Organic acid addition salts of s-acebutolol

Abstract

The present invention relates to a pharmaceutically acceptable acid addition salt comprising: (i) S-indolylcarbamate; and (ii) an organic acid, wherein the organic acid has: a pKa1 greater than or equal to 2.5; and a chemical formula of CxHy(CO2H)z, wherein x is 1 to 10, y is 2 to 20, and z is 1 or 2. The pharmaceutically acceptable acid addition salt is used to treat conditions such as cachexia, sarcopenia, neuromuscular disorders, and muscle weakness.

Description

TECHNICAL FIELD

[0001] The present invention relates to salts of S-indeanol and pharmaceutical compositions comprising the salts. Medical uses of the salts are also described. BACKGROUND

[0003] S-indeanol is a beta-adrenergic receptor antagonist, also known as (-)-indeanol. The systematic name of S-indeanol is (2S)-1-(1H-indol-4-yloxy)-3-(propan-2-ylamino)propan-2-ol, and the structure of the compound is shown below.

[0004]

[0005] S-indeanol has affinity for both beta-adrenergic receptors and 5-HT1 a receptors and can be used to treat a variety of disorders. WO 2008 / 068477 Al describes the treatment of cachexia with S-indeanol.

[0006] Indenolol is approved for use in the treatment of certain conditions in the form of the racemate. It has been found that S-indeanol is the more pharmacologically active enantiomer. The present invention found that S-indeanol has characteristics that make it difficult to formulate as an oral medicament, such as a tablet. In particular, S-indeanol sometimes and under certain conditions degrades and discolors during storage.

[0007] It is necessary to develop solid forms of S-indeanol that are well suited for use in a clinical setting. In particular, it is desirable to develop a solid that is crystalline, stable, and has a suitable color for pharmaceutical applications.

[0008] S-indeanol tartrate is described in Kaumann et al., British Journal of Pharmacology, 1986 89(1) 207-218. S-indeanol hydrochloride is described in Japanese Patent Application JPH01287064(A). Racemic indenolol benzoate is described in Kaul et al., Drug Development and Industrial Pharmacy, 22(11), 1063-1073 (1996). SUMMARY

[0010] The present inventors have found that S-indeanol salts formed with organic mono- and di-carboxylic acids having a pK a of at least 2.5 are well suited for pharmaceutical formulations. In particular, it has been found that these salts are stable, crystalline, and have an elevated melting point compared to S-indeanol free base. Several S-indeanol salts also have a pure white color, which is desirable for clinical use of a solid form.

[0011] The present invention provides pharmaceutically acceptable acid addition salts of: (i) S- pindolol; and (ii) an organic acid, wherein the organic acid has: a pK a1 ; and C x H y (CO2H) z , wherein x is 1 to 10, y is 2 to 20, and z is 1 or 2.

[0012] The present invention also provides a composition comprising at least 60% by weight of a pharmaceutically acceptable acid addition salt.

[0013] The present invention further provides a pharmaceutical composition comprising: (i) a pharmaceutically acceptable acid addition salt; and (ii) a pharmaceutically acceptable excipient, carrier or diluent.

[0014] The present invention also provides a pharmaceutically acceptable acid addition salt for use in the treatment of the human or animal body. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 XRPD 2 theta diffractogram showing S-pindolol free base Pattern 1.

[0016] Figure 2 XRPD 2 theta diffractogram showing the solid obtained from treatment of S-pindolol with fumaric acid.

[0017] Figure 3 TG / DSC thermogram showing S-pindolol hemifumarate Pattern 1.

[0018] Figure 4 TG / DSC thermogram showing S-pindolol hemifumarate Pattern 2.

[0019] Figure 5 TG / DSC thermogram showing S-pindolol hemifumarate Pattern 3.

[0020] Figure 6 XRPD 2 theta diffractogram showing S-pindolol benzoate Pattern 1.

[0021] Figure 7 FT-IR spectrum showing S-pindolol benzoate Pattern 1.

[0022] Figure 8 TG / DSC thermogram showing S-pindolol benzoate Pattern 1.

[0023] Figure 9 DSC thermogram showing S-pindolol benzoate Pattern 1 (first heating cycle).

[0024] Figure 10 DSC thermogram showing S-Indenolol Benzoate Form 1 (second heating cycle).

[0025] Figure 11 XRPD 2-theta diffractogram showing S-Indenolol Benzoate Form 2.

[0026] Figure 12 FT-IR spectrum showing S-Indenolol Benzoate Form 2.

[0027] Figure 13 TG / DSC thermogram showing S-Indenolol Benzoate Form 2.

[0028] Figure 14 DSC thermogram showing S-Indenolol Benzoate Form 2 (first heating cycle).

[0029] Figure 15 DSC thermogram showing S-Indenolol Benzoate Form 2 (second heating cycle).

[0030] Figure 16 XRPD 2-theta diffractogram showing S-Indenolol Succinate Form 1.

[0031] Figure 17 FT-IR spectrum showing S-Indenolol Succinate Form 1.

[0032] Figure 18 TG / DSC thermogram showing S-Indenolol Succinate Form 1.

[0033] Figure 19 DSC thermogram showing S-Indenolol Succinate Form 1 (first heating cycle).

[0034] Figure 20 DSC thermogram showing S-Indenolol Succinate Form 1 (second heating cycle).

[0035] Figure 21 XRPD diffractogram showing S-Indenolol Benzoate Form 2 obtained from methyl ethyl ketone.

[0036] Figure 22 XRPD diffractogram showing S-Indenolol Benzoate sample obtained from a competitive slurry experiment. DETAILED DESCRIPTION

[0038] The organic acid has a pK greater than or equal to 2.5 a1Therefore, organic acids are relatively weak acids. The organic acid preferably has a pK value of 3.0 to 5.0. a1 For example, the pK of the organic acid. a1 It can be between 4.0 and 4.5. pK a1 It is the acid dissociation constant from which the first proton is released from the acid. For monocarboxylic acids, pK a1 Simply corresponding to the acid dissociation constant pK a As used in this article, pK a1 The values ​​were measured at 25°C. (pK values ​​for organic acids) a and PK a1 The value is readily available to technical personnel.

[0039] Organic acids have C x H y (CO2H) z The chemical formula of an organic acid is given by a given formula, where x is 1 to 10, y is 2 to 20, and z is 1 or 2. Therefore, organic acids contain a hydrocarbon moiety (C...). x H y It consists of carbon (composed of hydrogen and carbon) and one or two carboxylic acid groups (CO₂H). Typically, x is 2 to 7, and H is 2 to 6. The C... x H y The group can be an aryl group, an alkyl group, or an alkenyl group. For example, the C x H y It can be divalent C 2-7 alkyl groups, divalent C 2-7 An alkenyl group or a divalent phenyl group optionally substituted with one or two methyl groups.

[0040] Organic acids can be, for example, benzoic acid, succinic acid, fumaric acid, malonic acid, acetic acid, propionic acid, glutaric acid, adipic acid, phenylacetic acid, methylbenzoic acid (including o-, m-, and p-methylbenzoic acid), and naphthoic acid (including 1- and 2-naphthoic acid).

[0041] The pK of these acids a1 The following table shows the acid, which is a monocarboxylic acid, and the pK... a1 It is the pK of the acid a .

[0042] Acid pK a1 ]]> Benzoic acid 4.19 Succinic acid 4.21 Fumaric acid 3.03 Malonic acid 2.83 Acetic acid 4.76 Propionic acid 4.88 Glutaric acid 4.34 Adipic acid 4.41 Phenylacetic acid 4.31 Methylbenzoic acid 4-5 1 -Naphthoic acid 3.67 2-Naphthoic acid 4.16

[0043] The structures of benzoic acid, succinic acid, and fumaric acid are as follows.

[0044]

[0045] Typically, the organic acid is benzoic acid or succinic acid. Preferably, the organic acid is benzoic acid.

[0046] The pharmaceutically acceptable acid addition salt is a salt of S- pindolol, and thus comprises a cation formed from S-pindolol. The cation formed from S-pindolol typically has the following structure:

[0047]

[0048] The enantiomeric excess of the S-enantiomer of the cation of pindolol in the pharmaceutically acceptable salt is typically at least 80%. Thus, at least 90 mole % of the cation in the salt is typically in the S-configuration. The enantiomeric excess is typically at least 95%. The cation of S-pindolol in the pharmaceutically acceptable acid addition salt is typically substantially in the S-configuration, and thus can have an enantiomeric excess of at least 99%. The enantiomeric excess can be measured by any standard technique, for example by measuring optical rotation or using chiral high performance liquid chromatography (HPLC).

[0049] Thus, the pharmaceutically acceptable acid addition salt typically does not comprise more than 10 mole % of the R-enantiomer of pindolol or a salt comprising a cation which is a protonated R-pindolol molecule. For example, the pharmaceutically acceptable acid addition salt typically comprises substantially no R-enantiomer of pindolol or a salt comprising a cation which is a protonated R-pindolol molecule.

[0050] The pharmaceutically acceptable acid addition salt is typically crystalline. The salt can thus have a three-dimensional crystal structure comprising repeating unit cells. The pharmaceutically acceptable acid addition salt can be in a solid form, for example a solid form comprising crystals or microcrystals of the pharmaceutically acceptable acid addition salt.

[0051] The pharmaceutically acceptable acid addition salt can be in the form of a solvate. A solvate of the salt is a solid form of the salt which comprises solvent molecules. For example, the salt can be a hydrate. Typically, the salt is not a solvate. For example, the pharmaceutically acceptable acid addition salt can be anhydrous.

[0052] The pharmaceutically acceptable acid addition salt typically has a melting point which is greater than the melting point of S-pindolol free base. The salt can have a melting point which is greater than or equal to 100 °C, for example 110 °C to 170 °C. Typically, the salt has a melting point of 130 °C to 160 °C. The melting point can be determined, for example, using differential scanning calorimetry (DSC).

[0053] The pharmaceutically acceptable acid addition salt can be formed by any suitable method. Typically, the S-indeanol free base is treated with an organic acid in a solvent. The solvent can 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 diethyl ether). The pharmaceutically acceptable acid addition salt prepared can be dissolved in the solvent or can be precipitated from solution. The pharmaceutically acceptable acid addition salt can be isolated by a suitable method, for example by filtration or by evaporation of the solvent.

[0054] The pharmaceutically acceptable acid addition salt can be an S-indeanol benzoate salt. This salt thus comprises a cation derived from S-indeanol and a benzoate anion. The stoichiometry of the cation and anion is typically about 1 : 1, for example 0.9: 1.0 to 1.1 : 1.0 (i.e. for every mole of anion, there can be 0.9 to 1.1 moles of cation). Preferably, the S-indeanol benzoate salt is an S-indeanol mono-benzoate salt. Thus, the salt can have the formula [C 14 H 21 N2O2] + [C6H6COO] - .

[0055] The pharmaceutically acceptable acid addition salt is typically crystalline. As described herein, the X-ray powder diffraction pattern is measured using CuKai radiation with a wavelength of 1.5418 A. The values of °2Θ are measured. If the X-ray powder diffraction pattern comprises a peak, the relative intensity of that peak is typically at least 5% or at least 10%. The error range for the values of °2Θ is typically ±0.2°2Θ, but the error range can alternatively be ±0.1°2Θ.

[0056] The S-indeanol benzoate salt can be in the form of a crystalline polymorph of the S-indeanol benzoate salt designated Pattern 1. The S-indeanol benzoate salt Pattern 1 typically has an X-ray powder diffraction (XRPD) pattern comprising peaks at 8.1°, 11.4° and 17.0° ± 0.2°2Θ.

[0057] The XRPD pattern of the S-indeanol benzoate salt Pattern 1 typically further comprises peaks at 5.7°, 12.5° and 18.4° ± 0.2°2Θ.

[0058] The XRPD pattern of S-Indenolol Benzoate Form 1 can 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 can include all of these peaks. The XRPD pattern of S-Indenolol Benzoate Form 1 can include the following peaks.

[0059]

[0060] The XRPD pattern of S-Indenolol Benzoate Form 1 can be substantially as shown in Figure 1. Figure 6

[0061] The infrared spectrum of S-Indenolol Benzoate Form 1 typically includes one or more peaks in the following ranges: 1638-1648 cm -1 -1, 2964-2974 cm -1 -1, 3022-3032 cm -1 -1, and 3250-3260 cm -1 -1. For example, the infrared spectrum can include peaks at about 1643 cm -1 -1, 2969 cm -1 -1, 3027 cm -1 -1, and 3255 cm -1 -1.

[0062] The melting point of S-Indenolol Benzoate Form 1 is typically in the range of 130 to 140 °C, for example about 135 °C.

[0063] S-Indenolol Benzoate Form 1 can be prepared by a process comprising recrystallizing S-Indenolol Benzoate from a solvent that is 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.

[0064] S-Indenolol Benzoate can be in the form of a crystalline polymorph of S-Indenolol Benzoate designated Form 2. S-Indenolol Benzoate Form 2 typically has an X-ray powder diffraction (XRPD) pattern that includes a peak at 9.2° ± 0.2° 2Θ.

[0065] ​S-Indenolol benzoate Form 2 typically has an X-ray powder diffraction (XRPD) pattern comprising peaks at 16.9°, 18.9° and 20.1° ± 0.2° 2Θ. The XRPD pattern of S- indenolol benzoate Form 2 typically also comprises peaks at 9.2°, 13.9° and 20.7° ± 0.2° 2Θ.

[0066] The XRPD pattern of S-Indenolol benzoate Form 2 can comprise five or more peaks at a 2Θ selected from 8.3°, 9.2°, 12.4°, 13.0°, 13.9°, 16.9°, 18.5°, 18.9°, 19.1°, 20.1°, 20.7°, 21.3°, 23.4°, 24.8°, 26.3°, 29.4° ± 0.2° 2Θ. The XRPD pattern can comprise all of these peaks. The XRPD pattern of S-Indenolol benzoate Form 2 can comprise the following peaks.

[0067]

[0068]

[0069] The XRPD pattern of S-Indenolol benzoate Form 2 can be substantially as shown in Figure 11 or Figure 21 .

[0070] The infrared spectrum of S-Indenolol benzoate Form 2 typically comprises one or more peaks in the following ranges: 1630-1640 cm -1 , 2924-2934 cm -1 , 3093-3103 cm -1 and 3214-3224 cm -1 . For example, the infrared spectrum can comprise peaks at about 1635 cm -1 , 2929 cm -1 , 3098 cm -1 and 3219 cm -1 .

[0071] The melting point of S-Indenolol benzoate Form 2 is typically in the range 153 to 163 °C, for example about 158 °C.

[0072] S-Indenolol benzoate Form 2 can be prepared by a process comprising recrystallising S-Indenolol benzoate from a solvent which is ethanol, methanol:water (e.g. 95:5% v / v), methyl ethyl ketone, tetrahydrofuran and water. For example, S-Indenolol benzoate Form 2 can be obtained by recrystallising S-Indenolol benzoate from methyl ethyl ketone.

[0073] It has been found that S-Indenolol Benzoate Form 2 is the thermodynamically stable form of S-Indenolol Benzoate. S-Indenolol Benzoate is thus preferably in the form of S-Indenolol Benzoate Form 2.

[0074] The pharmaceutically acceptable acid addition salt can be S-Indenolol Succinate. This salt thus comprises a cation derived from S-Indenolol and a succinate anion. The stoichiometry of the cation and the 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. The S-Indenolol Succinate can thus be S-Indenolol Hemisuccinate or S-Indenolol Monosuccinate. Preferably, the S-Indenolol Succinate is S-Indenolol Monosuccinate. Thus, the salt can have the formula [C 14 H 21 N2O2] + [HOOC(C2H4)COO] - or ([C 14 H 21 N2O2] + )2[OOC(C2H4)COO] 2- .

[0075] The S-Indenolol Succinate can be in the form of a crystalline polymorph of S-Indenolol Succinate designated Form 1. S-Indenolol Succinate Form 1 typically has an X-ray powder diffraction (XRPD) pattern comprising peaks at 13.3°, 16.7° and 19.5° ± 0.2° 2Θ.

[0076] The XRPD pattern of S-Indenolol Succinate Form 1 typically further comprises peaks at 8.3°, 12.2° and 12.8° ± 0.2° 2Θ. The error range in the peak positions can be ± 0.1° 2Θ.

[0077] The XRPD pattern of S-Indenolol Succinate Form 1 can comprise five or more peaks selected from 8.3°, 12.2°, 12.8°, 13.3°, 16.7°, 16.9°, 19.5°, 21.5°, 22.0°, 22.7°, 24.1°, 24.3°, 25.0° ± 0.2° 2Θ. The S-Indenolol Succinate Form 1 can have an XRPD pattern comprising peaks at 8.3°, 12.2°, 12.8°, 13.3°, 16.7°, 16.9°, 19.5°, 21.5°, 22.0°, 22.7°, 24.1°, 24.3°, 25.0° ± 0.2° 2Θ.

[0078] The XRPD pattern of Formula 1 can comprise the following peaks.

[0079]

[0080]

[0081] The XRPD pattern of S-Indenolol Succinate Form 1 can be substantially as shown in Figure 1.Figure 16 The infrared spectrum of S-acebutolol succinate Form 1 typically comprises one or more peaks in the following ranges: 1685-1695 cm

[0082] The infrared spectrum of S-acebutolol succinate Form 1 typically comprises one or more peaks in the following ranges: 1685-1695 cm -1 , 2965-2975 cm -1 , 3148-3158 cm -1 , and 3384-3394 cm -1 . For example, the infrared spectrum can comprise peaks at about 1690 cm -1 , 2970 cm -1 , 3153 cm -1 , and 3389 cm -1 .

[0083] The melting point of S-acebutolol succinate Form 1 is typically in the range of 110 to 120 °C, for example about 115 °C.

[0084] S-acebutolol succinate Form 1 can be produced by a method comprising: (i) providing S-acebutolol free base and succinic acid; (ii) adding THF to the S-acebutolol free base and succinic acid to produce a mixture; (iii) cycling the temperature of the mixture from a lower temperature of 15 °C to 30 °C to a higher temperature of 35 °C to 50 °C, and then back again, for a period of 3 to 5 hours, for a total time of 60 to 120 hours; (iv) filtering the resulting salt; and (v) drying the salt at a temperature of 35 °C to 50 °C for 18 to 48 hours.

[0085] The pharmaceutically acceptable acid addition salt typically has a purity of greater than or equal to about 90%, greater than or equal to about 95%, or greater than or equal to about 97%. The percent purity can be calculated as the area % based on HPLC separation.

[0086] The composition

[0087] The composition of the present application comprises at least 60% by weight of the pharmaceutically acceptable acid addition salt. The composition can comprise at least 80% by weight or at least 95% by weight of the pharmaceutically acceptable acid addition salt relative to the total weight of the composition. The composition can consist essentially of the pharmaceutically acceptable acid addition salt. The composition can consist of the pharmaceutically acceptable acid addition salt.

[0088] The composition therefore typically comprises no more than 30% by weight of R-acebutolol or a salt thereof relative to the total weight of the composition. For example, the composition can comprise no more than 10% by weight, or no more than 1% by weight of R-acebutolol or a salt thereof relative to the total weight of the composition.

[0089] The pharmaceutical composition of the present application comprises (i) a pharmaceutically acceptable acid addition salt and (ii) a pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical composition can be, for example, a tablet, a capsule, a powder, a solution or a suspension for oral administration; a solution or a suspension for injection; or a solution, a suspension or a powder for inhalation. The pharmaceutical composition is typically a tablet.

[0090] Pharmaceutically acceptable excipients, carriers and diluents are well known to the skilled person.

[0091] The diluent can be any pharmaceutically acceptable diluent. The diluent is typically suitable for parenteral administration or for oral administration. Examples of suitable liquid diluents include water, ethanol and glycerol. The diluent can alternatively be selected from solid diluents such as lactose, dextrose, sucrose, cellulose, corn starch and potato starch. The diluent can contain a buffering component to control the pH. The buffer can be derived from phosphate, citrate and acetate. The diluent can also contain sodium chloride.

[0092] The pharmaceutical composition can comprise an excipient selected from lubricants such as silica, talc, stearic, magnesium or calcium stearate and / or polyethylene glycols; binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrants such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; colouring agents; sweetening agents; wetting agents such as lecithin, polysorbates, laurylsulfate; and, generally, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical formulations can be prepared in known manner, for example by means of mixing, granulation, tabletting, sugar-coating or film-coating processes.

[0093] The pharmaceutical composition can be, for example, a tablet comprising one or more excipients selected from magnesium stearate, colloidal silicon dioxide, microcrystalline cellulose, strearyl fumarate and starch.

[0094] Liquid dispersion compositions for oral administration can be syrups, emulsions and suspensions. Syrups can contain a carrier such as sucrose, glycerol, mannitol or sorbitol.

[0095] Suspension or emulsion compositions can contain a carrier such as natural gums, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions for intramuscular injection can contain a pharmaceutically acceptable acid addition salt as well as a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride.

[0096] Solutions for injection or infusion, or for inhalation, can contain a carrier, such as sterile water, or they can be in the form of sterile, aqueous, isotonic saline solutions.

[0097] The pharmaceutical composition can comprise a pharmaceutically acceptable acid addition salt in an amount equivalent to 0.1 to 1000 mg of S-indeanol free base. For example, the pharmaceutical composition can comprise a pharmaceutically acceptable acid addition salt in an amount equivalent to 80 to 160 mg or 2.5 to 50 mg of S-indeanol free base. The pharmaceutical composition can comprise the salt in an amount equivalent to 2.5 to 15 mg of S-indeanol free base. For example, 3.7 mg of S-indeanol benzoate (molecular weight 370.4 gmol -1 ) is equivalent to 2.5 mg S-indeanol free base (molecular weight 248.3 gmol -1 ).

[0098] The pharmaceutical composition is typically substantially free of R-indeanol or a salt thereof. For example, the pharmaceutical composition can comprise less than 1.0 wt%, or less than 0.5 wt% of R-indeanol or a salt thereof.

[0099] Medical uses

[0100] The pharmaceutically acceptable acid addition salt can be used 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, glaucoma and anxiety. Typically the disease or condition is selected from cachexia and muscle weakness.

[0101] Cachexia can be caused by 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 burns or HIV / AIDS. Muscle weakness can be caused by an underlying condition. For example, muscle weakness can be caused by trauma, musculoskeletal injury, surgery or restricted mobility. Muscle weakness can be intensive care unit-acquired weakness (ICUAW). The neuromuscular disorder can be, for example, amyotrophic lateral sclerosis.

[0102] The present application also provides a method of treating or preventing a disease or condition selected from cachexia, sarcopenia, neuromuscular disorder, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina, glaucoma and anxiety in an individual, the method comprising administering to the individual a therapeutically effective amount of a pharmaceutically acceptable acid addition salt.

[0103] The pharmaceutically acceptable acid addition salt is typically administered orally or parenterally.

[0104] The effective amount of a pharmaceutically acceptable acid addition salt for a single dose is typically equivalent to 0.1 to 1000 mg of the free base of S-indolol. For example, a single dose of a pharmaceutically acceptable acid addition salt could be equivalent to 2.5 to 50 mg or 80 to 160 mg of the free base of S-indolol. A single dose could be equivalent to 2.5 to 15 mg of the salt of the free base of S-indolol. This dose can be administered once, twice, or three times a day.

[0105] The following examples illustrate the present invention. Example

[0106] Example 1 - Salts of S-Indolol

[0107] Analytical methods

[0108] X-ray powder diffraction (XRPD)

[0109] XRPD analysis was performed on a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the sample between 3° and 35°2θ. The material was gently ground to release any aggregates and loaded onto a porous plate with a Mylar polymer film to support the sample. The porous plate was then placed in a diffractometer and analyzed using Cu K radiation ( The system was operated in transmission mode (α1:α2 ratio = 0.5) with a step size of 0.0130°2θ and a step time of 18.87s, using a 40kV / 40mA generator. Data was visualized and images generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0110] Thermogravimetric / Differential Scanning Calorimetry (TG / DSC)

[0111] Approximately 5–10 mg of the substance was added to a pre-peeled, open aluminum dish, loaded into a DiscoverySDT 650 automated-simultaneous DSC instrument, and maintained at room temperature. The sample was then heated from 30 °C to 400 °C at a rate of 10 °C / min, during which time the weight change and thermal flow response (DSC) were recorded. Nitrogen gas was used as the purge gas at a flow rate of 300 cm⁻¹. 3 / min.

[0112] Differential scanning calorimetry (DSC)

[0113] Approximately 5 mg of material was weighed into an aluminium DSC pan and sealed non-hermetically with an aluminium lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 (equipped with an RC90 cooler) which was cooled and held at 20 °C. Once a stable heat flow response was obtained, the sample and reference were heated to 180 °C at a scan rate of 10 °C / min and the resulting heat flow response monitored. Nitrogen was used as the purge gas at a flow rate of 50 cm 3 / min.

[0114] Infrared Spectroscopy (IR)

[0115] Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed in the centre of the plate of the spectrometer and the spectrum obtained using the following parameters:

[0116] Resolution: 4 cm -1

[0117] Background scan time: 16 scans

[0118] Sample scan time: 16 scans

[0119] Data collection: 4000 to 400 cm -1

[0120] Resulting spectrum: Transmittance

[0121] Software: OPUS version 6

[0122] Nuclear Magnetic Resonance (NMR)

[0123] NMR experiments were performed on a Bruker AVIII HD spectrometer equipped with a DCH cryoprobe, operating at 500.12 MHz for protons. Experiments were performed in deuterated DMSO or methanol and each sample was prepared to approximately 10 mM concentration.

[0124] Dynamic Vapor Sorption (DVS)

[0125] Approximately 10–20 mg of sample was placed in a mesh vapor adsorption balance pan and loaded into an Intrinsic dynamic vapor adsorption balance via a surface measurement system. The sample was subjected to a ramp-up curve of 40–90% relative humidity (RH) in 10% increments, held at 25°C at each step until a steady-state weight was reached (dm / dt 0.004%, minimum step 30 min, maximum step 500 min). After completing the adsorption cycle, the sample was dried to 0% RH using the same procedure, followed by a second adsorption cycle back to 40% RH. Two cycles were performed. The weight change during the adsorption / desorption cycles was plotted to determine the hygroscopicity of the sample. Any retained solids were then analyzed by XRPD.

[0126] Variable-temperature X-ray powder diffraction (VT-XRPD)

[0127] VT-XRPD analysis was performed on a Philips X'Pert Pro multi-functional diffractometer equipped with a temperature chamber. Samples were scanned between 4° and 35.99°2θ using Cu K-rays. The α1:α2 ratio was 0.5, and the experiment was conducted using Bragg-Brentano geometry (step size 0.008°2θ) with a 40kV / 40mA generator. 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.

[0128] High-performance liquid chromatography-ultraviolet detection (HPLC-UV)

[0129] • Instrument: Dionex Ultimate 3000

[0130] • Column: Agilent Zorbax, SB-C18, 150mm × 4.6mm, 3.5μm

[0131] • Column temperature: 25℃

[0132] • Automatic sampler temperature: Ambient

[0133] • UV wavelength: 254nm

[0134] • Injection volume: 3 μl

[0135] • Flow rate: 1.0 ml / min

[0136] • Mobile phase A: 1.36 g Potassium dihydrogen phosphate + 1000 mL Water. Adjust pH to 4.0 ± 0.05 with phosphoric acid. Filter through 0.45 pm membrane and degas

[0137] • Mobile phase B: Acetonitrile: Methanol (95:5 v / v)

[0138] • Diluent: Water: Acetonitrile (20:80 v / v)

[0139] • Gradient program:

[0140]

[0141]

[0142] Characterization of S-Indoranol Free Base

[0143] The sample of S-Indoranol free base was characterized.

[0144] XRPD analysis showed that S-Indoranol free base is highly crystalline. The XRPD pattern (free base pattern 1) of S-Indoranol free base is shown in Figure 1

[0145] TG / DSC analysis found no mass loss by TG from about 200 °C up to degradation. This indicates that the substance is anhydrous and non-solvated. In DSC an endothermic event with onset at 82 °C and a peak at 84 °C was observed, which is attributed to a solid-solid transition. A larger endothermic event due to melting was observed with onset at 93 °C and a peak at 95 °C.

[0146] DVS analysis determined that the substance is slightly hygroscopic with a mass uptake of 0.36 wt% (0.05 eq. water) at 90% RH. XRPD analysis after DVS showed that the substance remained unchanged.

[0147] Primary salt study

[0148] Seventy-two 40 mg samples of ACM-001 free base were weighed into 2 mL vials. To each vial, 0.5 mL of the appropriate solvent was added, followed by 1.1 equivalents of the appropriate counterion.

[0149] ​The counterions used were those derived from the following acids: hydrochloric acid (pKa1of -6), sulfuric acid (pKa1of -3), p-toluenesulfonic acid.H2O (pKa1of -1.34), methanesulfonic acid (pKa1of -1.2), maleic acid (pKa1of 1.92), phosphoric acid (pKa1of 1.96), L-tartaric acid (pKa1of 3.02), fumaric acid (pKa1of 3.03), citric acid (pKa1of 3.13), S-(+)-mandelic acid (pKa1of 3.37), benzoic acid (pKa1of 4.19), and succinic acid (pKa1of 4.21).

[0150] The solvents used were water, ethanol, 2-propanol, ethyl acetate, acetone, and tetrahydrofuran (THF).

[0151] The samples were temperature cycled between ambient temperature and 40°C for 72 hours in 4 hour cycles. Any solids that formed were isolated by centrifugation prior to analysis by XRPD.

[0152] It was found that many of the solids obtained after the initial temperature cycling were 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.

[0153] Then 0.5 mL of antisolvent (acetone for the water experiments, heptane for all other samples) was added to the vials containing insufficient solids to perform XRPD analysis. These samples were then temperature cycled for an additional 24 hours at the previous temperature. Additional solids that formed during this stage were isolated by centrifugation and analyzed by XRPD. Samples with no solids were left uncapped and allowed to evaporate in the refrigerator (2-8°C) for up to one week. Any solids and gels obtained were analyzed by XPRD.

[0154] Samples that had been left in solution for 7 days, as well as samples obtained by temperature cycling, antisolvent addition, and evaporation at ambient were placed in an oven at 40°C for 72 hours to dry, and then analyzed by XRPD. Table 1 shows the observations made after drying, where "s" indicates the formation of solids, "gm" indicates the formation of a gel, and "cryst" indicates the formation of large crystals.

[0155]

[0156] It was found that 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 mostly amorphous. Many of these products were also strongly colored.

[0157] It was found that the XRPD of the product formed using hydrochloric acid corresponded to that of S-indinavir free base.

[0158] When S-indolol is treated with tartaric acid, a gel forms from most solvents. When ethyl acetate is used as a solvent, a solid product is formed. However, subsequent XRPD analysis revealed that the solid product from ethyl acetate and tartaric acid is the free base of S-indolol. Therefore, crystalline salts of S-indolol cannot be produced with tartaric acid.

[0159] The salts formed from fumaric acid, benzoic acid, and succinic acid are found to be crystalline, and their XPRD patterns differ from those of the free S-indolol base. Fumarates are colored when formed from water, ethanol, 2-propanol, and acetone, but white when formed from ethyl acetate and THF. Succinates are colored when formed from water, but white otherwise. Benzoates are white when formed from any solvent.

[0160] Therefore, primary salt screening revealed that crystalline solid salts can be formed from fumaric acid, benzoic acid, and succinic acid. Further characterization of the salts formed from these three acids was then conducted.

[0161] Characterization of fumarate

[0162] like Figure 2 As shown, the solids recovered from fumaric acid in experiments from ethanol, 2-propanol, acetone, and THF are crystalline and inconsistent with free base pattern 1. Fumarate pattern 1 is obtained from ethanol, pattern 2 from 2-propanol and THF, and pattern 3 from acetone.

[0163] Modes 1 and 2 are similar, although there are no peaks below 10°2θ in mode 1. Therefore, mode 2 could be a mixture containing mode 1.

[0164] Modes 1, 2, and 3 are characterized as follows.

[0165] Hemifumarate mode 1

[0166] During TG analysis, a 22.8% weight loss (0.40 equivalents of fumaric acid) was observed between 200°C and 280°C, likely due to degradation. Decomposition occurred above 200°C. An endothermic event associated with melting was observed in the DSC trace, initiating at 181°C and peaking at 188°C. A small endothermic event was noted at 157°C, higher than in the other two hemifumarate forms. TG and DSC traces at... Figure 3 It is displayed in the middle.

[0167] Note the presence of DMSO-d6 1 The 1H NMR spectrum shows half an equivalent of fumaric acid. Ethanol is absent. A peak shift and broad water peak are observed compared to the free base of S-indolol, indicating salt formation.

[0168] Hemifumarate Form 2

[0169] During TG analysis, a 21.9% weight loss (possibly 0.39 equivalents of fumaric acid) was observed between 180 °C and 280 °C, which can be due to degradation. 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 is associated with the onset of decomposition. The TG and DSC traces are shown in Figure 4 .

[0170] In DMSO-d6, 1 H NMR determined that there was approximately 0.5 equivalents of fumaric acid in the sample. There was 1.08 wt% (0.04 equivalents) of THF present. Peak shifts and broad water peaks compared to S-indeanol free base were observed, indicating salt formation had occurred.

[0171] Hemifumarate Form 3

[0172] In the TG trace, an 18.6% weight loss (possibly 0.34 equivalents of fumaric acid) was observed between 200 °C and about 270 °C. Decomposition occurred above 200 °C. Due to melting, one shallow endothermic event was observed in the DSC trace, with a peak at 150 °C. The TG and DSC traces are shown in Figure 5 .

[0173] In DMSO-d6, 1 H NMR found 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 equivalents). However, a peak was observed at this position in the spectrum of the free base NMR, so there can be some overlap. Peak shifts and broad water peaks compared to ACM-001 free base were observed, indicating salt formation had occurred.

[0174] Stability testing of fumarate forms

[0175] A sample of S-indeanol hemifumarate Form 2 was stored at 60 °C (sealed vial) or 40 °C / 75% RH (open vial) for 7 days. The sample stored at 60 °C converted to Form 1. The sample stored at 40 °C / 75% RH converted to a different form, Form 4.

[0176] Preparation and characterization of S-indeanol benzoate Form 1

[0177] Preparation of S-indeanol benzoate Form 1

[0178] In a scintillation vial, approximately 500 mg of S-Indenolol free base was added with 271.69 mg (1.1 equivalents) of benzoic acid. The sample vial containing the acid was rinsed with 1 mL of ethyl acetate and the wash was added to the scintillation vial. An additional 1 mL of ethyl acetate was added and a small amount of undissolved benzoic acid was noted as a beige solution.

[0179] The scintillation vial was capped and sealed with parafilm and then temperature cycled between ambient and 40 °C for approximately 72 hours in 4 hour cycles.

[0180] After 72 hours, a subsample was analyzed by XRPD. The sample matched the benzoic acid salt Pattern 1, so the sample was filtered over a Buchner funnel and placed in a pre-weighed sample vial. The solid was dried at 40 °C for approximately 21 hours.

[0181] The benzoic acid salt was characterized by XRPD, 1 H NMR, TG / DSC, DSC, and FT-IR.

[0182] Characterization of S-Indenolol Benzoate Pattern 1

[0183] XRPD analysis showed that the S-Indenolol benzoate was highly crystalline. This pattern (shown in Figure Figure 6 ) was assigned as S-Indenolol benzoate Pattern 1. The 2Θ values and peak intensities for S-Indenolol benzoate Pattern 1 are shown in Table 2 below.

[0184]

[0185]

[0186] Single crystal parameters were determined for S-Indenolol benzoate Pattern 1. The unit cell dimensions of the structure collected were found to be:

[0187] • Monoclinic P21

[0188] • α = 90°

[0189] • β = 98.981(2)°

[0190] • γ = 90°

[0191] •

[0192] • Z = 4, Z' = 2

[0193] The final refinement parameters were as follows:

[0194] • R1 [I > 2σ(I)] = 2.99%

[0195] • GooF (Goodness of fit) = 1.058

[0196] • wR2 (all data) = 8.28%

[0197] • R int = 3.15%

[0198] • Flack = -0.03 (4)

[0199] By 1 H NMR, a ratio of 1 : 1 of benzoic acid and S- indolol was observed, and a broad water peak was present, indicating that salt formation was successful. The presence of 0.69 wt% (0.03 equivalents) of ethyl acetate was observed.

[0200] FT-IP spectrum matched the provided structure, see Figure 7 . The following peaks were observed and assigned:

[0201] • Broad O-H stretch ~ 3255 - 2447 cm -1

[0202] • N-H stretch ~ 3255 cm -1

[0203] • Aromatic C-H stretch ~ 3027 cm -1

[0204] • Aliphatic C-H stretch ~ 2969 cm -1

[0205] • Olefin C=C ~ 1643 cm -1

[0206] TG and DSC scans of S-Indolol Benzoate Form 1 are shown in Figure 8 to 10 TG / DSC analysis found a 40% mass loss between 150 °C and 250 °C with subsequent degradation. The weight loss is likely due to degradation, but also corresponds to 2 equivalents of benzoic acid. An endothermic event with an onset of 130 °C and a peak at 135 °C was observed in DSC.

[0207] DSC analysis found a sharp endothermic event with an onset at 130 °C and a peak at 135 °C. This corresponds to melting and matches the TG / DSC data. No events were observed in the cooling cycle. In the second heating cycle a glass transition with midpoint at 44 °C and an endothermic event with an onset at 133 °C and a peak at 136 °C were observed.

[0208] Preparation and characterization of S-Indolol Benzoate Form 2

[0209] Preparation of S-indolol benzoate mode 2

[0210] Combine approximately 5 g of S-indolol free base with approximately 2.7 g of benzoic acid. Rinse the benzoic acid sample vial with 2 mL of ethyl acetate. Add the washings and another 16 mL of ethyl acetate to the combined sample to form a white slurry.

[0211] The sample was cycled at a temperature of 4 hours between ambient temperature and 40°C for approximately 24 hours.

[0212] Filter the substance through a Buchner funnel and leave it on filter paper to dry for about 5 minutes. Then, return the substance to the sample vial and vacuum dry at 40°C for about 6 hours.

[0213] Through XRPD, 1 Benzates were characterized by 1H NMR, TG / DSC, DSC and FT-IR.

[0214] Characterization of S-indolol benzoate mode 2

[0215] XRPD analysis showed that S-indolol benzoate is highly crystalline. The spectrum (as shown) Figure 11 The peak shown in the figure is designated as S-indolol benzoate mode 2. The 2θ values ​​and peak intensities of S-indolol benzoate mode 2 are shown in Table 3 below.

[0216]

[0217]

[0218] The single-crystal parameters of S-indolol benzoate mode 2 were determined. The cell sizes of the collected structures were found to be as follows:

[0219] Monoclinic P21

[0220] · α = 90°

[0221] · β=107.2020(10)°

[0222] · γ = 90°

[0223] ·

[0224] ·Z=2,Z`=1

[0225] The final refined parameters are as follows:

[0226] R1[I>2σ(I)]=2.58%

[0227] • GooF (Goodness of fit) = 1.040

[0228] • wR2 (all data) = 6.73%

[0229] • R int = 2.86%

[0230] • Flack = 0.01 (7)

[0231] By 1 H NMR, a 1 : 1 ratio of benzoic acid and S- indolol was observed. Also found in the spectrum was 0.25 wt% (0.01 eq) of ethyl acetate. Broad water peaks and peak shifts indicated that salt formation was successful.

[0232] FT-IP spectrum matched the structure provided, see Figure 12 . The following peaks were observed and assigned:

[0233] • Broad O-H stretch ~ 3219-2377 cm -1

[0234] • N-H stretch ~ 3219 cm -1

[0235] • Aromatic C-H stretch ~ 3098 cm -1

[0236] • Aliphatic C-H stretch ~ 2929 cm -1

[0237] • Olefin C=C ~ 1635 cm -1

[0238] TG and DSC scans of S-Indolol Benzoate Form 2 are shown in Figure 13 to 15 . TG / DSC analysis found a 42.8% mass loss in the TG trace. This can be due to degradation. A sharp endothermic event associated with melting was observed in the DSC trace, starting at 156 °C and peaking at 158 °C.

[0239] DSC analysis found a sharp endothermic event starting at 157 °C and peaking at 159 °C. This corresponds to melting and matches the TG / DSC data. No events were observed in the cooling cycle. A possible glass transition with midpoint at 27 °C was observed in the second heating cycle.

[0240] Preparation and characterization of S-Indolol Succinate Form 1

[0241] Preparation of S-Indolol Succinate Form 1

[0242] To a scintillation vial containing approximately 500 mg of S-Indenolol free base was added 264.68 mg (1.1 equivalents) of succinic acid. The sample vial containing the acid was rinsed with 1 mL of THF and the wash was added to the scintillation vial. An additional 2 mL was added and a beige slurry was noted. The scintillation vial was capped and sealed with parafilm and then temperature cycled between ambient and 40 °C for approximately 72 hours in 4 hour cycles. After 72 hours, the sample was filtered on a Buchner funnel and left to dry on the filter paper for approximately 5 minutes. The material was then placed in a pre-weighed sample vial and dried at 40 °C for approximately 21 hours.

[0243] S-Indenolol succinate was characterized by XRPD, 1 H NMR, TG / DSC, DSC and FT-IR.

[0244] Characterization of S-Indenolol succinate Form 1

[0245] XRPD analysis showed that S-Indenolol succinate was highly crystalline. The pattern (shown in Figure Figure 16 ) was assigned as S-Indenolol succinate Form 1. The 2Θ values and peak intensities for S-Indenolol succinate Form 1 are shown in Table 4 below.

[0246]

[0247] 1 H NMR found a 1:1 ratio of ACM-001 and succinic acid, as well as 0.04 equivalents of THF.

[0248] The FT-IP spectrum matched the structure provided, see Figure 17 . The following peaks were observed and assigned:

[0249] • Broad O-H stretch ~ 3389 - 2676 cm -1

[0250] • N-H stretch ~ 3389 cm -1

[0251] • Aromatic C-H stretch ~ 3153 cm -1

[0252] • Aliphatic C-H stretch ~ 2970 cm -1

[0253] • Olefin C=C ~ 1690 cm -1

[0254] TG and DSC scans of S-Indenolol succinate Form 1 were performed at Figure 18 to 20TG / DSC analysis found a sharp endothermic event with an onset at 110 °C and a peak at 114 °C. This corresponds to melting and matches the TG / DSC data. No events were observed in the cooling cycle. A glass transition with midpoint at 39 °C was observed in the second heating cycle.

[0255] DSC analysis found a sharp endothermic event with an onset at 110 °C and a peak at 114 °C. This corresponds to melting and matches the TG / DSC data. No events were observed in the cooling cycle. A glass transition with midpoint at 39 °C was observed in the second heating cycle.

[0256] The stability of S-indeanol succinate Form 1 was evaluated. The succinate Form 1 salt retained its form after storage at 60 °C and 40 °C / 75% RH for 7 days. No color change was observed, purity was maintained, and there was no change in the solid form of the succinate Form 1 after four weeks of storage under all conditions.

[0257] The succinate was also analyzed by DVS. The succinate Form 1 was retained with a mass uptake of 0.70 wt% (0.14 equivalents) water at 90% RH during DVS analysis.

[0258] Summary of Salt Characteristics

[0259] A summary of the characteristics of S-indeanol free base Form 1, S-indeanol benzoate Form 1, S-indeanol benzoate Form 2, and S-indeanol succinate Form 1 are given in Table 5 below.

[0260]

[0261] Conclusion for Example 1

[0262] S-indeanol free base was found to be crystalline with an unclear morphology. The thermal properties found were: degradation after 200 °C; a solid-solid transition at 83 °C; and melting at 93 °C. The free base is slightly hygroscopic, taking up 0.05 equivalents of water at a maximum of 90% RH.

[0263] Salt screening was successfully performed on S-indeanol. Using many counterions only amorphous products or gels were identified. Crystalline salt forms were identified using fumaric acid, benzoic acid, and succinic acid.

[0264] All of these crystalline salt forms have higher melting points than the free base and appear to be anhydrous from TG / DSC analysis. The DVS analysis of these samples 1 H NMR analysis found stoichiometric amounts of counterion and peak shifts compared to the free base spectrum, which indicates that salt formation was successful.

[0265] The hemifumarate salt was found to interconvert between different polymorphic forms during stability testing, which was considered to be a less desirable salt form. The fumarate salt product also tended to be colored.

[0266] The benzoate and succinate salts were successfully scaled up for secondary salt screening. Two polymorphic forms of S-acebutolol benzoate (Form 1 and Form 2) were identified. A single polymorphic form of S-acebutolol succinate (Form 1) was identified.

[0267] S-acebutolol benzoate Form 1 was found to be a crystalline white solid with a higher melting point than the free base (onset at 130°C, with decomposition onset at about 150°C).

[0268] S-acebutolol benzoate Form 2 was found to be a crystalline white solid with a higher melting point than the free base (melting point onset at 156°C, with decomposition).

[0269] S-acebutolol succinate Form 1 was found to be a crystalline off-white solid with a higher melting point than the free base (onset at 111°C, with decomposition onset at about 160°C).

[0270] The chemical and physical properties of S-acebutolol benzoate and S-acebutolol succinate are extremely favorable and make them highly suitable for development for pharmaceutical use. The pure white, better morphology, higher melting point, lower hygroscopicity, and stability identified for S-acebutolol benzoate mean that this salt is particularly preferred.

[0271] Example 2 - Polymorphs of S-acebutolol benzoate

[0272] Polymorph screening

[0273] A 200 μL aliquot of the appropriate solvent was added to about 36 mg of amorphous S-acebutolol benzoate sample to obtain a slurry. The sample was capped, sealed with parafilm, and placed in an incubator shaker to temperature cycle (and stir) between ambient and 40°C for about 72 hours at 4 hour cycles.

[0274] After 72 hours, observations were made and the samples were centrifuged in tubes containing filters to separate the solids and saturated solutions. The solids obtained were then dried at 40°C for about 24 hours and re-analyzed by XRPD to determine the polymorphs obtained. The results of the polymorph screening are shown in Table 6.

[0275]

[0276]

[0277] Most solvents returned 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 Figure 21 .

[0278] Competitive slurries

[0279] Four samples containing 10 mg of benzoate Pattern 1 and 10 mg of benzoate Pattern 2 were prepared. To two of these samples, 400 μL of 2-propanol was pipetted, and to the other two samples, 400 μL of water was pipetted. White slurries were obtained. One slurry of each solvent system was placed in an incubator shaker at 60 °C, and the second slurry of each solvent system was placed in a shaker at ambient conditions. After 24 hours, the solids were analyzed by centrifugation and by XRPD. From all four competitive slurry experiments, S- indinavir benzoate Pattern 2 was obtained (shown in Figure Figure 22 ), which indicates that Pattern 2 is the thermodynamically stable form.

[0280] Summary of characteristics of S-indinavir benzoate Pattern 1 and Pattern 2

[0281] A summary of the characteristics of S-indinavir benzoate Pattern 1 and S-indinavir benzoate Pattern 2 is given in Tables 7 and 8 below, where Table 8 includes the results of stability and solubility experiments.

[0282]

[0283]

[0284] Conclusion of Example 2

[0285] Most solvent systems produced S-indinavir benzoate Pattern 1. However, from ethanol, methanol / water mixture, methyl ethyl ketone, THF, and water, a different pattern was recovered, Pattern 2. A mixture of Patterns 1 and 2 was observed from anisole, butyl acetate, and toluene.

[0286] While from most of the solvent solubility screening samples, benzoate Pattern 1 was returned, from all of the polymorph screening experiments where crystalline material was produced, benzoate Pattern 2 was obtained, and this benzoate Pattern 2 appears to be the thermodynamic form based on the competitive slurry experiments and has a higher onset of melting than Pattern 1.

[0287] S-Indenolol benzoate Form 2 was found to be a crystalline white solid with birefringent crystals of about 10 μιη size that were not well formed. Form 2 is an anhydrous mono-benzoate. The thermal properties of S-Indenolol benzoate Form 2 were improved compared to Form 1, which supports the theory that Form 2 is the thermodynamic form. A higher melting point was obtained starting at 156 °C compared to 130 °C for Form 1. The decomposition of Form 2 occurred at the same temperature as the onset of melting. In addition, a glass transition with a midpoint at 27 °C was observed in the second heat cycle. S-Indenolol benzoate Form 2 was non-hygroscopic, absorbing 0.045 wt% (0.01 eq) water at 90% RH. HPLC analysis found the relative area purity of the material to be 99.9% and the ee of the chiral HPLC was 99.4%.

[0288] Seven-day and fourteen-day stability testing of S-Indenolol benzoate Form 2 found that Form 2 maintained its XRPD pattern and high chemical purity (relative area > 99.8%) under all stability conditions. Form 2 maintained its white color for 7 days under all stability conditions, and for 14 days at 60 °C and increased humidity.

[0289] Thermodynamic solubility experiments observed in pH 1.2, 4.5, 6.8 buffer solutions and unbuffered water determined that S-Indenolol benzoate Form 2 exhibited fairly high solubility (with free base concentrations of 23.5 mg / mL, 17.6 mg / mL, 9.9 mg / mL, and 10.3 mg / mL). S-Indenolol benzoate Form 2 improved the solubility of the free base in unbuffered water (1.8 mg / mL).

[0290] The chemical and physical properties of S-Indenolol benzoate Forms 1 and 2 make both of them developable salt forms. However, since S-Indenolol benzoate Form 2 is the thermodynamic form, it is the preferred salt form.

Claims

1. A pharmaceutically acceptable acid addition salt of: (i) S-indeanol; and (ii) benzoic acid, wherein the pharmaceutically acceptable acid addition salt is S-indeanol benzoate, and: the S-indeanol benzoate is in the form of S-indeanol benzoate crystalline polymorph Pattern 1 having an X-ray powder diffraction pattern comprising peaks at 8.1°, 11.4° and 17.0° ± 0.2° 2Q; or the S-indeanol benzoate is in the form of S-indeanol benzoate crystalline polymorph Pattern 2 having an X-ray powder diffraction pattern comprising peaks at 16.9°, 18.9° and 20.1° ± 0.2° 2Q.

2. The pharmaceutically acceptable acid addition salt according to claim 1, wherein the S- indeanol benzoate is in the form of S-indeanol benzoate crystalline polymorph Pattern 1 having an X-ray powder diffraction pattern comprising peaks at 8.1°, 11.4° and 17.0° ± 0.2° 2Q.

3. The pharmaceutically acceptable acid addition salt according to claim 2, wherein the S- indeanol benzoate is in the form of S-indeanol benzoate crystalline polymorph Pattern 1 and the X- ray powder diffraction pattern further comprises peaks at 5.7°, 12.5° and 18.4° ± 0.2° 2Q.

4. The pharmaceutically acceptable acid addition salt according to claim 1, wherein the S- indeanol benzoate is in the form of S-indeanol benzoate crystalline polymorph Pattern 2 having an X-ray powder diffraction pattern comprising peaks at 16.9°, 18.9° and 20.1° ± 0.2° 2Q.

5. The pharmaceutically acceptable acid addition salt according to claim 4, wherein the S- indeanol benzoate is in the form of S-indeanol benzoate crystalline polymorph Pattern 2 and the X- ray powder diffraction pattern further comprises peaks at 9.2°, 13.9° and 20.7° ± 0.2° 2Q.

6. A composition comprising at least 60% by weight of the pharmaceutically acceptable acid addition salt as defined in any one of claims 1 to 5 relative to the total weight of the composition.

7. The composition according to claim 6, wherein the composition comprises no more than 30% by weight of R-indeanol or a salt thereof relative to the total weight of the composition.

8. A pharmaceutical composition comprising (i) a pharmaceutically acceptable acid addition salt as defined in any one of claims 1 to 5 and (ii) a pharmaceutically acceptable excipient, carrier or diluent.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is a tablet.

10. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is substantially free of R-indeanol or a salt thereof.

11. Use of a pharmaceutically acceptable acid addition salt as defined in any one of claims 1 to 5 in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of cachexia, sarcopenia, neuromuscular disorders, muscle weakness, hypertension, heart failure, atrial fibrillation, heart attack, angina pectoris, glaucoma and anxiety.

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