Organic acid addition salt of S-pindolol

Abstract

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 pKa1 of 2.5 or higher; and the chemical formula CxHy(CO2H)z, where x is 1 to 10, y is 2 to 20, and z is 1 or 2. The pharmaceutically acceptable acid addition salt is useful for treating conditions such as cachexia, sarcoidosis, neuromuscular disorders, and muscle weakness.

Description

Technology Field

[0001] The present invention relates to a salt of S-pindolol and a pharmaceutical composition comprising said salt. Medical uses of the salt are also described. Background Technology

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

[0003]

[0004] S-findolol has affinity for both beta-adrenergic receptors and 5-HT1a receptors and is useful for treating a number of disorders. WO 2008 / 068477 A1 describes the treatment of cachexia with S-findolol.

[0005] Pindolol is authorized to treat certain conditions in the form of a racemic mixture. S-pindolol has been found to be a more pharmacologically active enantiomer. It is a finding of the present invention that S-pindolol possesses properties that may make it difficult to formulate as an oral drug, for example, as a tablet. In particular, S-pindolol may sometimes decompose under certain conditions and discolor during storage.

[0006] There is a need to develop a solid form of S-pindolol that is highly suitable for use in a clinical context. In particular, it is desirable to develop a solid that is crystalline, stable, and has a color suitable for pharmaceutical applications.

[0007] S-findolol tartrate is described in the literature [Reference: Kaumann et al., British Journal of Pharmacology 1986 89(1) 207-218]. S-findolol hydrochloride is described in Japanese patent application JPH01287064 (A). The racemic benzoate salt of pindolol is described in the literature [Reference: Pietilainen et al., Drug Development and Industrial Pharmacy, 22(11), 1063-1073 (1996)]. The problem to be solved

[0008] The inventors have at least 2.5 pK a It was discovered that salts of S-pindolol formed from organic monocarboxylic and dicarboxylic acids possessing [specific properties] are highly suitable for pharmaceutical formulations. In particular, these salts were found to be stable and crystalline, and to have an increased melting point compared to the free base of S-pindolol. Some of the S-pindolol salts also have a pure white color, which is desirable for clinical use in solid form. means of solving the problem

[0009] The present invention provides (i) S-findolol; 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 chemical formula C x H y (CO2H) z , where x is 1 to 10, y is 2 to 20, and z is 1 or 2.

[0010] The present invention also provides a composition comprising at least 60 weight percent of a pharmaceutically acceptable acid addition salt.

[0011] Further provided by the present invention is a pharmaceutical composition comprising (i) a pharmaceutically acceptable acid addition salt and (ii) a pharmaceutically acceptable excipient, carrier, or diluent.

[0012] Pharmaceutically acceptable acid addition salts for use in the treatment of human or animal bodies are also provided by the present invention. Brief explanation of the drawing

[0013] Figure 1 shows the XRPD 2θ diffraction pattern of S-pindolol glass base pattern 1. Figure 2 shows the XRPD 2θ diffraction pattern of a solid obtained from the treatment of S-pindolol with fumaric acid. Figure 3 shows the TG / DSC thermogram of S-pindolol hemi-fumarate pattern 1. Figure 4 shows the TG / DSC thermogram of S-pindolol hemi-fumarate pattern 2. Figure 5 shows the TG / DSC thermogram of S-pindolol hemi-fumarate pattern 3. Figure 6 shows the XRPD 2θ diffraction pattern of S-pindolol benzoate pattern 1. Figure 7 shows the FT-IR spectrum of S-pindolol benzoate pattern 1. Figure 8 shows the TG / DSC thermogram of S-pindolol benzoate pattern 1. Figure 9 shows the DSC thermogram of S-pindolol benzoate pattern 1 (first heating cycle). Figure 10 shows a DSC thermogram of S-pindolol benzoate pattern 1 (second heating cycle). Figure 11 shows the XRPD 2θ diffraction pattern of S-pindolol benzoate pattern 2. Figure 12 shows the FT-IR spectrum of S-pindolol benzoate pattern 2. Figure 13 shows the TG / DSC thermogram of S-pindolol benzoate pattern 2. Figure 14 shows a DSC thermogram of S-pindolol benzoate pattern 2 (first heating cycle). Figure 15 shows a DSC thermogram of S-pindolol benzoate pattern 2 (second heating cycle). Figure 16 shows the XRPD 2θ diffraction pattern of S-pindolol succinate pattern 1. Figure 17 shows the FT-IR spectrum of S-pindolol succinate pattern 1. Figure 18 shows the TG / DSC thermogram of S-pindolol succinate pattern 1. Figure 19 shows a DSC thermogram of S-findolol succinate pattern 1 (first heating cycle). Figure 20 shows a DSC thermogram of S-findolol succinate pattern 1 (second heating cycle). Figure 21 shows the XRPD diffraction pattern of S-pindolol benzoate pattern 2 obtained from methyl ethyl ketone. Figure 22 shows the XRPD diffraction pattern of an S-pindolol benzoate sample obtained from a competitive slurry experiment. Specific details for implementing the invention

[0014] Organic acids have a pK of 2.5 or higher a1 It has. As such, the organic acid is a relatively weak acid. The organic acid preferably has a pK of 3.0 to 5.0. a1 It has. For example, the pK of organic acids a1 It can be 4.0 to 4.5. pK a1 ε is the acid dissociation constant of the first proton dissociated from the acid. In the case of monocarboxylic acids, pK a1 is simply the acid dissociation constant pK a Corresponds to. pK used in this invention a1 The value is as measured at 25℃. pK of organic acids a and pK a1 The price is readily available to those in the industry.

[0015] Organic acids have the chemical formula C x H y (CO2H) z It has, where x is 1 to 10, y is 2 to 20, and z is 1 or 2. Therefore, the organic acid is a hydrocarbyl moiety (Cx H y It consists of , hydrogen and carbon) and one or two carboxylic acid groups (CO2H). Typically, x is 2 to 7 and H is 2 to 6. C x H y The group can be an arenyl group, an alkyl group, or an alkenyl group. For example, C x H y The group is 2 C 2-7 Alkyl group, divalent C 2-7 It may be an alkenyl group, or a divalent phenyl group optionally substituted with one or two methyl groups.

[0016] Organic acids may be, for example, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, propionic acid, glutaric acid, adipic acid, phenylacetic acid, toluic acid (including o-, m- and p-toluic acid) and naphthoic acid (including 1- and 2-naphthoic acid).

[0017] pK of such mountains a1 It is presented in the table below. If the acid is a monocarboxylic acid, the mentioned pK a1 is pK about that mountain a am.

[0018]

[0019] The structures of benzoic acid, succinic acid, and fumaric acid are as follows.

[0020]

[0021] Typically, the organic acid is benzoic acid or succinic acid. Preferably, the organic acid is benzoic acid.

[0022] Pharmaceutically acceptable acid addition salts are salts of S-pindolol and thus contain cations formed from S-pindolol. Cations formed from S-pindolol typically have the following structure:

[0023] .

[0024] 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-added salts is typically substantially in the S-configuration and thus may have an enantiomer excess of at least 99%. The enantiomer excess can be measured using any standard technique, for example, by measuring optical rotation or using chiral high-performance liquid chromatography (HPLC).

[0025] Therefore, pharmaceutically acceptable acid addition salts typically do not contain salts containing cations that are R-enantiomers of pindolol or protonated R-pindolol molecules in greater than 10 mol%. For example, pharmaceutically acceptable acid addition salts typically do not substantially contain salts containing cations that are R-enantiomers of pindolol or protonated R-pindolol molecules.

[0026] Pharmaceutically acceptable acid addition salts are typically crystalline. Therefore, the salt may have a three-dimensional crystal structure containing repeating unit cells. Pharmaceutically acceptable acid addition salts may be in a solid form, for example, a solid form containing crystals or crystallites of the pharmaceutically acceptable acid addition salt.

[0027] Pharmaceutically acceptable acid salts may be in the form of solvates. A solvate of a salt is a solid form of the salt containing solvent molecules. For example, a salt may be a hydrate. Typically, a salt is not a solvate. For example, a pharmaceutically acceptable acid addition salt may be anhydrous.

[0028] Pharmaceutically acceptable acid-added salts typically have a melting point higher than that of the S-pindolol free base. The salt may have a melting point of 100°C or higher, for example, between 110°C and 170°C. Typically, the salt has a melting point of 130°C to 160°C. The melting point can be determined, for example, using a differential scanning calorimeter (DSC).

[0029] Pharmaceutically acceptable acid addition salts may be formed by any suitable method. Typically, the S-pindolol free 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 soluble in the solvent or precipitate from the solution. The pharmaceutically acceptable acid addition salt may be isolated by a suitable method, e.g., filtration or solvent evaporation.

[0030] A pharmaceutically acceptable acid addition salt may be S-pindolol benzoate. Thus, the salt may comprise 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., for every mole of anion, 0.9 to 1.1 mol of cation may be present). Preferably, the S-pindolol benzoate is S-pindolol monobenzoate. Thus, the salt has the chemical formula [C 14 H 21 N2O2] + [C6H6COO] - It could be.

[0031] Pharmaceutically acceptable acid addition salts are typically crystalline. As mentioned herein, the value of °2θ is measured using the X-ray wavelength (λ = 1.54060 Å) of CuK α1 radiation. If the X-ray powder diffraction pattern contains a peak, the relative intensity of the peak is typically at least 5% or at least 10%. The error range of the °2θ value is typically ±0.2°2θ, but the error range may alternatively be ±0.1°2θ.

[0032] S-pindolol benzoate may be in the form of a crystalline polymorph of S-pindolol benzoate designated as Pattern 1. Pattern 1 of S-pindolol benzoate typically has an X-ray powder diffraction (XRPD) pattern containing peaks at 8.1°, 11.4°, and 17.0° ± 0.2°2θ.

[0033] The XRPD pattern of S-pindolol benzoate pattern 1 typically includes additional peaks at 5.7°, 12.5°, and 18.4°±0.2°2θ.

[0034] 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.

[0035]

[0036] The XRPD pattern of S-pindolol benzoate pattern 1 may substantially be as shown in FIG. 6.

[0037] The infrared spectrum of S-pindolol benzoate pattern 1 is typically in the following range: 1638–1648 cm⁻¹ -1 , 2964-2974cm -1, 3022-3032cm -1 and 3250-3260cm -1 It contains one or more peaks. For example, the infrared spectrum is at approximately 1643 cm⁻¹. -1 , 2969cm -1 , 3027cm -1 and 3255cm -1 It may include a peak.

[0038] The melting point of S-pindolol benzoate pattern 1 is typically in the range of 130 to 140°C, for example, about 135°C.

[0039] S-findolol benzoate pattern 1 can be produced by a process comprising the step of recrystallizing S-findolol benzoate from a solvent comprising 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, methylisobutyl ketone, and 2-ethoxyethanol.

[0040] S-pindolol benzoate may be a form of the crystalline polymorph of S-pindolol benzoate designated as Pattern 2. S-pindolol benzoate Pattern 2 typically has an X-ray powder diffraction (XRPD) pattern containing a peak at 9.2° ± 0.2°2θ.

[0041] S-pindolol benzoate pattern 2 typically has an X-ray powder diffraction (XRPD) pattern containing peaks at 16.9°, 18.9°, and 20.1°±0.2°2θ. The XRPD pattern of S-pindolol benzoate pattern 2 typically additionally contains peaks at 9.2°, 13.9°, and 20.7°±0.2°2θ.

[0042] 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°, and 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.

[0043]

[0044] The XRPD pattern of S-pindolol benzoate pattern 2 may substantially be as shown in FIG. 11 or FIG. 21.

[0045] The infrared spectrum of S-pindolol benzoate pattern 2 typically ranges from 1630 to 1640 cm⁻¹. -1 , 2924-2934cm -1 , 3093-3103cm -1 and 3214-3224cm -1 It contains one or more peaks. For example, the infrared spectrum is at approximately 1635 cm⁻¹. -1 , 2929cm -1 , 3098cm -1 and 3219cm -1 It may include a peak.

[0046] The melting point of S-pindolol benzoate pattern 2 is typically in the range of 153-163°C, for example, about 158°C.

[0047] S-pindolol benzoate pattern 2 can be produced by a process comprising the step of recrystallizing S-pindolol benzoate from a solvent 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.

[0048] S-findolol benzoate pattern 2 has been found to be a thermodynamically stable form of S-findolol benzoate. Therefore, S-findolol benzoate is preferably in the form of S-findolol benzoate pattern 2.

[0049] A pharmaceutically acceptable acid addition salt may be S-pindolol succinate. Accordingly, the salt may comprise 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, for example, 0.9:1.0 to 1.1:1.0 or 1.9:1.0 to 2.1:1.0. Thus, S-pindolol succinate may be S-pindolol hemisuccinate or S-pindolol monosuccinate. Preferably, S-pindolol succinate is S-pindolol monosuccinate. Accordingly, the salt has the chemical formula [C 14 H 21 N2O2] + [HOOC(C2H4)COO] - or ([C 14 H 21 N2O2] + )2[OOC(C2H4)COO] 2- It could be.

[0050] S-pindolol succinate may be a form of a crystalline polymorph of S-pindolol succinate designated 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.

[0051] The XRPD pattern of S-pindolol succinate pattern 1 typically includes additional peaks at 8.3°, 12.2°, and 12.8°±0.2°2θ. The error range at the peak positions may be ±0.1°2θ.

[0052] The XRPD pattern of S-findolol 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 1 of S-findolol succinate may include the following peaks.

[0053]

[0054] The XRPD pattern of S-pindolol succinate pattern 1 can substantially be as shown in FIG. 16.

[0055] The infrared spectrum of S-pindolol succinate pattern 1 typically ranges from 1685 to 1695 cm⁻¹. -1 , 2965-2975cm -1 , 3148-3158cm -1 and 3384-3394cm -1 It contains one or more peaks. For example, the infrared spectrum is at approximately 1690 cm⁻¹. -1 , 2970cm -1 , 3153cm -1 and 3389cm -1 It may include a peak.

[0056] The melting point of S-pindolol succinate pattern 1 is typically in the range of 110 to 120°C, for example, about 115°C.

[0057] S-pindolol succinate pattern 1 can be produced by a process comprising: (i) providing S-pindolol free base and succinic acid; (ii) adding THF to the S-pindolol free base and succinic acid to produce a mixture; (iii) circulating 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 and returning it for a total of 60 to 120 hours over a cycle lasting 3 to 5 hours; (iv) filtering the produced salt; and (v) drying the salt at a temperature of 35°C to 50°C for 18 to 48 hours.

[0058] Pharmaceutically acceptable acid addition salts typically have a purity of about 90% or more, about 95% or more, or about 97% or more. Percentage purity can be calculated as area% based on HPLC separation.

[0059] composition

[0060] The composition of the present invention comprises at least 60 weight percent of a pharmaceutically acceptable acid addition salt. The composition may comprise at least 80 weight percent or at least 95 weight percent 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.

[0061] Accordingly, the composition typically comprises 30% by weight or less of R-pindololl or a salt thereof based on the total weight of the composition. For example, the composition may comprise 10% by weight or less, or 1% by weight or less of R-pindololl or a salt thereof based on the total weight of the composition.

[0062] The pharmaceutical composition of the present invention comprises (i) a pharmaceutically acceptable acid addition salt, and (ii) a pharmaceutically acceptable excipient, carrier, or diluent. The pharmaceutical composition may be, for example, a tablet, capsule, powder, 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.

[0063] Pharmaceutically acceptable excipients, carriers, and diluents are well known to those skilled in the art.

[0064] The diluent may be any pharmaceutically acceptable diluent. The diluent is typically suitable for parenteral or oral administration. Examples of suitable liquid diluents include water, ethanol, and glycerol. Alternatively, the diluent may be selected from solid diluents such as lactose, dextrose, saccharose, cellulose, corn starch, and potato starch. The diluent may contain a buffer component to control pH. The buffer may be derived from phosphate, citrate, or acetate. The diluent may also contain sodium chloride.

[0065] The pharmaceutical composition may comprise a lubricant, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycol; a binder, e.g., starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; a degrading agent, e.g., starch, alginic acid, alginate, or sodium starch glycolate; a foaming mixture; a dye; a sweetener; a wetting agent, e.g., an excipient selected from lecithin, polysorbate, or lauryl sulfate; and, generally, a non-toxic and pharmacologically inert substance used in the pharmaceutical formulation. Such pharmaceutical formulations may be prepared by known methods, e.g., mixing, granulation, tableting, sugar coating, or film coating processes.

[0066] The pharmaceutical composition may be a tablet comprising, for example, one or more excipients selected from magnesium stearate, colloidal silica, microcrystalline cellulose, stearyl fumarate, and starch.

[0067] The composition, which is a liquid dispersion for oral administration, may be a syrup, an emulsion, and a suspension. The syrup may contain, for example, saccharose, glycerin, mannitol, or sorbitol as a carrier.

[0068] The composition, which is a suspension or emulsion, may contain, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol as a carrier. The suspension or solution for intramuscular injection may contain a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycol, for example, propylene glycol, together with a pharmaceutically acceptable acid addition salt, and, if necessary, a suitable amount of lidocaine hydrochloride.

[0069] Solutions for injection, infusion, or inhalation may contain, for example, sterile water as a carrier, or they may be in the form of sterile, aqueous, isotonic saline solutions.

[0070] The pharmaceutical composition may comprise a pharmaceutically acceptable acid addition salt in an amount equivalent to 0.1 to 1000 mg of S-pindolol free base. For example, the pharmaceutical composition may comprise a pharmaceutically acceptable acid addition salt in an amount equivalent to 80 to 160 mg or 2.5 to 50 mg of S-pindolol free base. The pharmaceutical composition may comprise a salt in an amount equivalent to 2.5 to 15 mg of S-pindolol free base. For example, 3.7 mg of S-pindolol benzoate (molecular weight 370.4 gmol -1 ) is 2.5 mg of S-pindolol free base (molecular weight 248.3 gmol -1 It is equivalent to ).

[0071] 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.

[0072] Medical use

[0073] Pharmaceutically acceptable acid salts are useful for the treatment or prevention of diseases or conditions selected from cachexia, sarcopenia, neuromuscular disorder, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma, and anxiety. Typically, the diseases or conditions selected from cachexia and muscle weakness.

[0074] Cachexia can occur due to an underlying condition. For example, cachexia can be caused by cancer, heart failure, chronic obstructive pulmonary disease (COPD), liver failure, kidney failure, stroke, rheumatoid arthritis, severe burn injury, or HIV / AIDS. Muscle weakness can occur due to an underlying condition. For example, muscle weakness can result from trauma, musculoskeletal injury, surgery, or immobilization. Muscle weakness may be ICU-acquired weakness (ICUAW). Neuromuscular disorders may be, for example, amyotrophic lateral sclerosis.

[0075] The present invention also provides a method for treating or preventing a disease or condition selected from cachexia, sarcoidosis, neuromuscular disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma and anxiety in an individual, the method comprising the step of administering a therapeutically effective amount of a pharmaceutically acceptable acid addition salt to the individual.

[0076] Pharmaceutically acceptable acid addition salts are typically administered orally or parenterally.

[0077] The effective amount of pharmaceutically acceptable acid addition salt is typically an amount equivalent to 0.1 to 1000 mg of S-pindolol free base per single dose. For example, a single dose of pharmaceutically acceptable acid addition salt may be a dose equivalent to 2.5 to 50 mg or 80 to 160 mg of S-pindolol free base. A single dose may be an amount of salt equivalent to 2.5 to 15 mg of S-pindolol free base. The dose may be administered once, twice, or three times daily.

[0078] The following examples illustrate the present invention.

[0079] Examples

[0080] Examples 1 - S- Pindolol's salt

[0081] Analysis method

[0082] X-ray powder diffraction XRPD )

[0083] XRPD analysis was performed on a PANalytical X'pert pro equipped with a PIXcel detector (128 channels), and samples were scanned from 3 to 35°2θ. The material was gently crushed to release random aggregates and loaded into a multi-well plate fitted with a Mylar polymer film to support the samples. The multi-well plate was then placed into a diffractometer and analyzed using Cu K radiation (α1λ = 1.54060Å; α2 = 1.54443Å; β = 1.39225Å; α1:α2 ratio = 0.5) operating in transmission mode (step size 0.0130°2θ, step time 18.87 sec) with a 40kV / 40mA generator setting. Data were visualized, and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0084] thermal weight / Differential Scanning Calorimeter (TG / DSC )

[0085] Approximately 5 to 10 mg of the substance was added to an open aluminum pan pre-measured by a container, loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC, and maintained 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 was recorded along with the thermal fluid reaction (DSC) during this time. Nitrogen was introduced at 300 cm² 3 It was used as purge gas at a flow rate of / min.

[0086] Differential Scanning Calorimeter ( DSC )

[0087] Approximately 5 mg of the material was weighed into an aluminum DSC pan and sealed airtight with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 (equipped with an RC90 cooler) cooled and maintained at 20°C. Once a stable thermal flow reaction was obtained, the sample and reference were heated to 180°C at a scan rate of 10°C / min, and the resulting thermal flow reaction was monitored. Nitrogen was introduced at 500 cm² 3 It was used as purge gas at a flow rate of / min.

[0088] Infrared spectroscopy (IR)

[0089] Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. A sufficient amount of material was placed in the center of the spectrometer plate, and the spectrum was obtained using the following parameters:

[0090] · Resolution: 4cm -1

[0091] · Background scan time: 16 scans

[0092] · Sample scan time: 16 scans

[0093] · Data collection: 4000 to 400 cm -1

[0094] · Result Spectrum: Transmittance

[0095] · Software: OPUS Version 6

[0096] nuclear magnetism Resonance (NMR)

[0097] NMR experiments were performed on a Bruker AVIII HD spectrometer equipped with a DCH cryo-probe operating at 500.12 MHz for protons. Experiments were conducted in deuterated DMSO or methanol, and each sample was prepared at a concentration of approximately 10 mM.

[0098] Dynamic steam sorption ( DVS)

[0099] Approximately 10 to 20 mg of the sample was placed in a mesh vapor adsorption balance pan and loaded onto the intrinsic dynamic vapor adsorption balance by a surface measurement system. The sample was applied to a gradient profile at 40 to 90% relative humidity (RH) in 10% increments and maintained at each step until a stable weight was achieved at 25°C (dm / dt 0.004%, minimum step length 30 min, maximum step length 500 min). After the completion of the adsorption cycle, the sample was dried to 0% RH using the same procedure, and then the second adsorption cycle was performed at 40% RH. Two cycles were performed. The weight change during the adsorption / desorption cycle was plotted to determine the hygroscopicity of the sample. Subsequently, XRPD analysis was performed on any retained solid phase.

[0100] Variable Temperature X-ray Powder Diffraction (VT- XRPD )

[0101] VT-XRPD analysis was performed on a Philips X'Pert Pro multi-purpose diffractometer equipped with a temperature chamber. Samples were scanned from 4 to 35.99°2θ using Cu K radiation (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) operating with Bragg-Brentano geometry (step size 0.008°2θ) using a 40kV / 40mA generator setting. The experimental parameters were performed 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℃ at 2℃ / min; hold for 5 minutes; scan at 115℃; cool to 30℃ at 10℃ / min; scan at 30℃.

[0102] High-performance liquid chromatography-ultraviolet detection ( HPLC -UV)

[0103] · Equipment: Dionex Ultimate 3000

[0104] · Column: Agilent Zorbax, SB-C18, 150 mm × 4.6 mm, 3.5 μm

[0105] · Column temperature: 25℃

[0106] · Automatic Sampler Temperature: Ambient Temperature

[0107] · UV wavelength: 254nm

[0108] · Injection volume: 3μl

[0109] · Flow rate: 1.0 ml / min

[0110] · Mobile Phase A: 1.36 g potassium dihydrogen phosphate + 1000 mL water. Adjust pH to 4.0 ± 0.05 using phosphoric acid. Filter through a 0.45 μm membrane and degas.

[0111] · Mobile phase B: Acetonitrile:methanol (95:5 v / v)

[0112] · Diluent: Water:Acetonitrile (20:80 v / v)

[0113] · Gradient Program:

[0114]

[0115] S- Pindolroll Characterization of free bases

[0116] Samples of S-pindolol free bases were characterized.

[0117] XRPD analysis showed that the S-pindolol free base is highly crystalline. The XRPD pattern of the S-pindolol free base (free base pattern 1) is shown in Fig. 1.

[0118] TG / DSC analysis did not detect mass loss due to TG until decomposition at approximately 200°C. This indicated that the material was anhydrous and non-solvent. An endothermic event was observed in DSC, with an onset at 82°C and a peak at 84°C attributed to a solid-solid transition. A larger endothermic event was observed, with an onset at 93°C and a peak at 95°C due to melting.

[0119] DVS analysis determined that the substance was slightly hygroscopic with a mass absorption of 0.36 wt% (0.05 eq. of water) at 90% RH. XRPD analysis after DVS showed that the substance remained unchanged.

[0120] Primary salt investigation

[0121] 72 samples of 40 mg of ACM-001 free base were weighed into 2 mL vials. After adding 0.5 mL of an appropriate solvent to each vial, 1.1 eq. of an appropriate counterion was added.

[0122] 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 (pKa11.92), phosphoric acid (pKa11.96), L-tartaric acid (pKa13.02), fumaric acid (pKa13.03), citric acid (pKa13.13), S-(+)-mandelic acid (pKa13.37), benzoic acid (pKa14.19), and succinic acid (pKa14.21).

[0123] The solvents used were water, ethanol, 2-propanol, ethyl acetate, acetone, and tetrahydrofuran (THF).

[0124] The samples were temperature-cycled between ambient temperature and 40°C in a 4-hour cycle for 72 hours. Any solid formed was isolated by centrifugation before being analyzed by XRPD.

[0125] It was found that a number of solids obtained after initial temperature cycling became colored. In particular, products formed using sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, phosphoric acid, L-tartaric acid, fumaric acid, and citric acid became colored when specific solvents were used.

[0126] Then, 0.5 mL of antisolvent was added to vials containing solids insufficient for XRPD analysis (acetone was used for experiments in water, and heptane was used for all other samples). These samples were then temperature-cycled for an additional 24 hours as before. The additional 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 samples were uncapped and allowed to evaporate for up to one week. The obtained solids and gels were analyzed by XRPD.

[0127] After 7 days, all samples remaining in the solution as well as those obtained by temperature cycling, antisolvent 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, where "s" indicates the formation of a solid, "gm" indicates the formation of a gum, and "cryst" indicates the formation of large crystals.

[0128]

[0129] 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 nearly amorphous. Many of these products were also heavily colored.

[0130] The XRPD of the product formed using hydrochloric acid was found to correspond to the XRPD of the S-pindolol free base.

[0131] When S-pindolol was treated with tartaric acid, gum was formed from most solvents. When ethyl acetate was used as a solvent, a solid product was formed. However, after XRPD analysis, the solid products from ethyl acetate and tartaric acid were found to be free bases of S-pindolol. Therefore, it was not possible to produce crystalline salts of S-pindolol and tartaric acid.

[0132] Salts formed from fumaric acid, benzoic acid, and succinic acid were found to be crystalline, and their XRPD patterns differ from those of the S-pindolol free base. Fumaric acid salts were colored when formed from water, ethanol, 2-propanol, and acetone, and were white when formed from ethyl acetate and THF. Succinic acid salts were colored when formed from water, otherwise they were white. Benzoic acid salts were white when formed from any solvent.

[0133] Therefore, the primary salt screen revealed that crystalline solid salt forms can be formed from fumaric acid, benzoic acid, and succinic acid. Salts formed from these three acids were further characterized.

[0134] Fumarate Characterization of salts

[0135] As shown in Fig. 2, the solid recovered from the fumaric acid experiment in ethanol, 2-propanol, acetone, and THF was crystalline and did not match free base pattern 1. Fumarate pattern 1 was obtained from ethanol, pattern 2 from 2-propanol and THF, and pattern 3 from acetone.

[0136] Pattern 1 and Pattern 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.

[0137] Patterns 1, 2, and 3 were characterized as follows.

[0138] Hemi- Fumarate Pattern 1

[0139] During the TG analysis, a 22.8 wt% loss (0.40 eq. fumaric acid) was observed between 200°C and 280°C, which may be due to decomposition. Decomposition occurred above 200°C. An endothermic event associated with melting was observed in the DSC trace, starting at 181°C and peaking at 188°C. A small endothermic event was observed at 157°C, higher than the two other hemi-fumarate forms. The TG and DSC traces are shown in Fig. 3.

[0140] DMSO-d6 1 Half of the fumaric acid equivalents were observed in the 1H NMR spectrum. Ethanol was absent. A peak shift and a broad water peak were observed compared to the S-pindolol free base, indicating that salt formation occurred.

[0141] Hemi - Fumarate Pattern 2

[0142] During the TG analysis, a loss of 21.9 wt% (potentially 0.39 eq. fumaric acid) was observed between 180°C and 280°C, which may be due to decomposition. Decomposition occurred above 200°C. Two shallow endothermic events were observed in the DSC trace with peaks at 152°C and 184°C. The second event was associated with the onset of decomposition. The TG and DSC traces are shown in Fig. 4.

[0143] DMSO-d6 1 ¹H NMR determined that approximately 0.5 equivalents of fumaric acid were present in the sample. 1.08 wt% (0.04 eq.) of THF was present. Peak shifts and a broad water peak were observed compared to the S-pindolol free base, indicating that salt formation occurred.

[0144] Hemi - Fumarate Pattern 3

[0145] In the TG trace, a loss of 18.6 wt% (potentially 0.34 eq. fumaric acid) was observed between 200°C and approximately 270°C. Decomposition occurred above 200°C. A single shallow endothermic event due to melting was observed in the DSC trace with a peak at 150°C. The TG and DSC traces are shown in Fig. 5.

[0146] DMSO-d6 1 H NMR detected a broad peak at 6.35 ppm corresponding to approximately 0.5 equivalents of fumaric acid. A possible acetone peak was observed at 2.09 ppm (7.09 wt% or 0.3 eq.). However, there may be some overlap as a peak was observed in the free base NMR spectrum at that position. Peak shifts and a broad water peak were observed compared to the ACM-001 free base, indicating that salt formation occurred.

[0147] Fumarate Stability test of salt form

[0148] Samples of S-pindolol hemi-fumarate pattern 2 were stored at 60°C (closed 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 a different form, pattern 4.

[0149] S- Pindolroll Benzoate Manufacturing and Characterization of Pattern 1

[0150] S- Pindolroll Benzoate Pattern 1 manufacturing

[0151] 271.69 mg (1.1 eq.) 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 washed with 1 mL of ethyl acetate, and the washing solution was added to the scintillation vial. Upon adding an additional 1 mL of ethyl acetate, a beige solution containing a small amount of undissolved benzoic acid was observed.

[0152] After capping the scintillation vial and sealing it with Parafilm, the temperature was cycled between ambient temperature and 40°C in 4-hour cycles for about 72 hours.

[0153] After 72 hours, the sub-sample 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.

[0154] Benzoate salts are XRPD, 1 It was characterized by ¹H NMR, TG / DSC, DSC, and FT-IR.

[0155] S- Pindolroll Benzoate Pattern 1 Characterization

[0156] XRPD analysis showed that S-pindolol benzoate was highly crystalline. The pattern (shown in Fig. 6) was designated as S-pindolol benzoate pattern 1. The 2θ values ​​and peak intensities for S-pindolol benzoate pattern 1 are presented in Table 2 below.

[0157]

[0158] A single determination parameter of S-pindolol benzoate pattern 1 was identified. The unit cell dimensions of the collected structure were found to be as follows:

[0159] · Single-shot P21

[0160] · a = 8.4937(5)Å α= 90°

[0161] · b = 15.2956(9)Å β = 98.981(2)°

[0162] · c = 15.5169(9)Å γ = 90°

[0163] · Volume = 1991.2(2)Å 3

[0164] · Z=4, Z`=2

[0165] The final purification parameters were as follows:

[0166] · R1[I > 2σ(I)] = 2.99%

[0167] · GooF (Goodness of Fitness) = 1.058

[0168] · wR2(all data) = 8.28%

[0169] · R int = 3.15%

[0170] · Flack = -0.03(4)

[0171] 1 By H NMR, a 1:1 ratio of benzoic acid to S-pindolol was observed, and a broad water peak was present, indicating that salt formation was successful. The presence of 0.69 wt% (0.03 eq.) of ethyl acetate was observed.

[0172] The FT-IR spectrum matched the supplied structure; refer to Fig. 7. The following peaks were observed and assigned:

[0173] · Extensive OH stretch ~ 3255 - 2447 cm -1

[0174] · NH Stretch ~ 3255 cm -1

[0175] · Aromatic CH Stretch ~ 3027 cm -1

[0176] · Aliphatic CH Stretching ~ 2969 cm -1

[0177] · Alkene C=C ~1643 cm -1

[0178] TG and DSC scans of S-pindolol benzoate pattern 1 are shown in FIGS. 8 to 10. TG / DSC analysis revealed a 40 mass% loss due to TG at 150°C to 250°C, followed by decomposition. This weight loss is likely due to decomposition but is identical to that of benzoic acid at 2 eq. An endothermic event was observed in DSC with an onset at 130°C and a peak at 135°C.

[0179] DSC analysis detected a rapid endothermic event with an onset at 130°C and a peak at 135°C. This corresponds to the melt and is consistent with TG / DSC data. No event was observed during the cooling cycle. A glass transition and endothermic event with a midpoint at 44°C was observed during the second heating cycle, with an onset at 133°C and a peak at 136°C.

[0180] S- Pindolroll Benzoate Manufacturing and Characterization of Pattern 2

[0181] S- Pindolroll Benzoate Pattern 2 manufacturing

[0182] Approximately 5 g of S-pindolol free base was combined with approximately 2.7 g of benzoic acid. The benzoic acid sample vial was washed with 2 mL of ethyl acetate. The washing solution and an additional 16 mL of ethyl acetate were added to the combined sample to form a white slurry.

[0183] The sample was temperature-cycled between ambient temperature and 40°C over a 4-hour cycle for approximately 24 hours.

[0184] The material was filtered through a Buchner funnel and dried on filter paper for about 5 minutes. Then, the material was returned to a sample vial and dried at 40°C under vacuum for about 6 hours.

[0185] Benzoate salts are XRPD, 1 It was characterized by ¹H NMR, TG / DSC, DSC, and FT-IR.

[0186] S- Pindolroll Benzoate Pattern 2 Characterization

[0187] XRPD analysis showed that S-pindolol benzoate was highly crystalline. The pattern (shown in Fig. 11) was designated as S-pindolol benzoate pattern 2. The 2θ values ​​and peak intensities for S-pindolol benzoate pattern 2 are presented in Table 3 below.

[0188]

[0189] A single determination parameter of S-pindolol benzoate pattern 2 was identified. The unit cell dimensions of the collected structure were found to be as follows:

[0190] · Single-shot P21

[0191] · a = 9.9330(2)Å α = 90 °

[0192] · b = 9.5832(2)Å β = 107.2020(10) °

[0193] · c = 10.9875(3)Å γ = 90 °

[0194] · Volume = 999.11(4)Å 3

[0195] · Z= 2, Z`= 1

[0196] The final purification parameters were as follows:

[0197] · R1[I > 2σ(I)] = 2.58%

[0198] · GooF (Goodness of Fit) = 1.040

[0199] · wR2(all data) = 6.73%

[0200] · R int = 2.86%

[0201] · Flack = 0.01(7)

[0202] 1 By ¹H NMR, a 1:1 ratio of benzoic acid to S-pindolol was observed. 0.25 wt% (0.01 eq.) of ethyl acetate was also found in the spectrum. Extensive water peaks and peak shifts indicated that salt formation was successful.

[0203] The FT-IR spectrum matched the supplied structure; refer to Fig. 12. The following peaks were observed and assigned:

[0204] · Extensive OH stretch ~ 3219 - 2377 cm -1

[0205] · NH Stretch ~ 3219 cm -1

[0206] · Aromatic CH Stretch ~ 3098 cm -1

[0207] · Aliphatic CH Stretch ~ 2929 cm -1

[0208] · Alkenes C=C ~1635 cm -1

[0209] TG and DSC scans of S-pindolol benzoate pattern 2 are shown in Figures 13 to 15. TG / DSC analysis revealed a mass loss of 42.8 wt% in the TG trace. This was likely due to decomposition. A rapid endothermic event associated with melting was observed in the DSC trace, with an onset at 156°C and a peak at 158°C.

[0210] DSC analysis detected a rapid endothermic event with an onset at 157°C and a peak at 159°C. This corresponds to the melt and is consistent with TG / DSC data. No event was observed during the cooling cycle. A possible glass transition with a midpoint of 27°C was observed during the second heating cycle.

[0211] S- Pindolroll succinate Manufacturing and Characterization of Pattern 1

[0212] S- Pindolroll succinate Pattern 1 manufacturing

[0213] 264.68 mg (1.1 eq.) of succinic acid was added to approximately 500 mg of S-pindolol free base in a scintillation vial. The acid-containing sample vial was washed with 1 mL of THF, and the washing 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 the temperature was cycled between ambient temperature and 40°C in 4-hour cycles for approximately 72 hours. After 72 hours, the sample was filtered over a Buchner funnel and dried on filter paper for approximately 5 minutes. Subsequently, the material was placed into a pre-weighed sample vial and dried at 40°C for approximately 21 hours.

[0214] Succinate salts are XRPD, 1 It was characterized by ¹H NMR, TG / DSC, DSC, and FT-IR.

[0215] S- Pindolroll succinate Pattern 1 Characterization

[0216] XRPD analysis showed that S-findolol succinate was highly crystalline. The pattern (shown in Fig. 16) was designated as S-findolol succinate pattern 1. The 2θ values ​​and peak intensities of S-findolol succinate pattern 1 are presented in Table 4 below.

[0217]

[0218] 1H NMR detected a 1:1 ratio of ACM-001 to succinic acid and 0.04 equivalents of THF.

[0219] The FT-IR spectrum matched the supplied structure; refer to Fig. 17. The following peaks were observed and assigned:

[0220] · Extensive OH stretch ~ 3389 - 2676 cm -1

[0221] · NH Stretch ~ 3389 cm -1

[0222] · Aromatic CH Stretch ~ 3153 cm -1

[0223] · Aliphatic CH Stretch ~ 2970 cm -1

[0224] · Alkenes C=C ~ 1690 cm -1

[0225] TG and DSC scans of S-pindolol succinate pattern 1 are shown in FIGS. 18 to 20. TG / DSC analysis revealed a 12% mass loss due to TG at 160°C to 250°C, followed by decomposition. This weight loss may be due to decomposition and corresponds to 0.42 eq. of succinic acid. An endothermic event was observed in DSC with an onset at 111°C and a peak at 115°C.

[0226] DSC analysis detected a rapid endothermic event with an onset at 110°C and a peak at 114°C. This corresponds to the melt and is consistent with TG / DSC data. No event was observed during the cooling cycle. A glass transition was observed with a midpoint at 39°C during the second heating cycle.

[0227] The stability of S-pindolol succinate pattern 1 was evaluated. The succinate pattern 1 salt maintained its form after storage for 7 days at 60°C and 40°C / 75% RH. No color change was observed, purity was maintained, and there was no change in the solid form of succinate pattern 1 after storage for 4 weeks under all conditions.

[0228] Succinate salts were also analyzed by DVS. During DVS analysis, succinate pattern 1 was maintained at a mass absorption of 0.70 wt% (0.14 eq.) of water at 90% RH.

[0229] Summary of the characteristics of salt

[0230] A summary of 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 is presented in Table 5 below.

[0231]

[0232] Examples 1. Conclusion

[0233] The S-pindolol free base was found to be crystalline with an indistinct form. The thermal properties found were as follows: decomposition after 200°C; solid-solid transition at 83°C; melt at 93°C. The free base was slightly hygroscopic with the absorption of 0.05 eq. of water up to 90% RH.

[0234] Salt screening was successfully performed in S-pindolol. With many counterions, only amorphous products or gums were identified. Crystalline salt forms were identified using fumaric acid, benzoic acid, and succinic acid.

[0235] All of these crystalline salt forms had higher melting points than free bases and were found to be anhydrous from TG / DSC analysis. Of these samples 1 1H NMR analysis revealed the stoichiometric amount and peak shift of the counterion compared to the free base spectrum, which indicated successful salt formation.

[0236] The hemi-fumarate salt was found to interconvert between different polymorphic forms during stability tests and was considered a less desirable salt form. The fumarate salt product also tended to become colored.

[0237] Benzoate and succinate salts were successfully scaled up for secondary salt screening. Two polymorphic forms of S-pindolol benzoate (Pattern 1 and Pattern 2) were identified. A single polymorphic form of S-pindolol succinate (Pattern 1) was identified.

[0238] S-pindolol benzoate pattern 1 was found to be a crystalline white solid with a higher melting point than free bases (onset at 130°C, whereas decomposition began around 150°C).

[0239] S-pindolol benzoate pattern 2 was found to be a crystalline white solid with a higher melting point than the free base (melting point onset at 156°C associated with co-decomposition).

[0240] S-pindolol succinate pattern 1 was found to be a crystalline grayish-white solid with a higher melting point than free bases (onset at 111°C, whereas decomposition began around 160°C).

[0241] The chemical and physical properties of S-pindolol benzoate and S-pindolol succinate are very favorable, making them highly suitable for the development of pharmaceutical applications. The pure white color, better form, higher melting point, lower hygroscopicity, and stability determined for S-pindolol benzoate mean that this salt is particularly desirable.

[0242] Examples 2 - S- Pindolroll Benzoate Polymorph

[0243] Polymorph screen

[0244] A 200 μL aliquot of a suitable solvent was added to approximately 36 mg of an amorphous S-findolol benzoate sample to obtain a slurry. The sample was capped, sealed with Parafilm, and placed in an incubator shaker for approximately 72 hours in 4-hour cycles, with a temperature cycle between ambient temperature and 40°C (while shaking).

[0245] After 72 hours, observation was performed, and the sample was centrifuged in a tube containing a filter to isolate the solid and the saturated solution. Subsequently, the obtained solid was dried at 40°C for approximately 24 hours and reanalyzed by XRPD to determine that polymorphs were obtained. The results of the polymorph screen are presented in Table 6.

[0246]

[0247] Most solvents returned Pattern 1. Pattern 2 was obtained from solvents, e.g., methyl ethyl ketone, ethanol, THF, and water. The XRPD pattern of Pattern 2 obtained from methyl ethyl ketone is shown in Fig. 21.

[0248] Competitive slurry

[0249] 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 samples. A white slurry was obtained. One slurry from each solvent system was placed in an incubator shaker at 60°C, and the second slurry from each solvent system was placed on the shaker under ambient conditions. After 24 hours, the solid was isolated by centrifugation and analyzed by XRPD. S-pindolol benzoate salt pattern 2 was obtained from all four competitive slurry experiments (as shown in Fig. 22), indicating that pattern 2 is a thermodynamically stable form.

[0250] S- Pindolroll Benzoate Summary of the characteristics of Patterns 1 and 2

[0251] A summary of the characteristics of S-findolol benzoate pattern 1 and S-findolol benzoate pattern 2 is presented below in Tables 7 and 8, where Table 8 includes the results of stability and solubility experiments.

[0252] [Table 7]

[0253]

[0254] [Table 8]

[0255]

[0256] Examples 2. Conclusion

[0257] Most solvent systems yielded S-pindolol benzoate pattern 1. However, a different pattern, pattern 2, 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.

[0258] Benzoate pattern 1 was returned from most solvent solubility screen samples, but benzoate pattern 2 was obtained from all polymorph screen experiments yielding crystalline material and was found to be the thermodynamic form based on competitive slurry experiments and higher melting onset compared to pattern 1.

[0259] S-pindolol benzoate pattern 2 was found to be a crystalline white solid with birefringent crystals of approximately 10 μm in size having an indistinct morphology. Pattern 2 was an anhydrous monobenzoate salt. The thermal properties of S-pindolol benzoate pattern 2 were improved compared to pattern 1, which supported the theory that pattern 2 is a thermodynamic form. A higher melting point was obtained with an onset at 156°C compared to 130°C for pattern 1. Decomposition of pattern 2 occurred at the same temperature as the onset of melting. Additionally, a glass transition was observed in the second heating cycle with a midpoint of 27°C. S-pindolol benzoate pattern 2 was non-hygroscopic with an absorption of 0.045 wt% (0.01 eq.) of water at 90% RH. HPLC analysis revealed that the substance has 99.9% purity by relative area and 99.4% ee by chiral HPLC.

[0260] In 7-day and 14-day stability tests of S-pindolol benzoate pattern 2, it was revealed that pattern 2 maintained its XRPD pattern and high chemical purity (over 99.8% by relative area) under all stability conditions. Pattern 2 maintained a white color for 7 days under all stability conditions and for 14 days at 60°C and elevated humidity.

[0261] Through thermodynamic solubility experiments, it was determined that S-pindolol benzoate pattern 2 exhibited significantly high solubility (with free base concentrations of 23.5 mg / mL, 17.6 mg / mL, 9.9 mg / mL, and 10.3 mg / mL) observed in buffered and unbuffered water at pH 1.2, 4.5, and 6.8, respectively. S-pindolol benzoate pattern 2 improved the solubility of the free base in unbuffered water, which was 1.8 mg / mL.

[0262] The chemical and physical properties of S-pindolol benzoate salt patterns 1 and 2 make both of them possible salt forms. However, S-pindolol benzoate pattern 2 was a preferred salt form because it is a thermodynamic form.

Claims

Claim 1 (i) S-pindolol; and (ii) a pharmaceutically acceptable acid addition salt of benzoic acid. Claim 2 In claim 1, the pharmaceutically acceptable acid addition salt is crystalline. Claim 3 A pharmaceutically acceptable acid addition salt, wherein the pharmaceutically acceptable acid salt is in the form of a solvate. Claim 4 In claim 1, the above salt is a pharmaceutically acceptable acid addition salt in which the salt is S-pindolol benzoate. Claim 5 In paragraph 4, the above-mentioned S-pindolol benzoate is a pharmaceutically acceptable acid addition salt in which S-pindolol monobenzoate. Claim 6 A pharmaceutically acceptable acid addition salt according to claim 4, wherein the 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. Claim 7 A pharmaceutically acceptable acid addition salt according to claim 6, wherein the x-ray powder diffraction pattern further includes peaks at 5.7°, 12.5°, and 18.4°± 0.2°2θ. Claim 8 A pharmaceutically acceptable acid addition salt according to claim 4, wherein the 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. Claim 9 A pharmaceutically acceptable acid addition salt according to claim 8, wherein the x-ray powder diffraction pattern further includes peaks at 9.2°, 13.9°, and 20.7°±0.2°2θ. Claim 10 A composition comprising at least 60 weight% of a pharmaceutically acceptable acid addition salt as defined in any one of claims 1 to 9, based on the total weight of the composition. Claim 11 A composition according to claim 10, wherein the composition comprises 30% by weight or less of R-pindolol or a salt thereof based on the total weight of the composition. Claim 12 A pharmaceutical composition comprising (i) a pharmaceutically acceptable acid addition salt defined in any one of claims 1 to 9, and (ii) a pharmaceutically acceptable excipient, carrier, or diluent, 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. Claim 13 A pharmaceutical composition according to claim 12, wherein the above pharmaceutical composition is a tablet. Claim 14 A pharmaceutical composition according to claim 13, wherein the composition comprises less than 1% by weight of R-pindolol or a salt thereof. Claim 15 A medicine 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, comprising as an active ingredient a pharmaceutically acceptable acid addition salt defined in any one of claims 1 to 9. Claim 16 In paragraph 15, a medicine in which the above disease or condition is cachexia or muscle weakness. Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete

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