may be a hydrate. Typically, the salt is not a solvate. For example, the pharmaceutically acceptable acid addition salt may be an anhydrous.

[0020] The salt may be in the form of a hydrate, which may contain 0.1 to 0.5 molecules of water per molecule of the salt (for example, about 0.25 molecules of water per molecule of the salt). The salt may be in the form of an ethanol solvate, which may contain 0.1 to 1.0 molecule of ethanol per molecule of the salt (for example, about 0.5 molecules of ethanol per molecule of the salt).

[0021] The pharmaceutically acceptable acid addition salt typically has a melting point higher than that of the free S-oxprenolol base. The salt may have a melting point of 70°C or higher, typically 80°C or higher. For example, the pharmaceutically acceptable acid addition salt typically has a melting point of 85°C to 90°C. The melting point of the pharmaceutically acceptable acid addition salt may be about 88°C. The melting point may be determined, for example, using differential scanning calorimetry (DSC).

[0022] The acid addition salts that are acceptable as pharmaceuticals consist of a cation derived from S-oxprenolol and a phosphate anion ([PO4] 3- ), hydrogen phosphate anion ([HPO4] 2- ) and dihydrogen phosphate anion ([H2PO4] - It may contain one or more anions selected from ).

[0023] The pharmaceutically acceptable acid addition salt may be S-oxprenolol dihydrogen phosphate. Therefore, the salt consists of a cation derived from S-oxprenolol and a dihydrogen phosphate anion (i.e., ([H2PO4] - )) may contain. The stoichiometric ratio of cation to anion is typically about 1:1, e.g., 0.9:1.0 to 1.1:1.0 (i.e., there may be 0.9 to 1.1 moles of cation per mole of anion). Therefore, S-oxprenolol dihydrogen phosphate is typically S-oxprenolol mono-dihydrogen phosphate. Thus, the salt is given by formula [C] as shown below. 15 H 23 NO3] + [H2PO4] - It can be anything.

[0024] [ka]

[0025] The stoichiometric ratio of cations to anions may alternatively be about 3:1, about 2:1, or about 1:2.

[0026] The pharmaceutically acceptable acid addition salts can be formed by any suitable method. Typically, the free base S-oxprenolol is combined in a solvent with an acid from which the counterion is derived (e.g., phosphoric acid). For example, S-oxprenolol can be dissolved in a solution of acid in a solvent. The solvent may include water, alcohols (methanol, ethanol, 1-propanol, isopropanol, etc.), ketones (e.g., acetone), esters (ethyl acetate), or ethers (e.g., tetrahydrofuran (THF), ethyl ether, tert-butyl methyl ether). Preferably, the solvent contains an alcohol. The solvent may contain at least 40% by volume of alcohol. The solvent typically contains ethanol.

[0027] A process for producing the pharmaceutically acceptable acid addition salt may include: (a) a step of combining S-oxprenolol and phosphoric acid in an alcohol-containing solvent to produce a solution of the pharmaceutically acceptable acid addition salt in an alcohol-containing solvent; (b) a step of adding an alkane-containing solvent to the solution of the pharmaceutically acceptable acid addition salt in an alcohol-containing solvent to produce a precipitate of the pharmaceutically acceptable acid addition salt; and (c) a step of isolating the precipitate of the pharmaceutically acceptable acid addition salt, for example by filtration. A process for producing the pharmaceutically acceptable acid addition salt may include: (a) a step of combining S-oxprenolol and phosphoric acid in ethanol to produce a solution of the pharmaceutically acceptable acid addition salt in ethanol; (b) a step of adding hexane or heptane to the solution of the pharmaceutically acceptable acid addition salt in ethanol to produce a precipitate of the pharmaceutically acceptable acid addition salt; and (c) a step of isolating the precipitate of the pharmaceutically acceptable acid addition salt, for example by filtration.

[0028] The pharmaceutically acceptable acid addition salt produced may dissolve in a solvent or precipitate from the solution. The pharmaceutically acceptable acid addition salt may be isolated by appropriate methods, such as filtration or solvent evaporation.

[0029] The pharmaceutically acceptable acid addition salts are typically crystalline. As described herein, the °2θ value is measured using the X-ray wavelength CuKα1 line (λ = 1.54060 Å). If the powder X-ray diffraction pattern contains a peak, the relative intensity of that peak is typically at least 5% or at least 10%. The error range of the °2θ value is typically ±0.2°2θ, but the error range may alternatively be ±0.1°2θ.

[0030] S-oxprenolol dihydrogen phosphate may be a crystalline polymorph of S-oxprenolol dihydrogen phosphate designated as pattern 3. Pattern 3 of S-oxprenolol dihydrogen phosphate typically has a powder X-ray diffraction (XRPD) pattern containing peaks at 4.8°, 7.1°, and 8.2°±0.2°²θ. The XRPD pattern may contain peaks at 4.8°, 7.1°, and 8.2°±0.1°²θ.

[0031] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 3 typically includes additional peaks at 22.5°, 22.7°, and 23.2°±0.2°²θ. The XRPD pattern may also include additional peaks at 22.5°, 22.7°, and 23.2°±0.1°²θ.

[0032] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 3 may contain seven or more peaks selected from 4.8°, 7.1°, 8.2°, 14.2°, 14.4°, 22.5°, 22.7°, 23.2°, 23.5°, and 23.8° ± 0.2°²θ. The XRPD pattern may include all of these peaks. The error range may be ±0.1°²θ.

[0033] The XRPD pattern of S-oxprenolol dihydrogen phosphate form 3 may include five or more peaks selected from 4.8°, 7.1°, 7.2°, 8.2°, 14.2°, 14.4°, 22.5°, 22.7°, 23.2°, 23.5°, 23.8° and 24.0° ± 0.2° 2θ. The XRPD pattern may include seven or more of these peaks. The XRPD pattern may include all of these peaks. The error range may be ±0.1° 2θ.

[0034] The XRPD pattern of S-oxprenolol dihydrogen phosphate form 3 may include the following peaks: 4.8°, 7.1°, 8.2°, 9.6°, 11.6°, 13.4°, 14.2°, 14.4°, 17.9°, 20.9°, 21.6°, 22.5°, 22.7°, 23.2°, 23.5°, 23.8°, 25.0°, 25.8° and 27.0° ± 0.2° 2θ. The error range may be ±0.1° 2θ.

[0035] The XRPD pattern of S-oxprenolol dihydrogen phosphate form 3 may include the following peaks.

[0036] [Table 1]

[0037] The XRPD pattern of S-oxprenolol dihydrogen phosphate form 3 may be substantially as shown in Figure 4.

[0038] S-oxprenolol dihydrogen phosphate form 3 may have the following unit cell parameters (determined by single crystal analysis). Orthorhombic P21 a = 7.76070(10) Å α = 90° b = 36.7729(6) Å β = 94.0602(11)° c = 12.9496(2) Å γ = 90° Volume = 3686.33(10) Å 3 Z = 8, Z’ = 4 Temperature = 100K

[0039] The infrared spectrum of S-oxprenolol dihydrogen phosphate pattern 3 is typically around 1210–1260 cm⁻¹. -1 (COC functional group) and approximately 1590 cm -1 The peak is included in (NH variation).

[0040] The melting point of S-oxprenolol dihydrogen phosphate pattern 3 is typically in the range of 85.0–90.0°C, for example, about 88°C. The melting point may be measured by DSC analysis.

[0041] S-oxprenolol dihydrogen phosphate pattern 3 can be produced by a process comprising recrystallizing S-oxprenolol dihydrogen phosphate from a solvent which is ethanol, isopropanol, acetone, a mixture of acetone and water, diisopropyl ether, n-heptane, n-hexane, methanol, methyl isobutyl ketone, tert-butyl methyl ether, or toluene. Typically, the solvent for recrystallization contains at least 90% by volume of the described solvent components.

[0042] S-oxprenolol dihydrogen phosphate pattern 3 can be obtained by adding THF (a poor solvent) to a 90% acetone:10% water solution of S-oxprenolol dihydrogen phosphate and storing the resulting mixture at 25°C for two weeks.

[0043] S-oxprenolol dihydrogen phosphate pattern 3 is typically a hydrate, and the unit cell typically contains about 0.25 molecules of water per molecule of S-oxprenolol dihydrogen phosphate.

[0044] S-oxprenolol dihydrogen phosphate may be a crystalline polymorph of S-oxprenolol dihydrogen phosphate designated as pattern 2. Pattern 2 of S-oxprenolol dihydrogen phosphate typically has a powder X-ray diffraction (XRPD) pattern containing peaks at 6.8°, 7.8°, and 22.5°±0.2°²θ. The XRPD pattern may contain peaks at 6.8°, 7.8°, and 22.5°±0.1°²θ.

[0045] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 2 typically includes further peaks at 4.4°, 17.0°, and 22.6°±0.2°²θ. The XRPD pattern may also include further peaks at 4.4°, 17.0°, and 22.6°±0.1°²θ.

[0046] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 2 may contain peaks at 4.4°, 6.8°, 7.8°, 17.0°, and 22.5°±0.2°²θ. The error range may be ±0.1°²θ.

[0047] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 2 may contain seven or more peaks selected from 4.4°, 6.8°, 7.8°, 17.0°, 22.5°, 22.9°, 23.5°, 23.6°, 24.2°, and 25.1° ± 0.2°²θ. The XRPD pattern may include all of these peaks. The error range may be ±0.1°²θ.

[0048] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 2 may contain five or more peaks selected from 4.4°, 6.8°, 7.8°, 17.0°, 22.5°, 22.6°, 22.9°, 23.5°, 23.6°, 24.2°, and 25.1° ± 0.2°²θ. The XRPD pattern may contain seven or more of these peaks. The XRPD pattern may contain all of these peaks. The error range may be ±0.1°²θ.

[0049] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 2 may include the following peaks: 4.4°, 6.8°, 7.8°, 13.0°, 17.0°, 17.2°, 19.3°, 21.9°, 22.5°, 22.9°, 23.5°, 23.6°, 24.2°, and 25.1° ± 0.2°²θ. The error range may be ± 0.1°²θ.

[0050] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 2 may include the following peaks.

[0051] [Table 2]

[0052] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 2 may be substantially as shown in Figure 3.

[0053] S-oxprenolol dihydrogen phosphate pattern 2 may have the following unit cell parameters (determined by single-crystal analysis): Orthorhombic P212121 a = 7.7822(4) Å α = 90° b = 13.2653(5) Å β = 90° c = 39.5732(15) Å γ = 90° Volume = 4085.3(3) Å 3 Z = 4, Z' = 2 Temperature = 100(2)K

[0054] S-oxprenolol dihydrogen phosphate pattern 2 can be produced by a process that involves recrystallizing S-oxprenolol dihydrogen phosphate from a solvent which is 1-propanol, 2-methyl-1-propanol, acetonitrile, anisole, benzyl alcohol, butyl acetate, isopropyl acetate, or methyl ethyl ketone.

[0055] S-oxprenolol dihydrogen phosphate pattern 2 is typically an ethanol solvate, and the unit cell typically contains about 0.5 molecules of ethanol per molecule of S-oxprenolol dihydrogen phosphate.

[0056] S-oxprenolol dihydrogen phosphate may be a crystalline polymorph of S-oxprenolol dihydrogen phosphate designated as Pattern 1. Pattern 1 of S-oxprenolol dihydrogen phosphate typically has a powder X-ray diffraction (XRPD) pattern containing peaks at 4.6°, 11.0°, and 20.6°±0.2°²θ. The XRPD pattern may contain peaks at 4.6°, 11.0°, and 20.6°±0.1°²θ.

[0057] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 1 typically includes further peaks at 17.1°, 18.4°, and 22.9°±0.2°²θ. The XRPD pattern may also include further peaks at 17.1°, 18.4°, and 22.9°±0.1°²θ.

[0058] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 1 may contain five or more peaks selected from 4.6°, 11.0°, 13.8°, 17.1°, 18.4°, 20.6°, 21.8°, 22.9°, and 26.3° ± 0.2°²θ. The XRPD pattern may contain seven or more of these peaks. The XRPD pattern may contain all of these peaks. The error range may be ± 0.1°²θ.

[0059] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 1 may include the following peaks.

[0060] [Table 3]

[0061] The XRPD pattern of S-oxprenolol dihydrogen phosphate pattern 1 may be substantially as shown in Figure 1.

[0062] Furthermore, S-oxprenolol dihydrogen phosphate is provided, characterized by an XRPD pattern containing peaks at 4.8°, 7.1°, and 8.2°±0.2°²θ. The XRPD pattern may further contain peaks at 22.5°, 22.7°, and 23.2°±0.2°²θ. The XRPD may contain seven or more peaks selected from 4.8°, 7.1°, 8.2°, 14.2°, 14.4°, 22.5°, 22.7°, 23.2°, 23.5°, and 23.8°±0.2°²θ. The error range may be ±0.1°²θ.

[0063] Furthermore, S-oxprenolol dihydrogen phosphate is provided, characterized by a powder X-ray diffraction pattern containing peaks at 6.8°, 7.8°, and 22.5°±0.2°²θ. The XRPD pattern may contain peaks at 4.4°, 6.8°, 7.8°, 17.0°, and 22.5°±0.2°²θ. The XRPD pattern may contain seven or more peaks selected from 4.4°, 6.8°, 7.8°, 17.0°, 22.5°, 22.9°, 23.5°, 23.6°, 24.2°, and 25.1°±0.2°²θ. The error range may be ±0.1°²θ.

[0064] Furthermore, S-oxprenolol dihydrogen phosphate is provided, characterized by a powder X-ray diffraction pattern containing peaks at 4.6°, 11.0°, and 20.6°±0.2°²θ. The XRPD pattern may further contain peaks at 17.1°, 18.4°, and 22.9°±0.2°²θ. The XRPD pattern may contain five or more peaks selected from 4.6°, 11.0°, 13.8°, 17.1°, 18.4°, 20.6°, 21.8°, 22.9°, and 26.3°±0.2°²θ. The error range may be ±0.1°²θ.

[0065] The present invention further provides pharmaceutically acceptable acid addition salts of (i) S-oxprenolol and (ii) an acid selected from oxalic acid, 1-hydroxy-2-naphthoic acid (xinafoic acid), hippuric acid (N-benzoylglycine), acetic acid, and naphthalene-1,5-disulfonic acid. The pharmaceutically acceptable acid addition salts formed from these acids may be as described above for salts formed with phosphoric acid.

[0066] The pharmaceutically acceptable acid addition salt may be (i) a salt of S-oxprenolol and (ii) oxalic acid, i.e., S-oxprenolol oxalate. The pharmaceutically acceptable acid addition salt may be S-oxprenolol hemioxalate ([C 15 H 23 NO3]2 + [O2CCO2] 2- ) or S-oxprenolol monooxalate ([C 15 H 23 NO3] + [HHO2CCO2] - ) may be the salt. The salt is typically S-oxprenolol monooxalate (i.e., S-oxprenolol hydrogen oxalate).

[0067] (i) S-oxprenolol and (ii) oxalic acid addition salts that are pharmaceutically acceptable are typically crystalline. S-oxprenolol oxalate may be a crystalline polymorph of S-oxprenolol oxalate designated as pattern 1. Pattern 1 of S-oxprenolol oxalate typically has a powder X-ray diffraction (XRPD) pattern containing peaks at 10.7°, 15.5° and 24.7°±0.2°²θ. The XRPD pattern may contain peaks at 10.7°, 15.5° and 24.7°±0.1°²θ.

[0068] The XRPD pattern of S-oxprenolol oxalate pattern 1 typically includes further peaks at 7.7°, 8.8°, and 17.0°±0.2°²θ. The XRPD pattern may also include further peaks at 7.7°, 8.8°, and 17.0°±0.1°²θ.

[0069] The XRPD pattern of S-oxprenolol oxalate pattern 1 may contain five or more peaks selected from 7.7°, 8.8°, 10.7°, 15.5°, 17.0°, 17.4°, 17.7°, 18.7°, 19.7°, 20.3°, 22.9°, 23.3°, 24.3°, 24.7°, 25.6°, and 26.3° ± 0.2°²θ. The XRPD pattern may contain seven or more of these peaks. The error range may be ±0.1°²θ.

[0070] The XRPD pattern may include all of these peaks. The XRPD pattern of S-oxprenolol oxalate pattern 1 may include the following peaks.

[0071] [Table 4]

[0072] S-oxprenolol oxalate may be a crystalline polymorph of S-oxprenolol oxalate designated as pattern 2. Pattern 2 of S-oxprenolol oxalate typically has a powder X-ray diffraction (XRPD) pattern containing peaks at 9.0°, 22.5°, and 24.4°±0.2°²θ. The XRPD pattern may contain peaks at 9.0°, 22.5°, and 24.4°±0.1°²θ.

[0073] The XRPD pattern of S-oxprenolol oxalate pattern 2 typically includes further peaks at 8.8°, 18.0°, and 23.3°±0.2°²θ. The XRPD pattern may also include further peaks at 8.8°, 18.0°, and 23.3°±0.1°²θ.

[0074] The XRPD pattern of S-oxprenolol oxalate pattern 2 may contain five or more peaks selected from 8.8°, 9.0°, 18.0°, 18.2°, 18.8°, 20.6°, 22.5°, 23.3°, 23.6°, 24.4°, and 24.9°±0.2°²θ. The XRPD pattern may contain seven or more of these peaks. The XRPD pattern may contain all of these peaks. The error range may be ±0.1°²θ.

[0075] The XRPD pattern of S-oxprenolol oxalate pattern 2 may include the following peaks.

[0076] [Table 5]

[0077] Furthermore, S-oxprenolol oxalate is provided, characterized by an XRPD pattern containing peaks at 10.7°, 15.5°, and 24.7°±0.2°2θ. The XRPD pattern may further contain peaks at 7.7°, 8.8°, and 17.0°±0.2°2θ. The XRPD pattern may contain five or more peaks selected from 7.7°, 8.8°, 10.7°, 15.5°, 17.0°, 17.4°, 17.7°, 18.7°, 19.7°, 20.3°, 22.9°, 23.3°, 24.3°, 24.7°, 25.6°, and 26.3°±0.2°2θ. The error range may be ±0.1°2θ.

[0078] Furthermore, S-oxprenolol oxalate is provided, characterized by an XRPD pattern containing peaks at 9.0°, 22.5°, and 24.4°±0.2°²θ. The XRPD pattern may further contain peaks at 8.8°, 18.0°, and 23.3°±0.2°. The XRPD pattern may contain five or more peaks selected from 8.8°, 9.0°, 18.0°, 18.2°, 18.8°, 20.6°, 22.5°, 23.3°, 23.6°, 24.4°, and 24.9°±0.2°²θ. The error range may be ±0.1°²θ.

[0079] composition The composition provided by the present invention contains at least 60% by weight of a pharmaceutically acceptable acid addition salt. The composition may contain at least 80% by weight or at least 95% by weight of a pharmaceutically acceptable acid addition salt based on the total weight of the composition. The composition may consist essentially of a pharmaceutically acceptable acid addition salt. The composition may consist of a pharmaceutically acceptable acid addition salt.

[0080] Therefore, the composition typically contains no more than 30% by weight of R-oxprenolol or its salt based on the total weight of the composition. For example, the composition may contain no more than 10% by weight or 1% by weight of R-oxprenolol or its salt based on the total weight of the composition.

[0081] The pharmaceutical composition of the present invention comprises (i) a pharmaceutically acceptable acid addition salt and (ii) a pharmaceutically acceptable excipient, carrier, or diluent. The pharmaceutical composition may be, for example, a tablet, capsule, powder, liquid, or suspension for oral administration; a liquid or suspension for injection; or a liquid, suspension, or powder for inhalation. The pharmaceutical composition is typically a tablet.

[0082] The pharmaceutical composition is typically substantially free of R-oxprenolol or its salts. For example, the pharmaceutical composition may contain less than 1.0% by weight or less than 0.5% by weight of R-oxprenolol or its salts. The enantiomer excess of the S-oxprenolol salt in the pharmaceutical composition is typically at least 80%, at least 90%, at least 95%, or at least 99%.

[0083] Excipients, carriers, and diluents that are acceptable as pharmaceuticals are well known to those skilled in the art.

[0084] The diluent may be any pharmaceutically acceptable diluent. The diluent is typically suitable for parenteral or oral administration. Examples of suitable liquid diluents include water, ethanol, and glycerol. Alternatively, the diluent may be selected from solid diluents such as lactose, glucose, sucrose, cellulose, corn starch, and potato starch. The diluent may contain a buffering component to control the pH. The buffer may be derived from phosphates, citrates, or acetates. The diluent may contain sodium chloride.

[0085] The pharmaceutical composition may include lubricants, such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; binders, such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrants, such as starch, alginic acid, alginate, or sodium starch glycolate; foaming mixtures; colorants; sweeteners; wetting agents, such as lecithin, polysorbate, or lauryl sulfate; and excipients selected from non-toxic and pharmacologically inert substances commonly used in pharmaceutical formulations. Such pharmaceutical formulations can be manufactured by known methods, for example, by mixing, granulation, tableting, sugar coating, or film coating processes.

[0086] The pharmaceutical composition may be a tablet containing, for example, one or more excipients selected from magnesium stearate, colloidal silica, microcrystalline cellulose, stearyl fumarate, and starch.

[0087] The composition, which is a liquid dispersion for oral administration, may be a syrup, emulsion, or suspension. The syrup may contain, for example, sucrose, glycerin, mannitol, or sorbitol as a carrier.

[0088] Compositions that are suspensions or emulsions may contain, for example, natural rubber, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol as a carrier. Suspensions or solutions for intramuscular injection may contain, together with a pharmaceutically acceptable acid addition salt, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol, and optionally, an appropriate amount of lidocaine hydrochloride.

[0089] Liquid preparations for injection, infusion, or inhalation may contain, for example, sterile water as a carrier, or they may be in the form of sterile isotonic saline.

[0090] The pharmaceutical composition may contain a pharmaceutically acceptable acid addition salt in an amount equivalent to 0.1 to 1000 mg of S-oxprenolol free base. For example, the pharmaceutical composition may contain a pharmaceutically acceptable acid addition salt in an amount equivalent to 20 to 400 mg or 100 to 300 mg of S-oxprenolol free base. For example, 134 mg of S-oxprenolol dihydrogen phosphate (molecular weight 363.3 gmol) -1 ) is 100 mg of S-oxprenolol free base (molecular weight 265.3 gmol) -1 This corresponds to ).

[0091] medical use Pharmacovigilant acid addition salts are useful for the treatment or prevention of diseases or conditions selected from cachexia, sarcopenia, neuromuscular diseases, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma, and anxiety disorders. Typically, these diseases or conditions are selected from cachexia, neuromuscular diseases, and muscle weakness.

[0092] Cachexia can be caused by an underlying disease. For example, cachexia can be caused by cancer, heart failure, chronic obstructive pulmonary disease (COPD), liver failure, kidney failure, stroke, rheumatoid arthritis, severe burns, or HIV / AIDS. Muscle weakness can be caused by an underlying disease. For example, muscle weakness can be caused by trauma, musculoskeletal injury, surgery, or immobilization. Muscle weakness may also be acquired muscle weakness in the intensive care unit (ICUAW). Neuromuscular diseases may include, for example, amyotrophic lateral sclerosis (ALS).

[0093] The present invention also provides a method for treating or preventing a disease or condition selected from cachexia, sarcopenia, neuromuscular disease, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma, and anxiety in an individual, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutically acceptable acid addition salt.

[0094] Medicinal acid addition salts are typically administered orally or parenterally.

[0095] The effective dose of a pharmaceutically acceptable acid addition salt is typically equivalent to 0.1 to 1000 mg of free S-oxprenolol base in a single dose. For example, a pharmaceutically acceptable single dose of an acid addition salt may be equivalent to 20 to 400 mg or 100 to 300 mg of free S-oxprenolol base. This dose can be administered once, twice, or three times a day, for example, twice or three times a day. For example, the total daily dose of a pharmaceutically acceptable acid addition salt may be equivalent to 300 to 800 mg of free S-oxprenolol base.

[0096] The following examples illustrate the present invention. [Examples]

[0097] Analysis method Powder X-ray diffraction (XRPD) XRPD analysis was performed using a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the sample between 3 and 35°²θ. The material was gently ground to disperse aggregates and loaded into a multiwell plate with Kapton or Mylar polymer film to support the sample. The multiwell plate was then placed in a diffractometer and analyzed using Cu K radiation (α1 λ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5) with transmission mode (step size 0.0130°²θ, step time 18.87 sec) and a generator setting of 40 kV / 40 mA. The data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0098] Polarizing microscope (PLM) The presence of crystalline material (birefringence) was determined using an Olympus BX50 microscope equipped with a cross-polarizing lens and a Motic camera. Images were captured using Motic Images Plus 3.0. Unless otherwise noted, all images were recorded using a 20x objective lens.

[0099] Thermogravimetric analysis / Differential scanning calorimetry (TGA / DSC) Approximately 5 mg of the material was placed in a tare-filled open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC, where it was kept at room temperature. The sample was then heated from 30°C to 400°C at a rate of 10°C / min, and the change in sample weight during this process was recorded along with the thermal flow response (DSC). Nitrogen was used as the sample purge gas at 200 cm⁻¹. 3 It was used at a flow rate of [number] minutes.

[0100] Example 1 - Characterization of S-oxprenolol Solid samples of S-oxprenolol were analyzed by XRPD and TGA / DSC.

[0101] S-oxprenoroll was determined to be crystalline by XRPD, and small birefringent particles were observed in PLM. Aggregation of the material was observed in PLM, with a mixture of large and small aggregates along with small discrete rod-shaped particles.

[0102] Thermal analysis of the material showed an endothermic event at a starting temperature of 56°C and a peak temperature of 59°C in DSC. No further thermal events were observed in DSC during further heating or cooling of the sample. TGA did not show a significant weight loss before decomposition, and the material decomposed above 150°C.

[0103] Due to the low melting point observed during molecular thermal analysis, additional development was carried out to identify solid forms with more desirable physical properties, such as a higher melting point.

[0104] Example 2 - Initial salt screening of S-oxprenolol Salt screening was performed for S-oxprenolol using 31 counterions and 6 solvent systems. The acids from which the counterions originated are shown in Table 1, and the solvent systems are shown in Table 2.

[0105] [Table 6]

[0106] [Table 7]

[0107] Salt screening was performed as follows: A solution was prepared by adding 100 μL of a suitable solvent to approximately 25 mg of free S-oxprenolol in a 1.5 mL screw-cap vial. For the water experiment, 300 μL was added to prepare a slurry. 1.05 equivalents of counterions were weighed into another 1.5 mL screw-cap vial. The slurry / solution of the counterions in 100-300 μL of a suitable solvent was added to the free base solution / slurry. For liquid counterions, a stock solution was prepared with the assigned solvent and added to the S-oxprenolol solution / slurry. For HCl, a stock solution was prepared with ethanol and used in the t-BME experiment for miscibility. For the D-gluconic acid experiment, water was used for the D-gluconic acid stock for miscibility.

[0108] Temperature cycling was performed for approximately 3 days in 4-hour cycles between ambient temperature (approximately 20°C) and 40°C. A retention period of 4 hours was provided at ambient temperature (approximately 20°C) followed by 4 hours at 40°C. After temperature cycling, the slurry was isolated by centrifugal filtration (nylon, 0.22 μm) and analyzed by XRPD. The solution was evaporated at ambient temperature (approximately 20°C) and pressure. The potential salt was dried under vacuum at 40°C for approximately 19 hours, re-analyzed by XRPD, stored at 40°C / 75% RH for approximately 19 hours, and re-analyzed by XRPD.

[0109] Of the counterions tested, most did not form solid crystalline salts with S-oxprenolol. Most counterions formed gum or oily substances with S-oxprenolol. The results are shown in Table 3.

[0110] [Table 8]

[0111] The following acids were found to form crystal structures with S-oxprenolol. ·phosphoric acid; 1-Hydroxy-2-Naphthoic Acid; ·hippuric acid; Oxalic acid; • Acetic acid; and Naphthalene-1,5-disulfonic acid.

[0112] We further evaluated the salt formation with these six types of acids.

[0113] Example 3 - Further salt development phosphoric acid The phosphate was prepared as follows: Approximately 500 mg of S-oxprenolol in a 20 mL screw-cap vial was dissolved in 2 mL of ethanol. 1.05 equivalents of phosphoric acid were added to the free base solution as a stock solution in 4 mL of ethanol. The pink solution was evaporated at ambient temperature (approximately 20°C) and pressure. After approximately 10 days, 100 μL of hexane was added. The preparation was dried under vacuum at ambient temperature (approximately 20°C) for approximately 26 hours. Partial dissolution was observed when 6 mL of ethanol was added. Precipitation was observed immediately after partial dissolution, and a stable slurry was formed. XRPD analysis was performed on the solid.

[0114] A small amount of solid was mixed with 200 μL of ethanol and stirred at ambient temperature (approximately 20°C) for about 30 minutes to evaluate whether the addition of ethanol caused dissolution. A movable slurry was prepared by adding 2 mL of ethanol to the immobile slurry. 200 μL of the slurry was also added. The slurry was isolated by Buchner filtration using grade 1 filter paper and dried under vacuum at ambient temperature (approximately 20°C) for about 22 hours. The dried solid was analyzed by XRPD.

[0115] The salt was identified as a monosalt of phosphoric acid, specifically S-oxprenolol dihydrogen phosphate.

[0116] The crystalline form of the salt with S-oxprenolol (S-oxprenolol dihydrogen phosphate) formed during the initial salt screening is designated as Pattern 1, and its XRPD properties are shown in Table 4 and Figure 1 below.

[0117] [Table 9]

[0118] XRPD analysis of dihydrogen phosphate pattern 1 after heating to 40°C, vacuum drying at ambient temperature (approximately 20°C), and storage at 40°C / 75%RH showed that dihydrogen phosphate pattern 1 was maintained.

[0119] Further analysis of dihydrogen phosphate pattern 1 from ethanol yielded the following results. Thermal analysis showed a 0.6% mass loss up to approximately 104°C. A further 1.0% loss was observed during the thermal event. The weight loss was equivalent to 0.3 equivalents of water. · 1 1H NMR analysis showed the absence of ethanol and confirmed that the material's structure was consistent with the observed characteristics. PLM analysis revealed birefringent particles with a rod-like morphology. • HPLC analysis showed a surface purity of 99.4%. The purity at the time of application was 99.9% surface purity.

[0120] 1-Hydroxy-2-naphthoic acid (xinafoic acid) Xinafoate pattern 1 was observed in experiments using ethanol, ethyl acetate, t-BME, THF, and water. XRPD analysis of xinafoate pattern 1 after vacuum drying at 40°C and storage at 40°C / 75%RH showed that xinafoate pattern 1 was maintained.

[0121] Thermal analysis of xinafoate pattern 1 from t-BME indicated that the material was anhydrous. DSC analysis showed an endothermic event with an onset temperature of approximately 78°C (peak 85°C).

[0122] Xinafoate had a relatively low melting point.

[0123] Hippuric acid (N-benzoylglycine) Hippurate pattern 1 was observed in experiments using acetone, ethyl acetate, and t-BME. XRPD analysis of hippurate pattern 1 after vacuum drying at 40°C showed that hippurate pattern 1 was maintained. Deliquescent formation into an amorphous material was observed upon storage at 40°C / 75%RH.

[0124] Hippurate showed low hygroscopic properties.

[0125] Oxalic acid In salt formation experiments with oxalic acid, two crystalline potential salts were obtained. The following results were obtained: The salts were determined to be monooxalates.

[0126] Oxalate pattern 1: Oxalate pattern 1 was observed in experiments using acetone, ethyl acetate, t-BME, and THF. XRPD analysis of oxalate pattern 1 after vacuum drying at 40°C and storage at 40°C / 75%RH showed that oxalate pattern 1 was maintained.

[0127] Further analysis of oxalate pattern 1 from THF yielded the following results. • Thermal analysis (Figure 31) showed that the material was anhydrous and decomposition began at approximately 175°C or higher. DSC analysis showed an endothermic event with an initiation temperature of approximately 128°C (peak 130°C). • 1H NMR analysis (Figure 32) showed the absence of THF, indicating that the material was consistent with its structure.

[0128] Further analysis of oxalate pattern 1 from ethyl acetate yielded the following results. PLM analysis revealed birefringent particles lacking a clear morphology. • A solubility of 32 mg / mL in water was observed.

[0129] Oxalate patterns 1 and 2: Oxalate pattern 2 was observed from ethanol and water. XRPD analysis of oxalate pattern 2 after vacuum drying at 40°C showed that a mixture of patterns 1 and 2 was obtained. After storage at 40°C / 75%RH, the mixture was observed to be largely unchanged.

[0130] Further analysis of mixtures of oxalate patterns 1 and 2 from ethanol yielded the following results. • Thermal analysis showed weight losses of 1.3% and 0.7% up to approximately 150°C. The observed weight loss was equivalent to 0.4 equivalents of water. DSC analysis showed two endothermic events at starting temperatures of approximately 51°C (peak 81°C) and 110°C (peak 127°C). A shoulder peak was observed at approximately 113°C. • 1H NMR analysis showed the absence of ethanol and that the material was consistent with the structure.

[0131] Figure 2 shows the XRPD diffractograms for oxalate patterns 1 and 2.

[0132] Acetic acid In salt formation experiments with acetic acid, two potential salt polymorphs were obtained. The following results were obtained:

[0133] Acetate pattern 1 was observed from all six solvent systems. XRPD analysis of acetate pattern 1 from ethanol and water after vacuum drying at 40°C showed that acetate pattern 1 was maintained. Pattern 1 from ethanol was maintained even after storage at 40°C / 75%RH, but partial deliquescence was observed. Pattern 1 from water was also maintained even after storage at 40°C / 75%RH. XRPD analysis of acetate pattern 1 from acetone, ethyl acetate, t-BME, and THF after vacuum drying at 40°C showed that pattern 2 was obtained.

[0134] Pattern 2 materials from acetone, ethyl acetate, and t-BME were observed to deliquesce after storage at 40°C / 75%RH. Ethyl acetate and t-BME yielded mainly amorphous materials after storage at 40°C / 75%RH. Pattern 2 material from acetone after vacuum drying at 40°C showed a preferred orientation, and the pattern 2 peaks remained even after storage at 40°C / 75%RH. Pattern 2 material from THF was observed to partially deliquesce after storage at 40°C / 75%RH, but still showed several pattern 2 peaks. Thermal analysis of acetate pattern 2 indicated that the material was anhydrous. An endothermic event was observed at approximately 60°C (peak 101°C).

[0135] Acetate showed low hygroscopic properties.

[0136] Naphthalene-1,5-disulfonic acid In the experiment with naphthalene-1,5-disulfonic acid, two crystalline potential salts were obtained by evaporation from the poor solvent addition experiment. Pattern 2 was observed only as a mixture with Pattern 1 from t-BME. In the diffractogram obtained from the t-BME experiment, additional peaks were observed at approximately 9.9, 11.6, 13.9, 16.7, and 16.9°²θ. The following results were obtained. Naphthalene-1,5-disulfonate pattern 1 was observed in experiments using acetone, ethanol, and THF. • Naphthalene-1,5-disulfonic acid material derived from acetone was observed to be a solid, while materials derived from ethanol, t-BME, and THF were observed to be sticky solids. XRPD analysis of naphthalene-1,5-disulfonate pattern 1 after vacuum drying at 40°C showed that pattern 1 was maintained.

[0137] Analysis of naphthalene-1,5-disulfonate pattern 1 from acetone after the addition of a poor solvent yielded the following results. Initial thermal analysis before vacuum drying showed a 3.9% decrease up to approximately 200°C. The observed decrease corresponded to 0.4 equivalents of acetone. DSC analysis showed a broad endothermic event with an initiation temperature of approximately 28°C (peak 94°C). • Thermal analysis after vacuum drying at 40°C showed a 3.3% decrease up to approximately 100°C. The observed decrease corresponded to 0.3 equivalents of acetone. DSC analysis showed a broad endothermic event with a peak at approximately 100°C. The onset temperature could not be determined.

[0138] Conclusions on further salt development Six crystalline salts were generated during the initial salt screening. These salts were formed from phosphoric acid, 1-hydroxy-2-naphthoic acid, hippuric acid, oxalic acid, acetic acid, and naphthalene-1,5-disulfonic acid.

[0139] The formation and physical properties of these six salts were further investigated.

[0140] A salt formed with phosphoric acid (S-oxprenolol dihydrogen phosphate) was found to be suitable for use in pharmaceutical formulations. In particular, S-oxprenolol dihydrogen phosphate had a high melting point and good crystallinity.

[0141] Oxalates also possessed desirable physical properties. However, oxalates did not have a favorable toxicity profile, making these salts less suitable for pharmaceutical formulations.

[0142] The remaining crystalline salts were not very suitable for pharmaceutical formulations. Xinafoate and naphthalene-1,5-disulfonate had large molecular weights that were not justified by changes in their physical properties. Hippurate and acetate exhibited poor hygroscopic properties.

[0143] Example 4 - Polymorphic screening of dihydrogen phosphates Amorphous S-oxprenolol dihydrogen phosphate was produced by freeze-drying the salt from water.

[0144] To gain an understanding of solubility and to assist in selecting an appropriate solvent system for polymorph screening, solvent solubility screening was performed. The results of the approximate solubility screening of amorphous S-oxprenolol dihydrogen phosphate are shown in Table 5 (showing pattern 2, pattern 3, or a mixture of patterns 2 and 3) and are summarized below. • High solubility exceeding 194 mg / mL was observed for 50% acetone, 50% water (%v / v), DMSO, methanol, DMF, and water. • For 90% 2-propanol:10% water (%v / v), DMA, and NMP, moderate solubility of 47 mg / mL or higher was observed. • Low solubility of less than 10 mg / mL was observed in 24 of the 32 solvent systems tested. XRPD analysis primarily yielded phosphate patterns 2 or 3, with a mixture of patterns 2 and 3 observed.

[0145] [Table 10]

[0146] Patterns 2 and 3 were characterized by XRPD, and the results are shown in Tables 6 and 7 below.

[0147] [Table 11]

[0148] [Table 12]

[0149] The XRPD diffractograms for patterns 2 and 3 of S-oxprenolol dihydrogen phosphate are shown in Figures 3 and 4, respectively.

[0150] Further samples of pattern 3 were prepared as follows. Approximately 2.5 g of S-oxprenolol in a 100 mL Duran flask was dissolved in 10 mL of ethanol. 1.05 equivalents of phosphoric acid were added to the free base solution as a 0.5 M stock solution in 20 mL of ethanol. • 30 mL of heptane was stirred in a 250 mL Duran flask at ambient temperature (approximately 20°C), and the S-oxprenolol / phosphate solution was added dropwise over approximately 9 minutes. Off-white precipitates were observed. • Approximately 0.5 mL of slurry was isolated by centrifugal filtration (nylon, 0.22 μm) and analyzed by XRPD. The slurry was isolated by Buchner filtration using Grade 1 filter paper and dried under vacuum at ambient temperature (approximately 20°C) for approximately 69 hours. The isolation yield was 2.97 g, or 87%. • XRPD analysis showed that phosphate pattern 2 was obtained before drying, and phosphate pattern 3 was obtained after drying. • Thermal analysis showed a 2.1% decrease up to approximately 100°C, followed by a 0.1% decrease up to approximately 120°C. The observed weight loss was equivalent to 0.5 equivalents of water. DSC analysis showed an endothermic event with an initiation temperature of approximately 88°C (peak 91°C), followed by a shallow endothermic event with an initiation temperature of approximately 171°C (peak 172°C). · 1 ¹H NMR analysis showed 0.1 equivalents of ethanol. • Using 1.0 equivalent of triphenyl phosphate 31 NMR analysis indicated that the salt was a monophosphate.

[0151] Phosphate pattern 2 was isolated from temperature cycling in 1-butanol. XRPD analysis after drying showed that the solid was converted to phosphate pattern 3.

[0152] conclusion S-oxprenolol dihydrogen phosphate pattern 3 was identified as the most suitable polymorph for scale-up. Pattern 3 exhibits good crystallinity with a rod-like morphology, a high melting point, and stability.

[0153] Example 4 - Comparison of dihydrogen phosphate polymorphs S-oxprenolol dihydrogen phosphate pattern 3 was found to have improved suitability for scale-up compared to patterns 1 and 2. In particular, pattern 3 was found to have improved stability compared to patterns 1 and 2.

[0154] S-oxprenolol dihydrogen phosphate pattern 3 was observed to exhibit excellent stability, achieving HPLC purity exceeding 99.9% area after storage for 7 days at ambient temperature and after storage for 7 days at 40°C / 75%RH in both cases.

[0155] In contrast, patterns 1 and 2 of S-oxprenolol dihydrogen phosphate were found to have problems with stability and scale-up ability.

[0156] Example 5 - Single Crystal Analysis Single-crystal X-ray diffraction (SXRD) Appropriate crystals of S-oxprenolol dihydrogen phosphate patterns 2 and 3 were selected and mounted in loops using paratone oil. Data were collected using a Bruker D8 Venture diffractometer with a Photon III detector operating in shutterless mode, using Cu-Kα radiation (1.54178 Å) at 100 K. All non-hydrogen atoms were identified by Fourier mapping, and their positions were refined before describing the thermal motion of all non-hydrogen atoms anisotropically.

[0157] The structures were solved using the ShelXT (intrinsic phase method) structure determination program in the Olex2 software package and refined using the ShelXL refinement package with least squares method. Data were collected, solved, and refined using the chiral orthorhombic space group P212121 for pattern 2 and the chiral monoclinic space group P21 for pattern 3. A series of constraints were applied for final refinement. All CH, CH2, and NH2 groups were refined with a fixed Uiso of 1.2x. All CH3, OH, and OH2 groups were refined with a fixed Uiso of 1.5x.

[0158] S-Oxprenolol dihydrogen phosphate pattern 2 Single crystals of S-oxprenolol dihydrogen phosphate pattern 2 were grown by rapidly cooling an ethanol solution of S-oxprenolol dihydrogen phosphate from ambient temperature to 4°C.

[0159] The unit cell dimensions of the collected structures were as follows: Orthorhombic P212121 a = 7.7822(4) Å α = 90° b = 13.2653(5) Å β = 90° c = 39.5732(15) Å γ = 90° Volume = 4085.3(3) Å 3 Z = 4, Z' = 2 Temperature = 100(2)K

[0160] The asymmetric unit consisted of two formula units of S-oxprenolol dihydrogen phosphate and one ethanol molecule (i.e., hemiethanol solvate).

[0161] The final refinement parameters were as follows: R1[I > 2σ(I)] = 2.80 % GooF (Goodness of fit) = 1.039 wR2 (all data) = 7.76% R int = 5.69% Flack x parameter = 0.012(4)

[0162] S-Oxprenolol dihydrogen phosphate pattern 3 Single crystals of S-oxprenolol dihydrogen phosphate pattern 3 were obtained by adding THF (a poor solvent) to a solution of 90% acetone and 10% water and storing it under ambient conditions for about two weeks.

[0163] The unit cell dimensions of the collected structures were as follows: Orthorhombic P21 a = 7.76070(10) Å α = 90° b = 36.7729(6) Å β = 94.0602(11)° c = 12.9496(2) Å γ = 90° Volume = 3686.33(10) Å 3 Z = 8, Z' = 4 Temperature = 100K

[0164] The asymmetric unit consisted of four formula units of S-oxprenolol dihydrogen phosphate and one water molecule (i.e., 0.25 water molecules per S-oxprenolol dihydrogen phosphate molecule).

[0165] The final refinement parameters were as follows: R1[I > 2σ(I)] = 3.09% GooF (Goodness of fit) = 1.038 wR2 (all data) = 8.10% R int = 5.42% Flack x parameter = 0.000(6)

Claims

1. (i) S-oxprenolol; and (ii) Phosphate, A pharmaceutically acceptable acid addition salt.

2. The pharmaceutically acceptable acid addition salt according to claim 1, wherein the pharmaceutically acceptable acid addition salt is crystalline.

3. The pharmaceutically acceptable acid addition salt according to claim 1 or claim 2, wherein the pharmaceutically acceptable acid addition salt is S-oxprenolol dihydrogen phosphate.

4. The pharmaceutically acceptable acid addition salt according to any one of the above claims, wherein the pharmaceutically acceptable acid addition salt is S-oxprenolol mono-dihydrogen phosphate.

5. The pharmaceutically acceptable acid addition salt according to claim 3 or claim 4, wherein the S-oxprenolol dihydrogen phosphate is in the form of S-oxprenolol dihydrogen phosphate crystal polymorph pattern 3 having a powder X-ray diffraction pattern containing peaks at 4.8°, 7.1°, and 8.2°±0.2°2θ.

6. The pharmaceutically acceptable acid addition salt according to claim 5, wherein the powder X-ray diffraction pattern further includes peaks at 22.5°, 22.7°, and 23.2°±0.2° 2θ.

7. The pharmaceutically acceptable acid addition salt according to claim 5 or 6, wherein the powder X-ray diffraction pattern includes seven or more peaks selected from 4.8°, 7.1°, 8.2°, 14.2°, 14.4°, 22.5°, 22.7°, 23.2°, 23.5°, and 23.8°±0.2°²θ.

8. A pharmaceutically acceptable acid addition salt according to any one of the above claims, having a melting point of 80°C or higher.

9. A pharmaceutically acceptable acid addition salt according to claim 8, having a melting point of 85°C to 90°C.

10. A composition comprising at least 60% by weight of a pharmaceutically acceptable acid addition salt according to any one of the above claims, based on the total weight of the composition.

11. The composition according to claim 10, comprising 30% by weight or less of R-oxprenolol or a salt thereof based on the total weight of the composition.

12. (i) a pharmaceutically acceptable acid addition salt according to any one of claims 1 to 9, and (ii) a pharmaceutically acceptable excipient, carrier or diluent.

13. The pharmaceutical composition according to claim 12, wherein the enantiomer excess of the pharmaceutically acceptable acid addition salt in the pharmaceutical composition is at least 90%, preferably at least 95%.

14. The pharmaceutical composition according to claim 12 or claim 13, wherein the pharmaceutical composition is a tablet.

15. A pharmaceutically acceptable acid addition salt according to any one of claims 1 to 9, for use in the treatment of the body of a human or animal.

16. A pharmaceutically acceptable acid addition salt according to any one of claims 1 to 9, for use in the treatment or prevention of a disease or condition selected from cachexia, sarcopenia, neuromuscular disease, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma, and anxiety.

17. An acid addition salt that is pharmaceutically acceptable for use according to claim 16, wherein the disease or condition is selected from cachexia, neuromuscular disease and muscle weakness.

18. The pharmaceutically acceptable acid addition salt for use according to claim 16 or 17, wherein the neuromuscular disease is amyotrophic lateral sclerosis.

19. A method for treating or preventing a disease or condition selected from cachexia, sarcopenia, neuromuscular disease, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma, and anxiety disorder in a patient, comprising administering a therapeutically effective amount of a pharmaceutically acceptable acid addition salt described in any one of claims 1 to 9.

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