Organic acid addition salts of S-pindolol

Abstract

This invention provides compounds useful for treating conditions such as cachexia, sarcopenia, neuromuscular disorders, and muscle weakness. [Solution] (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 higher. a1 and C x H y (CO2H) z A pharmaceutically acceptable acid addition salt is provided, having the chemical formula shown, where x is 1 to 10, y is 2 to 20, and z is 1 or 2.

Description

[Technical Field]

[0001] This invention relates to a salt of S-pindolol and a pharmaceutical composition containing the salt. The medical use of the salt is also described. [Background technology]

[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-indole-4-yloxy)-3-(propan-2-ylamino)propan-2-ol, and the structure of this compound is shown below. [ka]

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

[0004] Pindolol is approved in racemic form for the treatment of certain conditions. S-Pindolol is known to be a more pharmacologically active enantiomer. The discovery of this invention is that S-Pindolol possesses properties that make it difficult to formulate into oral medications such as tablets. In particular, S-Pindolol may, in some cases, decompose and discolor during storage under certain conditions.

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

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

[0007] The inventors have determined that the pK is at least 2.5 a We found that salts of S-pindolol formed with organic mono- and di-carboxylic acids are well-suited for pharmaceutical formulations. In particular, these salts were found to be stable and crystalline, and to have a higher melting point compared to free S-pindolol base. Some of the S-pindolol salts also have a pure white color, which is desirable for clinical use in solid form.

[0008] 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 higher. a1 and C x H y (CO2H) z This relates to pharmaceutically acceptable acid addition salts having the chemical formula shown, where x is 1 to 10, y is 2 to 20, and z is 1 or 2.

[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 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 XRPD2θ diffractogram of S-pindolol free base pattern 1. [Figure 2] Figure 2 shows the XRPD2θ diffractogram of the solid obtained from the treatment of S-pindolol with fumaric acid. [Figure 3] Figure 3 shows the TG / DSC thermogram of S-pindolol hemifumarate pattern 1. [Figure 4] Figure 4 shows the TG / DSC thermogram of S-pindolol hemifumarate pattern 2. [Figure 5] Figure 5 shows the TG / DSC thermogram of S-pindolol hemifumarate pattern 3. [Figure 6] Figure 6 shows the XRPD2θ diffractogram of S-pindolol benzoate pattern 1. [Figure 7] Figure 7 shows the FT-IR spectrum of S-pindolol benzoate pattern 1. [Figure 8] Figure 8 shows the TG / DSC thermogram of S-pindolol benzoate pattern 1. [Figure 9] Figure 9 shows the DSC thermogram (first heating cycle) of S-pindolol benzoate pattern 1. [Figure 10] Figure 10 shows the DSC thermogram (second heating cycle) of S-pindolol benzoate pattern 1. [Figure 11] Figure 11 shows the XRPD2θ diffractogram of S-pindolol benzoate pattern 2. [Figure 12] Figure 12 shows the FT-IR spectrum of S-pindolol benzoate pattern 2. [Figure 13] Figure 13 shows the TG / DSC thermogram of S-pindolol benzoate pattern 2. [Figure 14]Figure 14 shows the DSC thermogram (first heating cycle) of S-pindolol benzoate pattern 2. [Figure 15] Figure 15 shows the DSC thermogram (second heating cycle) of S-pindolol benzoate pattern 2. [Figure 16] Figure 16 shows the XRPD 2θ diffractogram of S-pindolol succinate pattern 1. [Figure 17] Figure 17 shows the FT-IR spectrum of S-pindolol succinate pattern 1. [Figure 18] Figure 18 shows the TG / DSC thermogram of S-pindolol succinate pattern 1. [Figure 19] Figure 19 shows the DSC thermogram (first heating cycle) of S-pindolol succinate pattern 1. [Figure 20] Figure 20 shows the DSC thermogram (second heating cycle) of S-pindolol succinate pattern 1. [Figure 21] Figure 21 shows the XRPD diffractogram of S-pindolol benzoate pattern 2 obtained from methyl ethyl ketone. [Figure 22] Figure 22 shows the XRPD diffractogram of a sample of S-pindolol benzoate obtained from a competitive slurry experiment.

BEST 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 a1 of 3.0 to 5.0. For example, the pK a1 of the organic acid can be from 4.0 to 4.5. pK a1 is the acid dissociation constant of the first proton dissociated from the acid. In the case of a monocarboxylic acid, pK a1 simply corresponds to the acid dissociation constant pK a . The pK a1 values used herein are measured at 25°C. The pK aValue and pK a1 The values ​​are readily available to those skilled in the art.

[0014] Organic acids are C x H y (CO2H) z It has the chemical formula shown, where x is 1 to 10, y is 2 to 20, and z is 1 or 2. Therefore, organic acids have a hydrocarbyl moiety (C x H y It contains hydrogen and carbon (composed of hydrogen and carbon) and one or two carboxylic acid groups (CO2H). Typically, x is 2-7 and H is 2-6. x H y The group can be an allenyl group, an alkyl group, or an alkenyl group. For example, C x H y The group is divalent C 2-7 Alkyl alkyl groups, divalent C 2-7 It may be an alkenyl group, or a divalent phenyl group which may be substituted with one or two methyl groups.

[0015] Organic acids may include, for example, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, propionic acid, glutaric acid, adipic acid, phenylacetic acid, fruic acid (including o-, m-, and p-fruic acid), and naphthoic acid (including 1- and 2-naphthoic acid).

[0016] The pK of these acids a1 The following table shows the values ​​when the acid is a monocarboxylic acid. a1 The pK of that acid a That is the case. [Table 1]

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

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

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

[0020] The enantiomer excess of the S-enantiomer of the pindolol cation in pharmaceutically acceptable salts is typically at least 80%. Therefore, at least 90 mol% of the cations in the salt are typically in the S configuration. The enantiomer excess is typically at least 95%. The S-pindolol cation in pharmaceutically acceptable acid addition salts is typically substantially in the S configuration and therefore may have an enantiomer excess of at least 99%. The enantiomer excess can be measured by any standard technique, for example, by optical rotation or by chiral high-performance liquid chromatography (HPLC).

[0021] Therefore, pharmaceutically acceptable acid addition salts typically contain no more than 10 mol% of a salt containing a cation that is the R-enantiomer of pindolol or a protonated R-pindolol molecule. For example, pharmaceutically acceptable acid addition salts typically contain substantially no salt containing a cation that is the R-enantiomer of pindolol or a protonated R-pindolol molecule.

[0022] Medicinally acceptable acid addition salts are typically crystalline. Therefore, the salts may have a three-dimensional crystalline structure containing repeating unit cells. Medicinally acceptable acid addition salts can be in solid form, such as crystals or crystallites of the medicinally acceptable acid addition salt.

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

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

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

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

[0027] Medicinally acceptable acid addition salts are typically crystalline. The °2θ values ​​described herein are measured using the X-ray wavelength of CuKα1 radiation (λ = 1.54060 Å). If the X-ray powder 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 instead be ±0.1°2θ.

[0028] S-pindolol benzoate can be a crystalline polymorph of S-pindolol benzoate represented as pattern 1. S-pindolol benzoate pattern 1 typically has an X-ray powder diffraction (XRPD) pattern that includes peaks at 8.1°, 11.4°, and 17.0°±0.2°²θ.

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

[0030] The XRPD pattern of 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 S-pindolol benzoate pattern 1 may include the following peaks. [Table 2]

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

[0032] The infrared spectrum of S-pindolol benzoate pattern 1 is typically 1638–1648 cm⁻¹. -1 , 2964~2974cm -1, 3022~3032cm -1 and 3250~3260cm -1 It contains one or more peaks in the range. For example, the infrared spectrum is approximately 1643 cm⁻¹. -1 , 2969cm -1 , 3027cm -1 and 3255cm -1 This may include a peak in [location].

[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 comprising recrystallizing S-pindolol benzoate from solvents including 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 a crystalline polymorph of S-pindolol benzoate represented as pattern 2. S-pindolol benzoate pattern 2 typically has X-ray powder diffraction (XRPD) with a peak at 9.2°±0.2°2θ.

[0036] S-pindolol benzoate pattern 2 typically has an X-ray powder diffraction (XRPD) pattern that includes 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 contain 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°, and 29.4°±0.2°²θ. The XRPD pattern may contain all of these peaks. The XRPD pattern of S-pindolol benzoate pattern 2 may contain 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 is typically 1630-1640 cm⁻¹. -1 , 2924~2934cm -1 , 3093~3103cm -1 and 3214~3224cm -1 It contains one or more peaks in the range. For example, the infrared spectrum is approximately 1635 cm⁻¹. -1 , 2929cm -1 , 3098cm -1 and 3219cm -1 This may include a peak in [location].

[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 involving the recrystallization of S-pindolol benzoate from solvents such as 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] It was found that S-pindolol benzoate pattern 2 is a 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 may be S-pindolol succinate. Therefore, the salt may contain a cation and a succinate anion derived from S-pindolol. The stoichiometry of the cation and anion is typically about 1:1 or about 2:1, e.g., 0.9:1.0 to 1.1:1.0 or 1.9:1.0 to 2.1:1.0. Therefore, S-pindolol succinate may be S-pindolol hemisuccinate or S-pindolol monosuccinate. Preferably, S-pindolol succinate is S-pindolol monosuccinate. Therefore, the salt has the formula [C 14 H 21 N2O2] + [HOOC(C2H4)COO] - or ([C 14 H 21 N2O2] + )2[OOC(C2H4)COO] 2- This can be shown by:

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

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

[0046] The XRPD pattern of S-pindolol succinate pattern 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°, and 25.0°±0.2°²θ. The XRPD pattern of S-pindolol succinate pattern 1 may include the following peaks. [Table 4]

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

[0048] The infrared spectrum of S-pindolol succinate pattern 1 is typically 1685–1695 cm⁻¹. -1 , 2965~2975cm -1 3148~3158cm -1 and 3384~3394cm -1 It contains one or more peaks in the range. For example, the infrared spectrum is approximately 1690 cm⁻¹. -1 , 2970cm -1 , 3153cm -1 and 3389cm -1 This may include a peak in [location].

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

[0050] S-pindolol succinate pattern 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) carrying out a cycle of raising the temperature of the mixture from a low temperature of 15°C to 30°C to a high temperature of 35°C to 50°C in a cycle lasting 3 to 5 hours, and then returning, for a total of 60 to 120 hours; (iv) filtering the resulting salt; and (v) drying the salt at 35 to 50°C for 18 to 48 hours.

[0051] Medicinally acceptable acid addition salts typically have a purity of approximately 90% or higher, approximately 95% or higher, or approximately 97% or higher. Percent purity can be calculated as area percentage 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 essentially consist of a pharmaceutically acceptable acid addition salt. The composition may consist of a pharmaceutically acceptable acid addition salt.

[0053] Therefore, 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 comprises (i) a pharmaceutically acceptable acid addition salt and (ii) a pharmaceutically acceptable additive, 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.

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

[0056] The diluent can be any pharmaceutically acceptable diluent. Diluents are typically suitable for non-enteral 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, dextrose, saccharose, cellulose, corn starch, and potato starch. The diluent may contain buffering components to control pH. Buffers may be derived from phosphates, citrates, or acetates. 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, alginate, or sodium starch glycolate; foaming mixtures; dyes; sweeteners; wetting agents, such as lecithin, polysorbate, or lauryl sulfate; and additives selected from common, non-toxic, and pharmacologically inert substances used in pharmaceutical formulations. Such pharmaceutical formulations may be manufactured by known methods, for example, by mixing, granulation, tableting, sugar coating, or film coating processes.

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

[0059] The composition, which is a dispersion for oral administration, may be a syrup, emulsion, or suspension. The syrup may contain, for example, saccharose, glycerin, mannitol, or sorbitol as a carrier.

[0060] 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, along with a pharmaceutically acceptable acid addition salt, a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycol, such as propylene glycol, and optionally an appropriate amount of lidocaine hydrochloride.

[0061] The liquid preparation for injection, intravenous infusion, or inhalation may contain, for example, sterile water as a carrier, or may be in the form of sterile isotonic saline.

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

[0063] The pharmaceutical composition is typically substantially free of R-pindolol 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-pindolol or its salts.

[0064] Pharmaceutical use Medicinally 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 pectoris, glaucoma, and anxiety. Typically, the diseases or conditions selected are cachexia and muscle weakness.

[0065] Cahexy can be caused by underlying medical conditions. For example, cachexy 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 underlying medical conditions. For example, muscle weakness can be caused by trauma, musculoskeletal injury, surgery, or immobilization. Muscle weakness may be acquired muscle weakness in the intensive care unit (ICUAW). Neuromuscular disorders may include, for example, amyotrophic lateral sclerosis (ALS).

[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 pectoris, glaucoma, and anxiety, comprising administering to the individual a therapeutically effective amount of a pharmaceutically acceptable acid addition salt.

[0067] Medicinally acceptable acid addition salts are typically administered orally or non-enterally.

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

[0069] The following examples illustrate the present invention. [Examples]

[0070] Example 1: Salt of S-pindolol

[0071] (Analysis method) X-ray powder diffraction (XRPD) XRPD analysis was performed using a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the sample at 3–35°²θ. The material was gently broken up, clumps were separated, and the sample was placed on a multiwell plate with a Mylar polymer film for support. The multiwell plate was then placed in a diffractometer and analyzed using CuK radiation (α1λ=1.54060Å; α2=1.54443Å; β=1.39225Å; α1:α2 ratio=0.5) in transmission mode (step size 0.0130°²θ, step time 18.87 sec) with a generator setting of 40kV / 40mA. 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 weight had been measured beforehand, placed in a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC, and 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 heat flow response (DSC). Nitrogen was used as a purge gas at a rate of 300 cm³. 3 The flow rate was measured in units of / min.

[0073] Differential Scanning Calorimetry (DSC) Approximately 5 mg of the substance was weighed onto an aluminum DSC pan and sealed airtight with an aluminum lid. The sample pan was then placed in a TA Instruments Discovery DSC 2500 (equipped with an RC90 condenser) and maintained 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 a purge gas at a rate of 50 cm³. 3 The flow rate was measured in units of / min.

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

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

[0076] Dynamic vapor sorption (DVS) Approximately 10-20 mg of sample was placed in a mesh vapor sorption balance pan and mounted on an intrinsic dynamic vapor sorption balance using Surface Measurement Systems. The sample was subjected to a gradient profile increasing by 10% increments from 40% to 90% relative humidity (RH) at 25°C, maintaining the sample at each step until a stable weight was achieved (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes). After the sorption cycle was completed, 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 change during the sorption / desorption cycle was plotted to determine the hygroscopicity of the sample. Subsequently, XRPD analysis was performed on the retained solid.

[0077] Temperature-Tunable X-ray Powder Diffraction (VT-XRPD) VT-XRPD analysis was performed using a Philips X'Pert Pro Multipurpose diffractometer equipped with a temperature chamber. CuK radiation (α1λ=1.54060Å; α2=1.54443Å; β=1.39225Å; α1:α2 ratio=0.5) was used with a Bragg-Brentano geometry (step size 0.008°2θ) using a 40kV / 40mA generator setting, and the sample was scanned from 4 to 35.99°2θ. The experimental parameters were as follows: scan at 30°C; heat to 75°C at 10°C / min; hold for 5 minutes; scan at 75°C; heat to 87°C at 2°C / min; hold for 5 minutes; scan at 87°C; heat to 105°C at 2°C / min; hold for 5 minutes; scan at 105°C; heat to 115°C at 2°C / min; hold for 5 minutes; scan at 115°C; cool to 30°C at 10°C / min; scan at 30°C.

[0078] High-performance liquid chromatography-ultraviolet detection (HPLC-UV) • Instrument: Dionex Ultimate 3000 • Column: Agilent Zorbax, SB-C18, 150mm x 4.6mm, 3.5μm Column temperature: 25℃ • Autosampler temperature: Ambient temperature ·UV wavelength: 254nm ·Injection volume: 3μl ·Flow rate: 1.0ml / min Mobile phase A: 1.36 g potassium dihydrogen phosphate + 1000 mL 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 (95:5v / v) • Diluent: Water: Acetonitrile (20:80v / v) ·Gradual Program: [Table 5]

[0079] (Characterization of free S-pindolol bases) Samples of free S-pindolol base were characterized.

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

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

[0082] DVS analysis determined that the substance is slightly hygroscopic, with an adsorption capacity 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 survey) Seventy-two samples of 40 mg of ACM-001 free base were weighed into 2 mL vials. 0.5 mL of appropriate solvent was added to each vial, followed by 1.1 equivalents of appropriate counterions.

[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, with 4-hour cycles between ambient temperature and 40°C. All formed solids were isolated by centrifugation before analysis by XRPD.

[0087] Some of the solids obtained after the initial 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 used with specific solvents.

[0088] Subsequently, 0.5 mL of the reverse solvent was added to the vial containing insufficient solid for XRPD analysis (acetone was used for experiments in water, and heptane for all other samples). These samples were then subjected to the aforementioned temperature cycle for another 24 hours. Any further solids generated 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 allowed to evaporate for up to one week. The resulting solids and gels were analyzed by XRPD.

[0089] After 7 days, all samples remaining in the solution, as well as those obtained by temperature cycling, reverse solvent addition, and evaporation at ambient temperature, were dried in a 40°C oven for 72 hours and then analyzed by XRPD. Table 1 shows the observations made after drying; "s" indicates solid formation, "gm" indicates gum formation, and "cryst" indicates large crystal formation. [Table 6]

[0090] 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 dark in color.

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

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

[0093] Salts formed from fumaric acid, benzoic acid, and succinic acid were found to be crystals with different XRPD patterns than those of free S-pindolol base. Fumarates were colored when formed from water, ethanol, 2-propanol, and acetone, and white when formed from ethyl acetate and THF. Succinates were colored when formed from water, but white in other cases. Benzoates were white when formed from any solvent.

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

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

[0096] Patterns 1 and 2 are similar, but peaks less than 10°2θ were not present in Pattern 1. Therefore, Pattern 2 may be a mixture containing Pattern 1.

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

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

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

[0100] Hemifumarate pattern 2 During 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. Decomposition occurred above 200°C. In the DSC trace, two shallow endothermic events were observed with peaks at 152°C and 184°C. The second event was associated with the initiation of decomposition. The TG and DSC traces are shown in Figure 4.

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

[0102] Hemifumarate pattern 3 During the TG trace, a weight loss of 18.6% (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 was observed, with a peak at 150°C. The TG and DSC traces are shown in Figure 5.

[0103] During DMSO-d6 1 In 1H NMR, a broad peak corresponding to approximately 0.5 equivalents of fumaric acid was observed at 6.35 ppm. A peak potentially representing acetone was observed at 2.09 ppm (7.09 wt% or 0.3 equivalents). However, some overlap is possible as a peak was observed in the free base NMR spectrum at that position. A peak shift 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 for 7 days at 60°C (sealed vial) or 40°C / 75%RH (open vial). Samples stored at 60°C were converted to pattern 1. Samples stored at 40°C / 75%RH were converted to another form, pattern 4.

[0105] (Manufacturing and characterization of S-pindolol benzoate pattern 1) Production of S-pindolol benzoate pattern 1 271.69 mg (1.1 equivalents) of benzoic acid was added to approximately 500 mg of free S-pindolol base in a scintillation vial. The sample vial containing the acid was rinsed with 1 mL of ethyl acetate, and the washing solution was added to the scintillation vial. Another 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 vials were capped, sealed with Parafilm, and then subjected to a temperature cycle of approximately 72 hours in 4-hour cycles between ambient temperature and 40°C.

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

[0108] Benzoates, XRPD, 1 The samples were characterized by 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) is denoted as 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 unit cell dimensions of the collected structures were found to be as follows: • Monoclinic P21 a=8.4937(5) Åα=90° ·b=15.2956(9)Åβ=98.981(2)° · c=15.5169(9) Åγ=90° Volume = 1991.2(2) Å 3 Z=4, Z'=2

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

[0112] 1 ¹H NMR revealed benzoic acid and S-pindolol in a 1:1 ratio, along with a broad peak of water, indicating the formation of a salt. The presence of 0.69 wt% (0.03 equivalents) of ethyl acetate was also observed.

[0113] The FT-IR spectrum was consistent with the provided structure. See Figure 7. The following peaks were observed and assigned: • Broadcloth OH stretch approximately 3255~2447cm -1 • NH stretch approximately 3255cm -1 • Aromatic CH stretch approximately 30-27cm -1 • Fatpharic CH stretch approximately 2969cm -1 • Alken C=C approx. 1643cm -1

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

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

[0116] (Manufacturing and characterization of S-pindolol benzoate pattern 2) Manufacturing of S-pindolol benzoate pattern 2 Approximately 5 g of free S-pindolol base was combined with approximately 2.7 g of benzoic acid. The benzoic acid sample vial was rinsed with 2 mL of ethyl acetate. The washing solution and another 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, with 4-hour cycles between ambient temperature and 40°C.

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

[0119] Benzoates, XRPD, 1 The samples were characterized by 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 denoted 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 identified. The unit cell dimensions of the collected structures were found to be as follows: • Monoclinic P21 a=9.9330(2) Åα=90° ·b=9.5832(2)Åβ=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% • GooF (Fitness) = 1.040 wR2 (all data) = 6.73% ·R int =2.86% Flack=0.01(7)

[0123] 1 ¹H NMR revealed benzoic acid and S-pindolol in a 1:1 ratio. 0.25 wt% (0.01 equivalents) of ethyl acetate was observed in the spectrum. The broad peak and peak shift of water indicate that a salt was formed.

[0124] The FT-IR spectrum was consistent with the provided structure. See Figure 12. The following peaks were observed and assigned: • Broadcloth OH stretch approximately 3219~2377cm -1 • NH stretch approximately 32-19cm -1 • Aromatic CH stretch approximately 3098cm -1 • Fat-type CH stretch approximately 29-29cm -1 • Alken C=C approx. 1635cm -1

[0125] TG and DSC scans of S-pindolol benzoate pattern 2 are shown in Figures 13-15. TG / DSC analysis revealed a mass loss of 42.8 wt% in the TG trace, which is thought to be due to decomposition. In the DSC trace, a sharp endothermic event associated with melting was observed, starting at 156°C and peaking at 158°C.

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

[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 wash solution was 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 performed 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. Thereafter, 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 CH stretch approximately 3153cm -1 • Fatty CH stretch approximately 2970cm -1 • Alken C=C approx. 1690cm -1

[0132] TG and DSC scans of S-pindolol succinate pattern 1 are shown in Figures 18-20. TG / DSC analysis revealed a 12% mass loss due to TG and subsequent decomposition between 160°C and 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 was observed, starting at 111°C and peaking at 115°C.

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

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

[0135] Succinate was also analyzed by DVS. During the DVS analysis, succinate pattern 1 was retained at 90% RH with an adsorption capacity of 0.70 wt% (0.14 equivalents) of water.

[0136] (Summary of salt properties) Table 5 below summarizes the characteristics of S-pindolol free base pattern 1, S-pindolol benzoate pattern 1, S-pindolol benzoate pattern 2, and S-pindolol succinate pattern 1. [Table 10]

[0137] (Conclusion of Example 1) The S-pindolol free base was found to be crystals with an unclear morphology. The thermal properties were found to be decomposition after 200 °C, 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 of S-pindolol was successfully carried out. With many counterions, only amorphous products or gums were identified. The salt crystal forms were identified using fumaric acid, benzoic acid, and succinic acid.

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

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

[0141] Scaling up of the benzoate and succinate 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 accompanied by simultaneous 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 (decomposition begins at 111°C and starts at approximately 160°C).

[0145] The chemical and physical properties of S-pindolol benzoate and S-pindolol succinate are highly advantageous for pharmaceutical applications and suitable for development. The pure white color, better morphology, higher melting point, lower hygroscopicity, and stability determined for S-pindolol benzoate mean that this salt is particularly preferable.

[0146] Example 2: Polymorph of S-pindolol benzoate

[0147] (Polymorphic screening) A slurry was obtained by adding approximately 36 mg of amorphous S-pindolol benzoate sample to a 200 μL aliquot of a suitable solvent. The sample was covered, sealed with Parafilm, and placed in an incubator shaker, where it was subjected to a temperature cycle of approximately 72 hours in 4-hour cycles between ambient temperature and 40°C (while stirring).

[0148] After 72 hours, the samples were observed and centrifuged in a filter-containing tube to separate the solid from the saturated solution. The resulting solid was then dried for approximately 1 hour. The obtained polymorphs were determined by re-analysis using XRPD at 40°C for 24 hours. The results of the polymorph screening are shown in Table 6. Subsequently, the obtained solid was dried at 40°C for approximately 24 hours and re-analyzed using XRPD to determine that an amorphous material had been obtained. The results of the amorphous screening are shown in Table 6. [Table 11]

[0149] Most solvents returned 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 were prepared, each containing 10 mg of benzoate pattern 1 and 10 mg of benzoate pattern 2. 400 μL of 2-propanol was pipetteed into two of these samples, and 400 μL of water was pipetteed into the other two. White slurries were obtained. One slurry from each solvent system was placed in a 60°C incubator shaker, and a second slurry from each solvent system was placed in a shaker at ambient temperature. After 24 hours, the solids were isolated by centrifugation and analyzed by XRPD. S-pindolol benzoate pattern 2 was obtained from all four competing slurry experiments (shown in Figure 22), indicating that pattern 2 is a 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, with Table 8 including experimental results for stability and solubility. [Table 12] [Table 13]

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

[0153] Although benzoate pattern 1 returned from most solvent-soluble screening samples, benzoate pattern 2 was obtained from all polymorph screening experiments that yielded crystalline materials and was considered to be a thermodynamic form based on its higher melting point initiation compared to competing slurry experiments and pattern 1.

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

[0155] Stability tests of S-pindolol benzoate pattern 2 over 7 and 14 days showed that pattern 2 retained its XRPD pattern and high chemical purity (over 99.8% 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 and high humidity.

[0156] Thermodynamic solubility experiments determined that S-pindolol benzoate pattern 2 exhibited extremely high solubility in buffer and unbuffered water at pH 1.2, 4.5, and 6.8, respectively (with excipient concentrations of 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 free base at 1.8 mg / mL in unbuffered water.

[0157] S-pindolol benzoate patterns 1 and 2 are both developable salt forms based on their chemical and physical properties. However, S-pindolol benzoate pattern 2 was the preferred salt form due to its thermodynamic properties.

Claims

1. (i) S-pindolol; and (ii) Organic acids A pharmaceutically acceptable oxidative addition salt of an organic acid, wherein the organic acid has a pK of 2.5 or higher. a1 and C x H y (CO 2 H) z A pharmaceutically acceptable acid addition salt having the chemical formula shown, where 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, fruic 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 crystalline.

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

7. A 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 S-pindolol benzoate is S-pindolol monobenzoate.

9. A pharmaceutically acceptable acid addition salt according to claim 7 or 8, wherein S-pindolol benzoate is in the form of S-pindolol benzoate crystalline polymorph pattern 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. A pharmaceutically acceptable acid addition salt according to claim 7 or 8, wherein S-pindolol benzoate is in the form of S-pindolol benzoate crystalline polymorph pattern 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. A 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 S-pindolol succinate is S-pindolol monosuccinate.

15. A pharmaceutically acceptable acid addition salt according to claim 13 or 14, wherein S-pindolol succinate is in the form of S-pindolol succinate crystalline polymorph pattern 1 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 a 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. (i) a 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. A 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. A 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 disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma, and anxiety.

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

25. A method for 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, comprising administering to the individual a therapeutically effective amount of a pharmaceutically acceptable acid addition salt according to any one of claims 1 to 16.

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