Organic acid addition salts of s-pindolol

Abstract

To provide a solid form of S-pindolol that is crystalline, stable, and has a color suitable for pharmaceutical use.SOLUTION: Provided is a pharmaceutically acceptable acid addition salt of: (i) S-pindolol; and (ii) an organic acid, wherein the organic acid has a pKa1 of greater than or equal to 2.5 and a chemical formula represented by CxHy(CO2H)z, wherein x is 1 to 10, y is 2 to 20, and z is 1 or 2.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to salts of S-pindolol and pharmaceutical compositions containing such salts. The medical use of such salts is also described.

Background Art

[0002] S-pindolol is a β-adrenergic receptor antagonist and is also known as (-)-pindolol. The systematic name of S-pindolol is (2S)-1-(1H-indol-4-yloxy)-3-(propan-2-ylamino)propan-2-ol, and the structure of this compound is shown below.

Chemical Formula

[0003] S-pindolol has an affinity for both β-adrenergic receptors and 5-HT1a receptors and is useful for treating many disorders. WO2008 / 068477A1 describes the treatment of cachexia with S-pindolol.

[0004] Pindolol is approved for the treatment of certain conditions in racemic form. S-pindolol is known to be the more pharmacologically active enantiomer. It has been discovered in the present invention that S-pindolol has properties that can make it difficult to formulate as an oral drug such as a tablet. In particular, S-pindolol can decompose and discolor during storage, sometimes under specific conditions.

[0005] There is a need to develop a solid form of S-pindolol that is well-suited for use in clinical situations. In particular, it is desirable to develop a solid that is crystalline, stable, and has a color suitable for pharmaceutical use.

[0006] The S-pindolol tartrate is described in Kaumann et al, British Journal of Pharmacology 1986 89 (1) 207-218. The S-pindolol hydrochloride is described in the Japanese Patent Application JPH01287064(A). The racemic benzoate of pindolol is described in Pietilainen et al, Drug Development and Industrial Pharmacy, 22(11), 1063-1073 (1996).

Summary of the Invention

[0007] The inventors have found that salts of S-pindolol formed with organic mono- and di-carboxylic acids having a pK of at least 2.5 are well suited for pharmaceutical formulations. In particular, these salts have been found to be stable, crystalline, and have a higher melting point compared to the S-pindolol free base. Some of the S-pindolol salts also have the desirable pure white color for clinical use in solid form. a The present invention relates to (i) S-pindolol; and (ii) a pharmaceutically acceptable acid addition salt of an organic acid, wherein the organic acid has a pK of 2.5 or more and a chemical formula represented by C

[0008] H a1 and C x H y (CO2H) z wherein x is 1 to 10, y is 2 to 20, and z is 1 or 2, and relates to a pharmaceutically acceptable acid addition salt.

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

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

[0011] The present invention also provides a pharmaceutically acceptable acid addition salt for use in the treatment of the human or animal body.

Brief Description of the Drawings

[0012]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Mode for Carrying Out the Invention

[0013] The organic acid has a pK of 2.5 or more. a1 That is, the organic acid is a relatively weak acid. The organic acid preferably has a pK of 3.0 to 5.0. For example, the pK of the organic acid can be from 4.0 to 4.5. The pK is the acid dissociation constant of the first proton dissociated from the acid. In the case of a monocarboxylic acid, the pK simply corresponds to the acid dissociation constant pK. The pK value used in this specification is measured at 25°C. The pK of the organic acid a1 a1 a1 is the acid dissociation constant of the first proton dissociated from the acid. In the case of a monocarboxylic acid, the pK a1 corresponds simply to the acid dissociation constant pK a The pK used in this specification a1 values are those measured at 25°C. The pK of the organic acid a ​​Values and pK a1 The values are readily available to those skilled in the art.

[0014] The organic acid has the chemical formula represented by C x H y (CO2H) z wherein x is 1 to 10, y is 2 to 20, and z is 1 or 2. Thus, the organic acid contains a hydrocarbyl moiety (C x H y , consisting of hydrogen and carbon) and one or two carboxylic acid groups (CO2H). Typically, x is 2 to 7 and H is 2 to 6. The C x H y group can be an arenyl group, an alkyl group, or an alkenyl group. For example, the C x H y group can be a divalent C 2-7 alkyl group, a divalent C 2-7 alkenyl group, or a divalent phenyl group optionally substituted with one or two methyl groups.

[0015] The organic acid can be, for example, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, propionic acid, glutaric acid, adipic acid, phenylacetic acid, phthalic acid (including o-, m-, and p-phthalic acid), and naphthoic acid (including 1- and 2-naphthoic acid).

[0016] The pK a1 of these acids is shown in the following table. When the acid is a monocarboxylic acid, the pK a1 described is the pK a of that acid.

Table 1

[0017] The structures of benzoic acid, succinic acid, and fumaric acid are as follows.

Chemical formula

[0018] Typically, the organic acid is benzoic acid or succinic acid. Preferably, the organic acid is benzoic acid.

[0019] The pharmaceutically acceptable acid addition salts are salts of S-pindolol and thus contain cations formed from S-pindolol. The cations formed from S-pindolol typically have the following structure:

Chemical formula

[0020] The enantiomeric excess of the S-enantiomer of the pindolol cation in the pharmaceutically acceptable salts is typically at least 80%. Thus, of the cations in the salt, at least 90 mol% are typically in the S configuration. The enantiomeric excess is typically at least 95%. The cations of S-pindolol in the pharmaceutically acceptable acid addition salts are 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, for example by polarimetry or using chiral high performance liquid chromatography (HPLC).

[0021] Thus, the pharmaceutically acceptable acid addition salts typically contain no more than 10 mol% of salts containing cations that are the R-enantiomer of pindolol or protonated R-pindolol molecules. For example, the pharmaceutically acceptable acid addition salts typically contain substantially no salts containing cations that are the R-enantiomer of pindolol or protonated R-pindolol molecules.

[0022] The pharmaceutically acceptable acid addition salts are typically crystalline. Thus, the salts can have a three-dimensional crystal structure containing repeating unit cells. The pharmaceutically acceptable acid addition salts can be in solid form, for example, in the form of crystals or crystallites of the pharmaceutically acceptable acid addition salts.

[0023] Pharmaceutically acceptable acid salts can be in the form of solvates. The solvate of a salt is the solid form of the salt containing solvent molecules. For example, the salt can be a hydrate. Typically, the salt is not a solvate. For example, a pharmaceutically acceptable acid addition salt can be anhydrous.

[0024] Pharmaceutically acceptable acid addition salts typically have a melting point higher than that of the S-pindolol free base. The salt can have a melting point of 100 °C or higher, for example, 110 °C to 170 °C. Typically, the melting point of the salt is 130 °C to 160 °C. The melting point can be determined, for example, using differential scanning calorimetry (DSC).

[0025] Pharmaceutically acceptable acid addition salts can be formed by any suitable method. Typically, the S-pindolol free base is treated with an organic acid in a solvent. The solvent can be water, an alcohol (such as ethanol or 2-propanol), an ester (such as ethyl acetate), a ketone (such as acetone) or an ether (such as tetrahydrofuran (THF) or ethyl ether). The resulting pharmaceutically acceptable acid addition salt can dissolve in the solvent or precipitate from the solution. The pharmaceutically acceptable acid addition salt can be isolated by a suitable method, such as filtration or solvent evaporation.

[0026] The pharmaceutically acceptable acid addition salt can be S-pindolol benzoate. Thus, the salt can contain a cation derived from S-pindolol and a benzoate anion. The stoichiometry of the cation and anion can typically be about 1:1, for example, 0.9:1.0 to 1.1:1.0 (i.e., 0.9 to 1.1 moles of cation can be present per mole of anion). Preferably, the S-pindolol benzoate is S-pindolol monobenzoate. Thus, the salt can be represented by the formula [C 14 H 21 N2O2] + [C6H6COO] - as shown.

[0027] Pharmaceutically acceptable acid addition salts are typically crystalline. The °2θ values described herein are measured using an X-ray wavelength of CuKα1 radiation (λ = 1.54060 Å). When the X-ray powder diffraction pattern includes peaks, the relative intensity of those peaks is typically at least 5% or at least 10%. The error range of the °2θ values is typically ±0.2°2θ, but alternatively the error range may be ±0.1°2θ.

[0028] The S-pindolol benzoate can be in the form of the crystalline polymorph of S-pindolol benzoate represented by Pattern 1. The S-pindolol benzoate Pattern 1 typically has an X-ray powder diffraction (XRPD) pattern including peaks at 8.1°, 11.4°, and 17.0° ± 0.2° 2θ.

[0029] The XRPD pattern of the S-pindolol benzoate Pattern 1 typically further includes peaks at 5.7°, 12.5°, and 18.4° ± 0.2° 2θ.

[0030] The XRPD pattern of the S-pindolol benzoate Pattern 1 may include five or more peaks selected from 5.7°, 8.1°, 11.4°, 12.5°, 12.8°, 15.4°, 16.2°, 17.0°, 18.4°, 20.2°, 23.0°, 23.8°, 24.0°, and 25.1° ± 0.2° 2θ. The XRPD pattern may include all of these peaks. The XRPD pattern of the S-pindolol benzoate Pattern 1 may include the following peaks.

Table 2

[0031] The XRPD pattern of the S-pindolol benzoate Pattern 1 may be substantially as shown in Figure 6.

[0032] The infrared spectrum of the S-pindolol benzoate Pattern 1 is typically 1638 - 1648 cm -1 , 2964 - 2974 cm -1, 3022~3032 cm -1 and 3250~3260 cm -1 contains one or more peaks in the range of. For example, the infrared spectrum is about 1643 cm -1 , 2969 cm -1 , 3027 cm -1 and 3255 cm -1 and may contain peaks at.

[0033] The melting point of S-pindolol benzoate Pattern 1 is typically in the range of 130~140 °C, for example, about 135 °C.

[0034] S-pindolol benzoate Pattern 1 can be produced by a process including recrystallizing S-pindolol benzoate from solvents that are 1-butanol, 1-propanol, 1,2-dichloroethane, 1,4-dioxane, 2-methyl THF, 2-methyl-1-propanol, 2-propanol, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methanol, methyl isobutyl ketone and 2-ethoxyethanol.

[0035] S-pindolol benzoate can be in the form of a crystalline polymorph of S-pindolol benzoate designated as Pattern 2. S-pindolol benzoate Pattern 2 typically has an X-ray powder diffraction (XRPD) with peaks at 9.2° ± 0.2° 2θ.

[0036] S-pindolol benzoate Pattern 2 typically has an X-ray powder diffraction (XRPD) pattern with peaks at 16.9°, 18.9° and 20.1° ± 0.2° 2θ. The XRPD pattern of S-pindolol benzoate Pattern 2 typically further includes peaks at 9.2°, 13.9° and 20.7° ± 0.2° 2θ.

[0037] The XRPD pattern of S-pindolol benzoate Pattern 2 may include five or more peaks selected from 8.3°, 9.2°, 12.4°, 13.0°, 13.9°, 16.9°, 18.5°, 18.9°, 19.1°, 20.1°, 20.7°, 21.3°, 23.4°, 24.8°, 26.3°, 29.4° ± 0.2° 2θ. The XRPD pattern may include all of these peaks. The XRPD pattern of S-pindolol benzoate Pattern 2 may include the following peaks.

Table 3

[0038] The XRPD pattern of S-pindolol benzoate Pattern 2 may be substantially as shown in Figure 11 or Figure 21.

[0039] The infrared spectrum of S-pindolol benzoate Pattern 2 typically includes one or more peaks in the range of 1630 - 1640 cm -1 , 2924 - 2934 cm -1 , 3093 - 3103 cm -1 and 3214 - 3224 cm -1 . For example, the infrared spectrum may include peaks at about 1635 cm -1 , 2929 cm -1 , 3098 cm -1 and 3219 cm -1 .

[0040] The melting point of S-pindolol benzoate Pattern 2 is typically in the range of 153 - 163 °C, for example about 158 °C.

[0041] S-pindolol benzoate Pattern 2 can be produced by a process that includes recrystallizing S-pindolol benzoate from solvents that are ethanol, methanol: water (e.g., 95:5% v / v), methyl ethyl ketone, tetrahydrofuran and water. For example, S-pindolol benzoate Pattern 2 can be obtained by recrystallizing S-pindolol benzoate from methyl ethyl ketone.

[0042] The S-pindolol benzoate pattern 2 was found to be the thermodynamically stable form of S-pindolol benzoate. Therefore, S-pindolol benzoate is preferably in the form of S-pindolol benzoate pattern 2.

[0043] A pharmaceutically acceptable acid addition salt can be S-pindolol succinate. Therefore, the salt can contain a cation derived from S-pindolol and a succinate anion. The stoichiometry of the cation and anion can typically be about 1:1 or about 2:1, such as from 0.9:1.0 to 1.1:1.0 or from 1.9:1.0 to 2.1:1.0. Therefore, S-pindolol succinate can be S-pindolol hemisuccinate or S-pindolol monosuccinate. Preferably, S-pindolol succinate is S-pindolol monosuccinate. Therefore, the salt can be represented by the formula [C 14 H 21 N2O2] + [HOOC(C2H4)COO] - or ([C 14 H 21 N2O2] + )2[OOC(C2H4)COO] 2- as shown.

[0044] S-pindolol succinate can be in the form of a crystalline polymorph of S-pindolol succinate designated as pattern 1. The S-pindolol succinate pattern 1 typically has an X-ray powder diffraction (XRPD) pattern that includes peaks at 13.3°, 16.7°, and 19.5° ± 0.2° 2θ.

[0045] The XRPD pattern of S-pindolol succinate pattern 1 typically further includes peaks at 8.3°, 12.2°, and 12.8° ± 0.2° 2θ. The error range of the peak positions can be ±0.1° 2θ.

[0046] The XRPD pattern of S-pindolol succinate Form 1 may include five or more peaks selected from 8.3°, 12.2°, 12.8°, 13.3°, 16.7°, 16.9°, 19.5°, 21.5°, 22.0°, 22.7°, 24.1°, 24.3°, 25.0° ± 0.2° 2θ. The XRPD pattern of S-pindolol succinate Form 1 may include the following peaks. [Table 4]

[0047] The XRPD pattern of S-pindolol succinate Form 1 may be substantially as shown in Figure 16.

[0048] The infrared spectrum of S-pindolol succinate Form 1 typically includes one or more peaks in the ranges of 1685 - 1695 cm -1 , 2965 - 2975 cm -1 , 3148 - 3158 cm -1 and 3384 - 3394 cm -1 . For example, the infrared spectrum may include peaks at about 1690 cm -1 , 2970 cm -1 , 3153 cm -1 and 3389 cm -1 .

[0049] The melting point of S-pindolol succinate Form 1 is typically in the range of 110 - 120 °C, for example about 115 °C.

[0050] S-pindolol succinate Form 1 can be produced by a process comprising: (i) preparing S-pindolol free base and succinic acid; (ii) adding THF to S-pindolol free base and succinic acid to obtain a mixture; (iii) performing a cycle of heating the mixture from a low temperature of 15 °C - 30 °C to a high temperature of 35 °C - 50 °C and then back to the low temperature for a total of 60 - 120 hours in cycles lasting 3 - 5 hours; (iv) filtering the resulting salt; (v) drying the salt at 35 - 50 °C for 18 - 48 hours.

[0051] Pharmaceutically acceptable acid addition salts typically have a purity of about 90% or more, about 95% or more, or about 97% or more. The percent purity can be calculated as area % based on HPLC separation.

[0052] Composition The composition of 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.

[0053] Thus, the composition typically contains 30% by weight or less of R-pindolol or a salt thereof, based on the total weight of the composition. For example, the composition may contain 10% by weight or less or 1% by weight or less of R-pindolol or a salt thereof, based on the total weight of the composition.

[0054] The pharmaceutical composition of the present invention contains (i) a pharmaceutically acceptable acid addition salt and (ii) a pharmaceutically acceptable additive, carrier or diluent. The pharmaceutical composition can be, for example, a tablet, capsule, powder, solution or suspension for oral administration; a solution or suspension for injection; or a solution, suspension or powder for inhalation. The pharmaceutical composition is typically a tablet.

[0055] Pharmaceutically acceptable additives, carriers and diluents are well known to those skilled in the art.

[0056] The diluent can 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 can be selected from solid diluents such as lactose, dextrose, sucrose, cellulose, corn starch and potato starch. The diluent may contain a buffering component for controlling pH. The buffer can be derived from phosphate, citrate or acetate. The diluent may also contain sodium chloride.

[0057] The pharmaceutical composition may contain lubricants such as silica, talc, stearic acid, magnesium stearate or calcium stearate, and / or polyethylene glycol; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregating agents such as starch, alginic acid, alginates or sodium starch glycolate; foaming mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbate, lauryl sulfate; and additives selected from common, non-toxic and pharmacologically inert substances used in pharmaceutical formulations. Such pharmaceutical formulations can be manufactured by known methods, for example, by mixing, granulating, tableting, sugar coating or film coating processes.

[0058] The pharmaceutical composition can be tablets containing one or more additives selected from, for example, magnesium stearate, colloidal silica, crystalline cellulose, stearyl fumarate and starch.

[0059] Compositions that are dispersions for oral administration can be syrups, emulsions and suspensions. Syrups can contain, for example, sucrose, glycerin, mannitol or sorbitol as a carrier.

[0060] Compositions that are suspensions or emulsions can contain, for example, natural rubber, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as a carrier. Suspensions or solutions for intramuscular injection can contain a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if appropriate, a suitable amount of lidocaine hydrochloride, together with a pharmaceutically acceptable acid addition salt.

[0061] Solutions for injection or infusion or for inhalation can contain, for example, sterile water as a carrier, or can be in the form of sterile isotonic saline.

[0062] The pharmaceutical composition may contain a pharmaceutically acceptable acid addition salt in an amount corresponding to 0.1 to 1000 mg of S-pindolol free base. For example, the pharmaceutical composition may contain a pharmaceutically acceptable acid addition salt in an amount corresponding to 80 to 160 mg or 2.5 to 50 mg of S-pindolol free base. The pharmaceutical composition may contain a salt in an amount corresponding to 2.5 to 15 mg of S-pindolol free base. For example, 3.7 mg of S-pindolol benzoate (molecular weight 370.4 g / mol) corresponds to 2.5 mg of S-pindolol free base (molecular weight 248.3 g / mol).

[0063] The pharmaceutical composition typically does not substantially contain R-pindolol or a salt thereof. For example, the pharmaceutical composition may contain less than 1.0% by weight or less than 0.5% by weight of R-pindolol or a salt thereof.

[0064] Pharmaceutical uses The pharmaceutically acceptable acid addition salts are useful for the treatment or prevention of diseases or conditions selected from cachexia, sarcopenia, neuromuscular disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina, glaucoma and anxiety. Typically, the disease or condition is selected from cachexia and muscle weakness.

[0065] 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 can be intensive care unit-acquired weakness (ICUAW). The neuromuscular disorder can be, for example, amyotrophic lateral sclerosis.

[0066] The present invention also provides a method for treating or preventing in an individual a disease or condition selected from cachexia, sarcopenia, neuromuscular disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina, glaucoma and anxiety, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutically acceptable acid addition salt.

[0067] The pharmaceutically acceptable acid addition salts are typically administered orally or parenterally.

[0068] The effective amount of the pharmaceutically acceptable acid addition salt for a single dose is typically an amount corresponding to 0.1 - 1000 mg of S-pindolol free base. For example, the single dose of the pharmaceutically acceptable acid addition salt can be a dose corresponding to 2.5 - 50 mg or 80 - 160 mg of S-pindolol free base. The single dose can be an amount of the salt corresponding to 2.5 - 15 mg of S-pindolol free base. The dose can be administered once, twice or three times a day.

[0069] The following examples illustrate the present invention.

Example

[0070] Example 1: Salt of S-pindolol

[0071] (Analysis method) X-ray powder diffraction (XRPD) XRPD analysis was performed on a PANalytical X'pert pro equipped with a PIXcel detector (128 channels), and the sample was scanned at 3 - 35° 2θ. The substance was gently crushed to break up lumps and placed on a multi-well plate equipped with a Mylar polymer film to support the sample. Subsequently, the multi-well plate was placed in the diffractometer and analyzed using CuK radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) in transmission mode (step size 0.0130° 2θ, step time 18.87 s) with a generator setting of 40 kV / 40 mA. The data was visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0072] Thermogravimetric / differential scanning calorimetry (TG / DSC) Approximately 5 - 10 mg of the substance was added to an open aluminum pan whose tare had been measured in advance, placed in a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC, and held at room temperature. Subsequently, the sample was heated from 30 °C to 400 °C at a rate of 10 °C / min, and the change in sample weight during that time was recorded together with the heat flow response (DSC). Nitrogen was used as the purge gas at a flow rate of 300 cm 3 / min.

[0073] Differential scanning calorimetry (DSC) Approximately 5 mg of the substance was weighed on an aluminum DSC pan and sealed non-hermetically with an aluminum lid. Subsequently, the sample pan was placed in a TA Instruments Discovery DSC 2500 (equipped with an RC90 cooler) and held at 20 °C. Once a stable heat flow response was obtained, the sample and reference were heated to 180 °C at a scan rate of 10 °C / min, and the resulting heat flow response was monitored. Nitrogen was used as the purge gas at a flow rate of 50 cm 3 / min.

[0074] Infrared spectroscopy (IR) Infrared spectroscopy was performed using a Bruker ALPHA P spectrometer. A sufficient amount of the substance was placed in the center of the spectrometer plate, and spectra were obtained using the following parameters. · Resolution: 4 cm -1 · Background scan time: 16 scans · Sample scan time: 16 scans · Data collection: 4000 - 400 cm -1 · Result spectrum: Transmittance · Software: OPUS version 6

[0075] Nuclear magnetic resonance (NMR) The NMR experiment was performed using a Bruker AVIIIHD spectrometer equipped with a DCH cryostat operating at 500.12 MHz for protons. The experiment was carried out in deuterated DMSO or methanol, and each sample was prepared at a concentration of approximately 10 mM.

[0076] Dynamic vapor sorption (DVS) Approximately 10 - 20 mg of the sample was placed in the mesh vapor sorption balance pan and loaded onto a proprietary dynamic vapor sorption balance by Surface Measurement Systems. The sample was subjected to a ramp profile that increased by 10% each from 40% to 90% relative humidity (RH) while maintaining the sample at each step at 25 °C until a stable weight was achieved (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes). After completion of the sorption cycle, the sample was dried to 0% RH using the same procedure and then returned to 40% RH in a second sorption cycle. Two cycles were performed. The weight changes during the sorption / desorption cycles were plotted to determine the hygroscopicity of the sample. Subsequently, XRPD analysis was performed on the retained solid.

[0077] Variable temperature X-ray powder diffraction (VT-XRPD) VT-XRPD analysis was performed on a Philips X'Pert Pro Multipurpose diffractometer equipped with a temperature chamber. The sample was scanned from 4 to 35.99° 2θ using CuK radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) with a generator setting of 40 kV / 40 mA and performed in Bragg-Brentano geometry (step size 0.008° 2θ). The experimental parameters were carried out as follows: scanned at 30 °C; heated to 75 °C at 10 °C / min; held for 5 minutes; scanned at 75 °C; heated to 87 °C at 2 °C / min; held for 5 minutes; scanned at 87 °C; heated to 105 °C at 2 °C / min; held for 5 minutes; scanned at 105 °C; heated to 115 °C at 2 °C / min; held for 5 minutes; scanned at 115 °C; cooled to 30 °C at 10 °C / min; scanned at 30 °C.

[0078] High Performance Liquid Chromatography - Ultraviolet Detection (HPLC-UV) · Instrument: Dionex Ultimate 3000 · Column: Agilent Zorbax, SB-C18, 150 mm × 4.6 mm, 3.5 μm · Column temperature: 25 °C · Autosampler temperature: Ambient temperature · UV wavelength: 254 nm · Injection volume: 3 μl · Flow rate: 1.0 ml / min · Mobile phase A: 1.36 g of potassium dihydrogen phosphate + 1000 mL of water Adjust the pH to 4.0 ± 0.05 with phosphoric acid. Filter through a 0.45 μm membrane and degas. · Mobile phase B: Acetonitrile: Methanol (95:5 v / v) · Diluent: Water: Acetonitrile (20:80 v / v) · Gradient program:

Table 5

[0079] (Characterization of (S)-pindolol free base) A sample of the S-pindolol free base was characterized.

[0080] XRPD analysis showed that the S-pindolol free base is highly crystalline. The XRPD of the S-pindolol free base (free base pattern 1) is shown in Figure 1.

[0081] In the TG / DSC analysis, no mass loss due to TG was observed until decomposition at about 200 °C. This indicated that the substance is anhydrous and not solvated. In DSC, an endothermic event with an onset at 82 °C and a peak at 84 °C was observed, which was due to a solid-solid transition. A larger endothermic event due to melting, with an onset at 93 °C and a peak at 95 °C, was observed.

[0082] DVS analysis determined that the substance is slightly hygroscopic with an adsorption amount of 0.36 wt% (0.05 equivalents of water) at 90% RH. XRPD analysis after DVS showed that the substance remained unchanged.

[0083] (Primary salt investigation) 72 samples of 40 mg of the ACM-001 free base were weighed into 2 mL vials. 0.5 mL of the appropriate solvent was added to each vial, followed by 1.1 equivalents of the appropriate counterion.

[0084] The counterions used were derived from the following acids: hydrochloric acid (pKa1 = -6), sulfuric acid (pKa1 = -3), p-toluenesulfonic acid·H2O (pKa1 = -1.34), methanesulfonic acid (pKa1 = -1.2), maleic acid (pKa1 = 1.92), phosphoric acid (pKa1 = 1.96), L-tartaric acid (pKa1 = 3.02), fumaric acid (pKa1 = 3.03), citric acid (pKa1 = 3.13), S-(+)-mandelic acid (pKa1 = 3.37), benzoic acid (pKa1 = 4.19), and succinic acid (pKa1 = 4.21).

[0085] The solvents used were water, ethanol, 2-propanol, ethyl acetate, acetone, and tetrahydrofuran (THF).

[0086] The sample was subjected to a temperature cycle of approximately 72 hours in a cycle between the ambient temperature and 40 °C for 4 hours. All the solids formed were isolated by centrifugation before analysis by XRPD.

[0087] Some of the solids obtained after the first temperature cycle were found to be colored. In particular, the products formed using sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, phosphoric acid, L-tartaric acid, fumaric acid, and citric acid were colored when a specific solvent was used.

[0088] Subsequently, 0.5 mL of the reverse solvent was added to the vials containing solids insufficient for XRPD analysis (acetone was used for experiments in water and heptane was used for all other samples). Subsequently, these samples were subjected to the said temperature cycle for an additional 24 hours. The additional solids formed at this stage were isolated by centrifugation and analyzed by XRPD. Samples without solids were placed in a refrigerator (2 - 8 °C) for 72 hours. Since no solids were obtained, the lids of the samples were removed and evaporated for up to 1 week. The solids and gels obtained were analyzed by XRPD.

[0089] The samples remaining in the solution after 7 days, as well as all the samples obtained by temperature cycling, reverse solvent addition, and evaporation at ambient temperature, were placed in an oven at 40 °C for 72 hours to dry and then analyzed by XRPD. Table 1 shows the observations made after drying, where "s" indicates the formation of a solid, "gm" indicates the formation of a gum, and "cryst" indicates the formation of large crystals.

Table 6

[0090] The products obtained using sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, and L-mandelic acid were found to be mostly amorphous. Many of these products were also darkly colored.

[0091] The XRPD of the product formed using hydrochloric acid was found to correspond to that of the S-pindolol free base.

[0092] When S-pindolol was treated with tartaric acid, gum was formed from many solvents. When ethyl acetate was used as the solvent, a solid product was formed. However, after XRPD analysis, the solid product from ethyl acetate and tartaric acid was found to be the S-pindolol free base. Therefore, it was not possible to produce a crystalline salt of S-pindolol and tartaric acid.

[0093] The salts formed with fumaric acid, benzoic acid, and succinic acid were found to be crystals with XRPD patterns different from those of the S-pindolol free base. The fumarate was colored when formed from water, ethanol, 2-propanol, and acetone, and white when formed from ethyl acetate and THF. The succinate was colored when formed from water, but white otherwise. The benzoate was white when formed from any solvent.

[0094] Therefore, primary salt screening revealed that solid salt crystal forms could be formed from fumaric acid, benzoic acid, and succinic acid. The salts formed with these three acids were further characterized.

[0095] (Characterization of the fumarate) The solids recovered from the fumaric acid experiments in ethanol, 2-propanol, acetone, and THF were crystals, as shown in Figure 2, and did not match the free base pattern 1. Pattern 1 of the fumarate was obtained from ethanol, pattern 2 from 2-propanol and THF, and pattern 3 from acetone.

[0096] Patterns 1 and 2 were similar, but the peaks below 10° 2θ were not present in pattern 1. Therefore, pattern 2 could be a mixture containing pattern 1.

[0097] Patterns 1, 2, and 3 were characterized as follows.

[0098] Hemifumarate Pattern 1 During the TG analysis, a 22.8% weight loss (0.40 equivalents of fumaric acid) was observed between 200 °C and 280 °C, which may be due to decomposition. The decomposition occurred above 200 °C. In the DSC trace, an endothermic event related to melting was observed with an onset at 181 °C and a peak at 188 °C. A small endothermic event was recognized at 157 °C, which is higher than the other two hemifumarate forms. The TG and DSC traces are shown in Figure 3.

[0099] In DMSO-d6 1 Half an equivalent of fumaric acid was recognized in the 1H NMR spectrum. Ethanol was not present. Peak shifts and a broad peak of water were observed compared to the S-pindolol free base, indicating that salt formation occurred.

[0100] Hemifumarate Pattern 2 During the TG analysis, a 21.9% weight loss (potentially 0.39 equivalents of fumaric acid) was observed between 180 °C and 280 °C, which may be due to decomposition. The decomposition occurred above 200 °C. In the DSC trace, two shallow endothermic events with peaks at 152 °C and 184 °C were observed. The second event was related to the onset of decomposition. The TG and DSC traces are shown in Figure 4.

[0101] In DMSO-d6 1 In 1H NMR, it was determined that approximately 0.5 equivalents of fumaric acid were present in the sample. 1.08 wt% (0.04 equivalents) of THF was present. Peak shifts and a broad peak of water were observed compared to the S-pindolol free base, indicating that salt formation occurred.

[0102] Hemifumarate Pattern 3 During TG tracing, an 18.6% weight loss (potentially 0.34 equivalents of fumaric acid) was observed between 200 °C and approximately 270 °C. Decomposition occurred above 200 °C. In the DSC trace, one shallow endothermic event due to melting with a peak at 150 °C was observed. The TG and DSC traces are shown in Figure 5.

[0103] In DMSO-d6 1 In 1H NMR, a broad peak corresponding to approximately 0.5 equivalents of fumaric acid was seen at 6.35 ppm. A peak possibly due to acetone was observed at 2.09 ppm (7.09 wt% or 0.3 equivalents). However, there may be some overlap as peaks were observed in the free base NMR spectrum at that position. Peak shifts and a broad peak of water were observed compared to the ACM-001 free base, indicating that salt formation occurred.

[0104] Stability test of fumarate form Samples of S-pindolol hemifumarate pattern 2 were stored at 60 °C (sealed vial) or 40 °C / 75% RH (open vial) for 7 days. Samples stored at 60 °C were converted to pattern 1. Samples stored at 40 °C / 75% RH were converted to pattern 4, another form.

[0105] (Manufacture and characterization of S-pindolol benzoate pattern 1) Manufacture of S-pindolol benzoate pattern 1 271.69 mg (1.1 equivalents) of benzoic acid was added to approximately 500 mg of S-pindolol free base in a scintillation vial. The sample vial containing the acid was rinsed with 1 mL of ethyl acetate and the washings were added to the scintillation vial. An additional 1 mL of ethyl acetate was added, and a beige-colored solution containing a small amount of undissolved benzoic acid was observed.

[0106] The scintillation vial was capped and sealed with parafilm, and then a temperature cycle was carried out for approximately 72 hours in a cycle between ambient temperature and 40 °C for 4 hours.

[0107] After 72 hours, the subsample was analyzed by XRPD. Since the sample matched the benzoate pattern 1, the sample was filtered through a Buchner funnel and placed in a pre-weighed sample vial. The solid was dried at 40 °C for about 21 hours.

[0108] The benzoate was characterized by XRPD, 1 1H NMR, TG / DSC, DSC and FT-IR.

[0109] Characterization of S-pindolol benzoate pattern 1 XRPD analysis showed that S-pindolol benzoate is highly crystalline. The pattern (shown in Figure 6) represents S-pindolol benzoate pattern 1. The 2θ and peak intensities for S-pindolol benzoate pattern 1 are shown in Table 2 below.

Table 7

[0110] The single crystal parameters of S-pindolol benzoate pattern 1 were identified. The dimensions of the unit cell of the collected structure were found to be as follows: · Monoclinic P21 · a = 8.4937(5) Å α = 90° · b = 15.2956(9) Å β = 98.981(2)° · c = 15.5169(9) Å γ = 90° · Volume = 1991.2(2) Å 3 · Z = 4, Z' = 2

[0111] The final accurate parameters were as follows: · R1[I>2σ(I)] = 2.99% · GooF (goodness of fit) = 1.058 · wR2 (all data) = 8.28% · R int = 3.15% · Flack = -0.03(4)

[0112] 1 By \(^1\)H NMR, benzoic acid and S-pinhol in a 1:1 ratio were observed, and a broad peak of water was present, indicating that a salt could be formed. The presence of 0.69 wt% (0.03 eq) of ethyl acetate was observed.

[0113] The FT-IR spectrum was consistent with the provided structure. See Figure 7. The following peaks were observed and assigned: · Broad O-H stretch at approximately 3255 - 2447 cm -1 · N-H stretch at approximately 3255 cm -1 · Aromatic C-H stretch at approximately 3027 cm -1 · Aliphatic C-H stretch at approximately 2969 cm -1 · Alkene C=C at approximately 1643 cm -1

[0114] TG and DSC scans of S-pinhol benzoate pattern 1 are shown in Figures 8 - 10. In the TG / DSC analysis, a 40% mass loss due to TG and subsequent decomposition were observed at 150 °C - 250 °C. This weight loss may be due to decomposition, but it also corresponds to 2 equivalents of benzoic acid. In DSC, an endothermic event with an onset at 130 °C and a peak at 135 °C was observed.

[0115] In the DSC analysis, a sharp endothermic event with an onset at 130 °C and a peak at 135 °C was observed. This corresponds to melting and is consistent with the TG / DSC data. No event was observed in the cooling cycle. In the second heating cycle, a glass transition with a midpoint at 44 °C and an endothermic event with an onset at 133 °C and a peak at 136 °C were observed.

[0116] (Manufacture and Property Evaluation of S-Pinhol Benzoate Pattern 2) Manufacture of S-Pinhol Benzoate Pattern 2 Approximately 5 g of S-pindolol free base was combined with approximately 2.7 g of benzoic acid. The sample vial of benzoic acid was rinsed with 2 mL of ethyl acetate. The washings and an additional 16 mL of ethyl acetate were added to the combined sample to form a white slurry.

[0117] The sample was subjected to a temperature cycle of approximately 24 hours in a cycle between ambient temperature and 40 °C for 4 hours.

[0118] The substance was filtered through a Buchner funnel and dried on the filter paper for approximately 5 minutes. Thereafter, the substance was returned to the sample vial and dried under vacuum at 40 °C for approximately 6 hours.

[0119] The benzoate was characterized by XRPD, 1 1H NMR, TG / DSC, DSC and FT-IR.

[0120] Characterization of S-pindolol benzoate Pattern 2 XRPD analysis showed that S-pindolol benzoate is highly crystalline. The pattern (shown in Figure 11) is designated as S-pindolol benzoate Pattern 2. The 2θ and peak intensities for S-pindolol benzoate Pattern 2 are shown in Table 3 below.

Table 8

[0121] The single crystal parameters of S-pindolol benzoate Pattern 2 were determined. The dimensions of the unit cell of the structure collected were found to be as follows: · Monoclinic P21 · a = 9.9330(2) Å α = 90° · b = 9.5832(2) Å β = 107.2020(10)° · c = 10.9875(3) Å γ = 90° · Volume = 999.11(4) Å 3 · Z = 2, Z' = 1

[0122] The final exact parameters were as follows: ·R1[I>2σ(I)] = 2.58% ·Goodness of Fit (GoF) = 1.040 ·wR2 (all data) = 6.73% ·R int = 2.86% ·Flack = 0.01(7)

[0123] 1 By 1H NMR, benzoic acid and S-pinhol in a 1:1 ratio were observed. 0.25 wt% (0.01 eq) of ethyl acetate was seen in the spectrum. The broad peak and peak shift of water indicate that salts could be formed.

[0124] The FT-IR spectrum was consistent with the provided structure. See Figure 12. The following peaks were observed and assigned: · Broad O-H stretch ~3219 - 2377 cm -1 · N-H stretch ~3219 cm -1 · Aromatic C-H stretch ~3098 cm -1 · Aliphatic C-H stretch ~2929 cm -1 · Alkene C=C ~1635 cm -1

[0125] TG and DSC scans of the S-pinhol benzoate pattern 2 are shown in Figures 13 - 15. In the TG / DSC analysis, a 42.8 wt% mass loss was seen in the TG trace. This is thought to be due to decomposition. In the DSC trace, a sharp endothermic event related to melting was observed with an onset at 156 °C and a peak at 158 °C.

[0126] In the DSC analysis, a sharp endothermic event with an onset at 157 °C and a peak at 159 °C was seen. This corresponds to melting and is consistent with the TG / DSC data. No event was observed in the cooling cycle. In the second heating cycle, a possible glass transition with a center point at 27 °C was observed.

[0127] (Manufacture and Characterization of S-Pindolol Succinate Pattern 1) Manufacture of S-Pindolol Succinate Pattern 1 264.68 mg (1.1 equivalents) of succinic acid was added to approximately 500 mg of S-pindolol free base in a scintillation vial. The sample vial containing the acid was rinsed with 1 mL of THF, and the washings were added to the scintillation vial. An additional 2 mL was added, and a beige slurry was observed. The scintillation vial was capped and sealed with parafilm, and then a temperature cycle of approximately 72 hours was carried out in a cycle between ambient temperature and 40 °C for 4 hours. After 72 hours, the sample was filtered through a Buchner funnel and dried on the filter paper for approximately 5 minutes. Subsequently, the substance was placed in a pre-weighed sample vial and dried at 40 °C for approximately 21 hours.

[0128] The succinate was characterized by XRPD, 1 1H NMR, TG / DSC, DSC, and FT-IR.

[0129] Characterization of S-Pindolol Succinate Pattern 1 XRPD analysis showed that S-pindolol succinate is highly crystalline. The pattern (shown in Figure 16) is designated as S-pindolol succinate Pattern 1. The 2θ and peak intensities for S-pindolol succinate Pattern 1 are shown in Table 4 below.

Table 9

[0130] 1 In 1H NMR, ACM-001 and succinic acid in a 1:1 ratio and 0.04 equivalents of THF were observed.

[0131] The FT-IR spectrum was consistent with the provided structure. See Figure 17. The following peaks were observed and assigned: · Broad O-H stretch at approximately 3389 - 2676 cm -1 · N-H stretch at approximately 3389 cm -1 · Aromatic C-H stretch at approximately 3153 cm -1 · Aliphatic C-H stretch at approximately 2970 cm -1 · Alkene C=C at approximately 1690 cm -1

[0132] TG and DSC scans of S-pindolol succinate pattern 1 are shown in FIGS. 18-20. In the TG / DSC analysis, a 12% mass loss due to TG and subsequent decomposition were observed at 160 °C - 250 °C. This weight loss may be due to decomposition, but it also corresponds to 0.42 equivalents of succinic acid. In DSC, an endothermic event with an onset at 111 °C and a peak at 115 °C was observed.

[0133] In the DSC analysis, a sharp endothermic event with an onset at 110 °C and a peak at 114 °C was observed. This corresponds to melting and is consistent with the TG / DSC data. No event was observed in the cooling cycle. In the second heating cycle, a glass transition with a midpoint at 39 °C was observed.

[0134] The stability of S-pindolol succinate pattern 1 was evaluated. The succinate pattern 1 maintained its form after storage at 60 °C and 40 °C / 75% RH for 7 days. After storage for 4 weeks under all conditions, no color change was observed, the purity was maintained, and there was no change in the solid form of the succinate pattern 1.

[0135] The succinate was also analyzed by DVS. During the DVS analysis, the succinate pattern 1 was held with an adsorbed water content of 0.70 wt% (0.14 equivalents) at 90% RH.

[0136] (Summary of Salt Properties) A summary of the properties of S-pindolol free base pattern 1, S-pindolol benzoate pattern 1, S-pindolol benzoate pattern 2, and S-pindolol succinate pattern 1 is shown in Table 5 below.

Table 10

[0137] (Conclusion of Example 1) The S-Pindolol free base was found to be crystals with an ill-defined morphology. The thermal properties were found to be decomposition after 200 °C, a solid-solid transition at 83 °C, and melting at 93 °C. The free base was slightly hygroscopic and incorporated 0.05 equivalents of water up to 90% RH.

[0138] Salt screening for S-Pindolol was successfully carried out. With many counterions, only amorphous products or gums were identified. Salt crystal forms were identified using fumaric acid, benzoic acid, and succinic acid.

[0139] All of these salt crystal forms had a higher melting point than the free base and were considered anhydrous from TG / DSC analysis. 1 H NMR analysis showed the stoichiometric amount of the counterion and peak shifts compared to the free base spectrum, indicating that salts could be formed.

[0140] The hemifumarate salt was found to interconvert between different polymorphic forms during the stability test and was considered a less desirable salt form. Also, the fumarate salt product tended to be colored.

[0141] Scaling up of the benzoate and succinate salts for secondary salt screening was successfully carried out. Two polymorphic forms (Pattern 1 and Pattern 2) of S-Pindolol benzoate were identified. One polymorphic form (Pattern 1) of S-Pindolol succinate was identified.

[0142] S-Pindolol benzoate Pattern 1 was found to be a crystalline white solid with a higher melting point than the free base (starting at 130 °C and starting to decompose at about 150 °C).

[0143] S-Pindolol benzoate Pattern 2 was found to be a crystalline white solid with a higher melting point than the free base (starting melting point at 156 °C with concomitant decomposition).

[0144] S-Pindolol succinate Pattern 1 was found to be a crystalline off-white solid with a higher melting point than the free base (starting at 111 °C and starting to decompose at about 160 °C).

[0145] The chemical and physical properties of S-Pindolol benzoate and S-Pindolol succinate are extremely advantageous for pharmaceutical use and are suitable for development. The pure white color, better form, higher melting point, lower hygroscopicity and stability determined for S-Pindolol benzoate mean that this salt is particularly preferred.

[0146] Example 2: Polymorphs of S-Pindolol benzoate

[0147] (Screening for polymorphs) 200 μL aliquots of appropriate solvents were added to approximately 36 mg of an amorphous S-Pindolol benzoate sample to obtain a slurry. The sample was capped, sealed with parafilm, and placed in an incubator shaker, and temperature cycling was carried out for about 72 hours in 4-hour cycles between ambient temperature and 40 °C (with stirring).

[0148] After 72 hours, observations were made and the sample was centrifuged in a tube containing a filter to isolate the solid and the saturated solution. The resulting solid was then dried for about 1 hour. It was reanalyzed by XRPD at 40 °C for 24 hours to determine the polymorphs obtained. The results of the polymorph screening are shown in Table 6. Subsequently, the resulting solid was dried at 40 °C for about 24 hours and reanalyzed by XRPD to determine that an amorphous form was obtained. The results of the amorphous screening are shown in Table 6.

Table 11

[0149] Most of the solvents reverted to Pattern 1. Pattern 2 was obtained from solvents such as methyl ethyl ketone, ethanol, THF, and water. The XRPD pattern of Pattern 2 obtained from methyl ethyl ketone is shown in Figure 1.

[0150] (Competitive slurry) Four samples containing 10 mg of benzoate pattern 1 and 10 mg of benzoate pattern 2 were prepared. 400 μL of 2-propanol was pipetted into two of these samples, and 400 μL of water was pipetted into the other two. A white slurry was obtained. One slurry of each solvent system was placed in an incubator shaker at 60 °C, and the second slurry of each solvent system was placed in a shaker under ambient temperature conditions. After 24 hours, the solids were isolated by centrifugation and analyzed by XRPD. S-Pindolol benzoate pattern 2 was obtained from all four competitive slurry experiments (shown in Figure 22), indicating that pattern 2 is the thermodynamically stable form.

[0151] (Summary of the properties of S-pindolol benzoate patterns 1 and 2) A summary of the properties of S-pindolol benzoate pattern 1 and S-pindolol benzoate pattern 2 is shown in Tables 7 and 8 below, and Table 8 includes the experimental results of stability and solubility. [Table 12] [Table 13]

[0152] (Conclusion of Example 2) S-Pindolol benzoate pattern 1 was obtained in most solvent systems. However, pattern 2, which is a different pattern, was recovered from ethanol, methanol / water mixtures, methyl ethyl ketone, THF, and water. A mixture of patterns 1 and 2 was observed from anisole, butyl acetate, and toluene.

[0153] Despite the fact that benzoate pattern 1 returned from most of the solvent solubility screening samples, benzoate pattern 2 was obtained from all polymorph screening experiments that resulted in crystalline substances and was considered to be in a thermodynamic form based on competitive slurry experiments and a higher melting point onset compared to pattern 1.

[0154] S-Pindolol benzoate pattern 2 was found to be a crystalline white solid with birefringent crystals of indefinite morphology and a size of approximately 10 μm. Pattern 2 was the anhydrous monobenzoate. The thermal properties of S-pindolol benzoate pattern 2 were improved over pattern 1, which supports the theory that pattern 2 is the thermodynamic form. A higher melting point starting at 156 °C compared to 130 °C for pattern 1 was obtained. The decomposition of pattern 2 occurred at the same temperature as the onset of melting. Also, in the second heating cycle, a glass transition with a center point at 27 °C was observed. S-Pindolol benzoate pattern 2 was non-hygroscopic and incorporated 0.045 wt% (0.01 eq) of water at 90% RH. HPLC analysis showed that the substance had a purity of 99.9% by relative area and 99.4% ee by chiral HPLS.

[0155] In the 7- and 14-day stability tests of S-pindolol benzoate pattern 2, it was found that pattern 2 retained its XRPD pattern and high chemical purity (exceeding 99.8% by relative area) under all stability conditions. Pattern 2 retained its white color for 7 days under all stability conditions and for 14 days at 60 °C high humidity.

[0156] Thermodynamic solubility experiments determined that S-pindolol benzoate pattern 2 exhibited extremely high solubility as observed in buffer solutions of pH 1.2, 4.5, 6.8 and non-buffered water, respectively (free base concentrations were 3.5 mg / mL, 17.6 mg / mL, 9.9 mg / mL and 10.3 mg / mL). S-Pindolol benzoate pattern 2 improved the solubility of the free base in non-buffered water, which was 1.8 mg / mL.

[0157] S-Pindolol benzoate patterns 1 and 2 are both salt forms that can be developed from chemical and physical properties. However, from its thermodynamic form, S-Pindolol benzoate pattern 2 was the preferred salt form.

Claims

1. (i) S-Pindolol; and (ii) an organic acid A pharmaceutically acceptable oxidative addition salt, wherein the organic acid has a pK of 2.5 or more a1 and C x H y (CO 2 H) z A pharmaceutically acceptable acid addition salt having a chemical formula represented by the formula, wherein x is 1 to 10, y is 2 to 20, and z is 1 or 2

2. The pharmaceutically acceptable acid addition salt according to claim 1, wherein the organic acid is benzoic acid, succinic acid, fumaric acid, malonic acid, glutaric acid, adipic acid, acetic acid, propionic acid, phenylacetic acid, fulvic acid or naphthoic acid.

3. The pharmaceutically acceptable acid addition salt according to claim 1 or 2, wherein the pharmaceutically acceptable acid addition salt is a crystal.

4. The pharmaceutically acceptable acid addition salt according to any one of claims 1 to 3, wherein the pharmaceutically acceptable acid salt is in the form of a solvate.

5. The pharmaceutically acceptable acid addition salt according to any one of claims 1 to 4, wherein the organic acid is benzoic acid or succinic acid.

6. The pharmaceutically acceptable acid addition salt according to any one of claims 1 to 5, wherein the organic acid is benzoic acid.

7. The pharmaceutically acceptable acid addition salt according to any one of claims 1 to 6, wherein the salt is S-Pindolol benzoate.

8. The pharmaceutically acceptable acid addition salt according to claim 7, wherein the S-Pindolol benzoate is S-Pindolol monobenzoate.

9. The pharmaceutically acceptable acid addition salt according to claim 7 or 8, wherein the S-Pindolol benzoate is in the form of S-Pindolol benzoate crystal polymorphic form 1 having an X-ray powder diffraction pattern including peaks at 8.1°, 11.4° and 17.0° ± 0.2° 2θ.

10. The pharmaceutically acceptable acid addition salt according to claim 9, wherein the X-ray powder diffraction pattern further includes peaks at 5.7°, 12.5° and 18.4° ± 0.2° 2θ.

11. The pharmaceutically acceptable acid addition salt according to claim 7 or 8, wherein the S-Pindolol benzoate is in the form of S-Pindolol benzoate crystal polymorphic form 2 having an X-ray powder diffraction pattern including peaks at 16.9°, 18.9° and 20.1° ± 0.2° 2θ.

12. The pharmaceutically acceptable acid addition salt according to claim 11, wherein the X-ray powder diffraction pattern further includes peaks at 9.2°, 13.9° and 20.7° ± 0.2° 2θ.

13. The pharmaceutically acceptable acid addition salt according to any one of claims 1 to 5, wherein the salt is S-Pindolol succinate.

14. The pharmaceutically acceptable acid addition salt according to claim 13, wherein the S-pindolol succinate is S-pindolol monosuccinate.

15. The pharmaceutically acceptable acid addition salt according to claim 13 or 14, wherein the S-pindolol succinate is in the form of polymorphic form 1 of S-pindolol succinate crystals having an X-ray powder diffraction pattern including peaks at 13.3°, 16.7° and 19.5° ± 0.2° 2θ.

16. The pharmaceutically acceptable acid addition salt according to claim 15, wherein the X-ray powder diffraction pattern further includes peaks at 8.3°, 12.2° and 12.8° ± 0.2° 2θ.

17. A composition comprising at least 60% by weight of the pharmaceutically acceptable acid addition salt according to any one of claims 1 to 16, based on the total weight of the composition.

18. The composition according to claim 17, comprising 30% by weight or less of R-pindolol or a salt thereof, based on the total weight of the composition.

19. A pharmaceutical composition comprising (i) the pharmaceutically acceptable acid addition salt according to any one of claims 1 to 16 and (ii) a pharmaceutically acceptable additive, carrier or diluent.

20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is a tablet.

21. The pharmaceutical composition according to claim 19 or 20, wherein the composition substantially does not contain R-pindolol or a salt thereof.

22. The pharmaceutically acceptable acid addition salt according to any one of claims 1 to 16 for use in the treatment of the human or animal body.

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

24. The pharmaceutically acceptable acid addition salt according to claim 23, wherein the disease or condition is cachexia or muscle weakness.

25. A method of treating or preventing in an individual a disease or condition selected from cachexia, sarcopenia, neuromuscular disorder, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma and anxiety, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutically acceptable acid addition salt according to any one of claims 1 to 16.

Images