Method for producing (s)-amlodipine succinate

Abstract

The present invention relates to a method for producing (S)-amlodipine succinate comprising reacting (S)-amlodipine (D)-hemitartrate or a solvate thereof with a first base in the presence of a two-phase solvent system comprising a first non-polar organic solvent and water to produce (S)-amlodipine base, removing the water layer, and reacting (S)-amlodipine base with succinic acid to produce (S)-amlodipine succinate. The present invention also relates to a formulation comprising (S)-amlodipine succinate.

Description

[0001] METHOD FOR PRODUCING (S)-AMLODIPINE SUCCINATE

[0002] Field of the Invention

[0003] The present invention relates to a method for producing (S)-amlodipine succinate. The present invention also relates to a formulation comprising (S)-amlodipine succinate.

[0004] Background

[0005] Amlodipine is a widely prescribed calcium channel blocker used primarily in the treatment of hypertension and angina. By inhibiting the influx of calcium ions into vascular smooth muscle and cardiac muscle, amlodipine effectively reduces blood pressure and alleviates chest pain.

[0006] Racemic amlodipine contains two enantiomers: (R)-amlodipine and (S)-amlodipine. (S)-amlodipine, the pharmacologically active enantiomer also known as levamlodipine or (S)- (-)-amlodipine, has been found to exhibit greater potency and efficacy in calcium channel blockade compared to its (R)- counterpart. By isolating and administering (S)-amlodipine, it is possible to achieve enhanced therapeutic outcomes with a reduced risk of adverse effects.

[0007] Processes affording (S)-amlodipine from racemic amlodipine besylate or racemic amlodipine free base have been described in the prior art literature. Racemic amlodipine besylate may be converted to racemic amlodipine free base using a two-phase solvent system comprising an organic solvent and an aqueous solution of a base. However, a number of methods and solvent systems require reaction conditions that are only suitable for laboratory scale. There remains a need for methods and solvent systems which may be used to obtain a high yield of sufficiently pure racemic amlodipine base and are suitable for scaling-up from laboratory scale.

[0008] A common approach for converting racemic amlodipine base into its enantiomers is resolution via (S)-amlodipine (L)-hemitartrate DMF-solvate. This approach uses (L)-tartaric acid in a mixture of DMF and water to provide (S)-amlodipine (L)-hemitartrate DMF-solvate in high yield and high isomeric purity. Another approach is resolution via (S)-amlodipine (D)- hemitartrate urea cocrystal. This approach uses (D)-tartaric acid and urea in acetone to provide (S)-amlodipine (D)-hemitartrate urea cocrystal. However, these methods can be sensitive to the reaction conditions and setup, highlighting the need for methods that are more robust and are suitable for scaling-up from laboratory scale. A further approach is resolution via (S)-amlodipine (D)-hemitartrate DMSO-solvate. This approach uses (D)-tartaric acid in DMSO to provide (S)-amlodipine (D)-hemitartrate DMSO-solvate. This method may be more robust and may be more suitable for scaling-up from laboratory scale compared to other prior art resolution methods.

[0009] After resolution, the (S)-amlodipine (L)-hemitartrate DMF-solvate, (S)-amlodipine (D)- hemitartrate DMSO-solvate or (S)-amlodipine (D)-hemitartrate urea cocrystal may be converted to (S)-amlodipine free base using a two-phase solvent system comprising an organic solvent and an aqueous solution of a base. (S)-amlodipine free base may then be converted to (S)-amlodipine succinate. (S)-amlodipine succinate has been described previously, but without detailed structural information or yields. The processes described in the art prepare the succinate salt by reacting (S)-amlodipine free base with succinic acid in ethanol or in an ethanol-water mixture. There remains a need for efficient and robust methods and solvent systems which may be used to obtain a high yield of (S)-amlodipine free base and (S)-amlodipine succinate.

[0010] Formulations of (S)-amlodipine salts have been described in the art. Common formulations include the maleate salt or the besylate salt. However, the known formulations usually contain uncommon and / or expensive stabilisers. Accordingly, there remains a need to develop a more stable formulation of (S)-amlodipine which avoids the use of such stabilisers.

[0011] Detailed Description

[0012] The present invention relates to a method for producing (S)-amlodipine succinate comprising: a) reacting (S)-amlodipine (D)-hemitartrate or a solvate thereof with a first base in the presence of a two-phase solvent system comprising a first non-polar organic solvent and water to produce (S)-amlodipine base; b) removing the water layer; and c) reacting (S)-amlodipine base with succinic acid to produce (S)-amlodipine succinate.

[0013] As used herein, “(S)-amlodipine” refers to the compound (S)-(-)-2-(2-aminoethoxy)- methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1 ,4- dihydropyridine. (S)-amlodipine is also known as levamlodipine or (S)-(-)-amlodipine. The terms “(S)-amlodipine free base” and “(S)-amlodipine base” may be used interchangeably and refer to the neutral form of (S)-amlodipine not bound to an acid to form a salt. Conversion of (S)-amlodipine (D)-hemitartrate or a solvate thereof to (S)-amlodipine base

[0014] Step a) of the present invention requires reacting (S)-amlodipine (D)-hemitartrate or a solvate thereof with a first base in the presence of a two-phase solvent system comprising a first non-polar organic solvent and water to produce (S)-amlodipine base.

[0015] (S)-amlodipine (D)-hemitartrate may exist in an unsolvated form as well as the solvated form, including the hydrated form. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. As used herein, the term “solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. For example, the solvent may be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol (MeOH), ethanol (EtOH), acetone, isopropanol, chloroform, dimethyl sulfoxide (DMSO), toluene, acetonitrile, ethyl acetate, tetra hydrofuran (THF), dimethylformamide (DMF) and water. As used herein, the term “hydrate” refers to a complex formed by combination of water molecules with molecules or ions of the solute. The term “solvate” is meant to include the term “hydrate”. Preferably, the (S)-amlodipine (D)-hemitartrate or a solvate thereof may be (S)-amlodipine (D)-hemitartrate solvate.

[0016] In preferred embodiments, the (S)-amlodipine (D)-hemitartrate or a solvate thereof may be (S)-amlodipine (D)-hemitartrate DMSO-solvate.

[0017] In some embodiments, the (S)-amlodipine (D)-hemitartrate solvate is not (S)- amlodipine (D)-hemitartrate DMF-solvate or (S)-amlodipine (D)-hemitartrate urea cocrystal.

[0018] Any base which liberates the (S)-amlodipine base from its (D)-hemitartrate salt may be used as the first base. A first base may be selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methoxide (NaOCHs), potassium carbonate (K2CO3), triethylamine (TEA), diisopropylamine (DI PEA), sodium acetate (NaOAc), potassium phosphate (K3PO4), sodium bicarbonate (NaHCOs), sodium carbonate (Na2COs), tetramethylammonium hydroxide (TMAH), pyridine, or a combination thereof. Preferably, an inorganic base may be used. An inorganic base may be selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methoxide (NaOCHs), potassium carbonate (K2CO3), sodium acetate (NaOAc), potassium phosphate (K3PO4), sodium bicarbonate (NaHCOs), sodium carbonate (Na2CO3), or a combination thereof. More preferably, a hydroxide base or a carbonate base or a combination thereof may be used. A hydroxide base or a carbonate base may be selected from sodium hydroxide (NaOH), potassium carbonate (K2CO3), sodium bicarbonate (NaHCOs), sodium carbonate (Na2CO3), or a combination thereof. Most preferably, sodium hydroxide (NaOH) and / or potassium carbonate (K2CO3) may be used. In some embodiments, the ratio of the total weight of (S)-amlodipine (D)-hemitartrate or a solvate thereof to the total weight of the first base may be selected from 8:1 to 3:1 , from 7:1 to 4:1 , from 6:1 to 5:1 , or 5.5:1.

[0019] In some embodiments, the concentration of the first base may be selected from 0.5 M to 1.1 M, from 0.57 M to 1.07 M, from 0.7 M to 0.9 M, or from 0.71 M to 0.85 M.

[0020] As used herein, the term “two-phase solvent system” refers to a mixture of two immiscible solvents that form separate layers when combined. For example, a common two- phase solvent system is a mixture of water and a non-polar organic solvent. When combined, these solvents form two distinct layers of the aqueous phase and the organic phase, allowing for effective separation and extraction of compounds that preferentially dissolve in one phase over the other.

[0021] Any solvent which is immiscible with water may be used as the first non-polar organic solvent. A first non-polar organic solvent may be selected from diethyl ether, dichloromethane (DCM), chloroform, benzene, toluene, hexane, cyclohexane, pentane, heptane, petroleum ether, isopropyl acetate, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBIIK), carbon tetrachloride, or a combination thereof. Preferably, a first non-polar organic solvent may be selected from toluene, isopropyl acetate, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBIIK), or a combination thereof. More preferably, toluene may be used.

[0022] Advantageously, it has been found that toluene may be a particularly suitable solvent for producing (S)-amlodipine succinate because it has a high (S)-amlodipine free base solubility and a low (S)-amlodipine succinate solubility and therefore helps provide (S)- amlodipine succinate in high yield.

[0023] Conversion of (S)-amlodipine base to (S)-amlodipine succinate

[0024] Steps b) and c) of the present invention require removing the water layer and reacting (S)-amlodipine base with succinic acid to produce (S)-amlodipine succinate.

[0025] The two-phase solvent system of step a) results in two distinct layers of the aqueous phase and the organic phase. Step b) involves removing the water layer to physically separate the aqueous phase (water layer) from the organic phase containing the (S)-amlodipine base. The water layer may be removed using a separatory funnel or another suitable container. The two distinct layers will separate according to their different densities, with the denser layer settling at the bottom and the less dense layer floating on top. The layers are identified and physically separated by removing one of the layers, for example, by opening a stopcock at the bottom of the separatory funnel and allowing only the denser layer to drain into a separate container. If necessary, the extraction may be repeated to ensure complete separation. The organic layer may also be dried using an anhydrous drying agent, such as magnesium sulphate, to remove any residual water.

[0026] Step c) involves reacting (S)-amlodipine base with succinic acid to produce (S)- amlodipine succinate. Steps b) and c) may be completed in a single production step. In other words, the method for producing (S)-amlodipine succinate from (S)-amlodipine base may be carried out in situ without the isolation and / or purification of any of the intermediate products.

[0027] As used herein, “(S)-amlodipine succinate” refers to the succinate salt of (S)- amlodipine formed by reaction of (S)-amlodipine base with succinic acid. The (S)-amlodipine succinate may contain a 1 :1 molar ratio of (S)-amlodipine with succinic acid, indicating that each molecule of (S)-amlodipine is associated with one molecule of succinic acid.

[0028] In preferred embodiments, (S)-amlodipine base may be reacted with succinic acid in the presence of a second organic solvent. A second organic solvent may be selected from methanol (MeOH), ethanol (EtOH), acetone, diethyl ether, tetrahydrofuran (THF), dichloromethane (DCM), chloroform, benzene, toluene, hexane, heptane, acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), pyridine, ethyl acetate, isopropyl acetate, isopropanol, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBIIK), carbon tetrachloride, 2-methyltetrahydrofuran (2-MeTHF), or a combination thereof. Preferably, a second organic solvent may be selected from methanol (MeOH), ethanol (EtOH), acetone, diethyl ether, tetrahydrofuran (THF), dichloromethane (DCM), toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBIIK), 2-methyltetrahydrofuran (2-MeTHF), or a combination thereof. More preferably, methanol (MeOH) may be used.

[0029] Advantageously, it has been found that there may be a robust purification effect on the residual content of (R)-amlodipine when using toluene as a first non-polar organic solvent and MeOH as a second organic solvent. The residual content may be repeatedly purified to approximately a third of the starting (R)-amlodipine content in the tested range of 1-4%. This purification occurs when starting from different solid forms of (S)-amlodipine afforded by a previous resolution step, such as (S)-amlodipine (L)-hemitartrate DMF-solvate, (S)-amlodipine (D)-hemiurea cocrystal or (S)-amlodipine (D)-hemitartrate DMSO-solvate. The yield of the conversion of the (S)-amlodipine salts to the succinate salt may also be unvaried when starting from the different salts.

[0030] In some embodiments, the ratio of the total volume of the first non-polar organic solvent to the total volume of the second organic solvent may be selected from 11 :1 to 1.1 :1 , from 10:1 to 1.2:1 , from 9:1 to 1.3:1 , from 8:1 to 1.4:1 , from 7:1 to 1.5:1 , from 6:1 to 1.6:1 , from 5:1 to 1.7:1 , from 4:1 to 1.8:1 , from 3:1 to 1.9:1 , or 2:1. Advantageously, it has been found that a solvent with a ratio of the total volume of toluene to the total volume of MeOH of 2:1 has a suitably low (S)-amlodipine succinate solubility. Reacting (S)-amlodipine (D)-hemitartrate or a solvate thereof with a first base in the presence of a two-phase solvent system comprising a first non-polar organic solvent and water to produce (S)-amlodipine base, removing the water layer, and reacting (S)-amlodipine base with succinic acid to produce (S)-amlodipine succinate, may be completed in a single production step. In other words, the method for producing (S)-amlodipine succinate from (S)- amlodipine (D)-hemitartrate or a solvate thereof may be carried out in situ without the isolation and / or purification of any of the intermediate products such as (S)-amlodipine base. By avoiding the need to extract the intermediate (S)-amlodipine free base, the method according to the present invention provides a more efficient and robust process for producing (S)- amlodipine succinate. Additionally, the method may be associated with a robust purification effect on the residual content of (R)-amlodipine. The method may result in a reduction of the residual (R)-amlodipine content to approximately 31 % (20-44%) of the starting content.

[0031] In some embodiments, the ratio of the total weight of (S)-amlodipine (D)-hemitartrate or a solvate thereof to the total weight of succinic acid may be selected from 7:1 to 2:1 , from 6:1 to 3:1 , from 5:1 to 4:1 , or 4.7:1.

[0032] In some embodiments, the (S)-amlodipine succinate may be obtained by crystallisation. Advantageously, the crystallisation processes may provide a high yield and purity of (S)-amlodipine succinate.

[0033] As used herein, the term “crystallisation” refers to the process of forming solid crystals from a solution or melt. The crystallisation process involves two main steps: nucleation, where small clusters of molecules form, and crystal growth, where these clusters grow into larger, stable crystals. Crystallisation may occur through various methods such as cooling a solution, evaporating a solvent, or adding a second solvent to reduce solubility. The reaction mixture may also be seeded with a small amount of the product to aid crystallisation.

[0034] Conversion of racemic amlodipine base to (S)-amlodipine succinate

[0035] In some embodiments, the method for producing (S)-amlodipine succinate may comprise: i) reacting racemic amlodipine base with (D)-tartaric acid to produce (S)-amlodipine (D)-hemitartrate or a solvate thereof; ii) reacting (S)-amlodipine (D)-hemitartrate or a solvate thereof with a first base in the presence of a two-phase solvent system comprising a first non-polar organic solvent and water to produce (S)-amlodipine base; iii) removing the water layer; and iv) reacting (S)-amlodipine base with succinic acid to produce (S)-amlodipine succinate. As used herein, the term “racemic” refers to a mixture where there are approximately equal amounts of both enantiomers of a chiral molecule. Enantiomers are mirror-image forms of a chiral molecule that cannot be superimposed on each other. For example, racemic amlodipine includes both (R)-amlodipine and (S)-amlodipine.

[0036] In preferred embodiments, the (S)-amlodipine (D)-hemitartrate or a solvate thereof may be (S)-amlodipine (D)-hemitartrate DMSO-solvate and may be produced by reacting racemic amlodipine base with (D)-tartaric acid in the presence of a solvent mixture comprising dimethyl sulfoxide (DMSO).

[0037] In some embodiments, the (S)-amlodipine (D)-hemitartrate solvate is not (S)- amlodipine (D)-hemitartrate DMF-solvate or (S)-amlodipine (D)-hemitartrate urea cocrystal.

[0038] Any suitable solvent may be used in the solvent mixture in addition to dimethyl sulfoxide (DMSO). For example, any solvent as described above in connection with the second organic solvent may be used in the solvent mixture. Preferably, the solvent mixture further comprises a ketone solvent. Any suitable ketone solvent may be used. Preferably, the solvent mixture comprises a ketone solvent selected from the group consisting of acetone, acetophenone, butanone, cyclopentanone, ethyl isopropyl ketone, 2-hexanone, isophorone, methyl isobutyl ketone, methyl isopropyl ketone, 3-methyl-2-pentanone, 2-pentanone and 3- pentanone. More preferably, the solvent mixture further comprises acetone.

[0039] Advantageously, it has been found that converting racemic amlodipine base into its enantiomers by resolution via (S)-amlodipine (D)-hemitartrate DMSO-solvate may be more robust and may be more suitable for scaling-up from laboratory scale compared to other prior art resolution methods.

[0040] Resolution via (S)-amlodipine (L)-hemitartrate DMF-solvate may be sensitive to the reaction temperature and to the amount and composition of the DMF-water solvent. This resolution method may also require approximately 16 L of DMF per 1 kg of isolated product which may be less suitable for large-scale production from a process economy point of view.

[0041] Resolution via (S)-amlodipine (D)-hemitartrate urea cocrystal may also be sensitive to the reaction conditions and setup. This resolution method may also require a higher volume of solvent and thus higher reactor volume than the resolution via (S)-amlodipine (D)- hemitartrate DMSO-solvate. Furthermore, this resolution method may not achieve a suitable purification effect and the best achievable residual content of (R)-amlodipine may be 3.7%, which may not be suitable to reach Active Pharmaceutical Ingredient (API) complying quality after single step conversion to (S)-amlodipine succinate.

[0042] Advantageously, resolution via (S)-amlodipine (D)-hemitartrate DMSO-solvate is more robust and more reproducible that resolution via (S)-amlodipine (L)-hemitartrate DMF-solvate or resolution via (S)-amlodipine (D)-hemitartrate urea cocrystal. In some embodiments, the ratio of the total weight of racemic amlodipine base to the total weight of (D)-tartaric acid may be selected from 13:1 to 8:1 , from 12:1 to 9:1 , from 11 :1 to 10:1 , or from 10.9:1 to 10.7:1.

[0043] In some embodiments, the (S)-amlodipine succinate and / or (S)-amlodipine (D)- hemitartrate or a solvate thereof may be obtained by crystallisation. Advantageously, the crystallisation processes may provide a high yield and purity of (S)-amlodipine succinate and / or (S)-amlodipine (D)-hemitartrate or a solvate thereof.

[0044] Steps ii) to iv) correspond to steps a) to c) as described above. Any embodiments as described above in connection with steps a) to c) also relate to steps ii) to iv).

[0045] Conversion of racemic amlodipine besylate to (S)-amlodipine succinate

[0046] In some embodiments, the method for producing (S)-amlodipine succinate may comprise:

[0047] 1) reacting racemic amlodipine besylate with a second base to produce racemic amlodipine base;

[0048] 2) reacting racemic amlodipine base with (D)-tartaric acid to produce (S)-amlodipine (D)-hemitartrate or a solvate thereof;

[0049] 3) reacting (S)-amlodipine (D)-hemitartrate or a solvate thereof with a first base in the presence of a two-phase solvent system comprising a first non-polar organic solvent and water to produce (S)-amlodipine base;

[0050] 4) removing the water layer; and

[0051] 5) reacting (S)-amlodipine base with succinic acid to produce (S)-amlodipine succinate.

[0052] As used herein, “racemic amlodipine besylate” refers to the besylate salt (or benzenesulfonate salt) of racemic amlodipine formed by reaction of racemic amlodipine with besylic acid (or benzenesulfonic acid). Racemic amlodipine besylate may be synthesised or purchased.

[0053] Any base which liberates the racemic amlodipine base from its besylate salt may be used as the second base. Any base as described above in connection with the first base may be used as the second base. Preferably, a second base may be selected from sodium hydroxide (NaOH), sodium bicarbonate (NaHCCh), sodium carbonate (Na2COs), or a combination thereof. More preferably, sodium hydroxide (NaOH) may be used.

[0054] Advantageously, it has been found that NaOH may be a particularly suitable base for producing racemic amlodipine base because it may result in a high yield of sufficiently pure racemic amlodipine base. In some embodiments, the ratio of the total weight of racemic amlodipine besylate to the total weight of the second base may be selected from 16:1 to 11 :1 , from 15:1 to 12:1 , from 14:1 to 13:1 , or 13:8:1.

[0055] In some embodiments, the concentration of the second base may be selected from 0.5 M to 2.5 M, from 1 M to 2 M, from 1.1 M to 1.3 M, or 1.2 M.

[0056] In preferred embodiments, racemic amlodipine base may be reacted with a second base in the presence of a solvent mixture comprising a third organic solvent and water. Any organic solvent as described above in connection with the second organic solvent may be used as the third organic solvent. Preferably, a third organic solvent may be selected from methanol (MeOH), dichloromethane (DCM), toluene, isopropyl acetate, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBIIK), 2-methyltetrahydrofuran (2-MeTHF), or a combination thereof. More preferably, methanol (MeOH) may be used.

[0057] Advantageously, it has been found that MeOH may be a particularly suitable solvent for producing racemic amlodipine base because it may be safe, robust and may omit any chlorinated solvents.

[0058] It has been found that the isolation of racemic amlodipine base using extraction into DCM in the presence of aqueous 2M NaOH and subsequent solvent switch into n-heptane provided high yields of fine crystalline material. A solvent switch into n-heptane may be required because the DCM solution of racemic amlodipine base may not be used in the subsequent resolution step directly. However, using this method and solvent system may result in some deficiencies from a large-scale process point of view. Specifically, this method may require low pressure, temperatures up to 80 °C and a duration of several hours for the solvent switch process to remove as much DCM as possible. In addition, the reaction mixture may have a tendency to suddenly crystallise which may cause sudden boiling of residual DCM which may be hard to control and condense. Although the DCM method may work well on laboratory scale, the MeOH method of the present invention may be more suitable for scaling- up from laboratory scale because it may avoid the technical and safety issues associated with the DCM method.

[0059] In some embodiments, the third organic solvent may be a third polar organic solvent. Any solvent which is miscible with water and therefore does not form a two-phase solvent system with water may be used as the third polar organic solvent. In other embodiments, the third organic solvent may be a third non-polar organic solvent. Any solvent which is immiscible with water and therefore does form a two-phase solvent system with water may be used as the third non-polar organic solvent. Any non-polar organic solvent as described above in connection with the first non-polar organic solvent may be used as the third non-polar organic solvent. In some embodiments, the (S)-amlodipine succinate, (S)-amlodipine (D)-hemitartrate or a solvate thereof and / or racemic amlodipine base may be obtained by crystallisation. Advantageously, the crystallisation processes may provide a high yield and purity of (S)- amlodipine succinate, (S)-amlodipine (D)-hemitartrate or a solvate thereof and / or racemic amlodipine base.

[0060] Steps 3) to 5) correspond to steps a) to c) as described above. Any embodiments as described above in connection with steps a) to c) also relate to steps 3) to 5). In addition, steps 2) to 5) correspond to steps i) to iv) as described above. Any embodiments as described above in connection with steps i) to iv) also relate to steps 2) to 5).

[0061] Formulations comprising (S)-amlodipine succinate

[0062] The present invention also relates to (S)-amlodipine succinate obtainable by the method of any of the embodiments described herein.

[0063] The present invention also relates to a formulation comprising (S)-amlodipine succinate. In some embodiments, the amount of (S)-amlodipine succinate in the formulation may be selected from 1 mg to 10 mg, from 1 mg to 9 mg, from 1 mg to 8 mg, from 1 mg to 7 mg, from 1 mg to 6 mg, from 1 mg to 5 mg, from 1 mg to 4 mg, from 1 mg to 3 mg, or from 1 mg to 2 mg. In further embodiments, the amount of (S)-amlodipine succinate in the formulation may be selected from 1 mg to 2 mg, from 2.75 mg to 3.75 mg, or from 6 to 7 mg. In preferred embodiments, the amount of (S)-amlodipine succinate in the formulation may be selected from approximately 1 .6 mg, 3.2 mg or 6.4 mg. In some embodiments, the amount of (S)-amlodipine in the formulation may be selected from 1 mg to 10 mg, from 1 mg to 9 mg, from 1 mg to 8 mg, from 1 mg to 7 mg, from 1 mg to 6 mg, from 1 mg to 5 mg, from 1 mg to 4 mg, from 1 mg to 3 mg, or from 1 mg to 2 mg. In further embodiments, the amount of (S)-amlodipine in the formulation may be selected from 0.75 mg to 1.75 mg, from 2 mg to 3 mg, or from 4.5 to 5.5 mg. In preferred embodiments, the amount of (S)-amlodipine in the formulation may be selected from approximately 1.25 mg, 2.5 mg or 5 mg.

[0064] In some embodiments, the amount of (S)-amlodipine succinate in the formulation may be selected from 1% to 30%, from 1 % to 25%, from 1% to 20%, from 1 % to 15%, from 1% to 13%, from 1 % to 12%, from 1 % to 11 %, from 1 % to 10%, from 2% to 9%, from 3% to 8%, from 4% to 7%, or from 5% to 6%, by weight, based on the total weight of the composition. In further embodiments, the amount of (S)-amlodipine succinate in the formulation may be selected from 2% to 3%, from 4.5% to 5.5%, or from 9.5% to 10.5%, by weight, based on the total weight of the composition. In preferred embodiments, the amount of (S)-amlodipine succinate in the formulation may be selected from approximately 2.5%, 5% or 10%, by weight, based on the total weight of the composition. In some embodiments, the amount of (S)-amlodipine in the formulation may be selected from 1% to 30%, from 1 % to 25%, from 1 % to 20%, from 1 % to 15%, from 1% to 13%, from 1 % to 12%, from 1 % to 11 %, from 1 % to 10%, from 2% to 9%, from 3% to 8%, from 4% to 7%, or from 5% to 6%, by weight, based on the total weight of the composition. In further embodiments, the amount of (S)-amlodipine in the formulation may be selected from 1.5% to 2.5%, from 3.5% to 4.5%, or from 7.5% to 8.5%, by weight, based on the total weight of the composition. In preferred embodiments, the amount of (S)-amlodipine in the formulation may be selected from approximately 2%, 4% or 8%, by weight, based on the total weight of the composition.

[0065] The amount or strength of (S)-amlodipine or a salt thereof in a tablet provided herein, whether expressed in e.g. milligrams or as a % by weight, should be taken as referring to the amount of (S)-amlodipine free base present in the tablet.

[0066] Advantageously, it has been found that the succinate salt is particularly stable compared to other (S)-amlodipine salts. A tablet formulation comprising (S)-amlodipine succinate was found to have higher stability under 25C / 60%RH for 2 years in the PVDC packaging material with respect to impurity D than any other tested (S)-amlodipine salt.

[0067] In some embodiments of the present invention, the formulation further comprises mannitol, croscarmellose sodium, stearic acid, magnesium stearate and silicon dioxide.

[0068] As used herein, “silicon dioxide” refers to silicon dioxide in any form suitable for use as an excipient. For example, colloidal silicon dioxide or colloidal silica may be used as an excipient in pharmaceutical formulations. Silicon dioxide is also known as silica.

[0069] In some embodiments, the formulation comprises from 1 mg to 20 mg (S)-amlodipine succinate, from 95 mg to 115 mg mannitol, from 0.01 mg to 20 mg croscarmellose sodium, from 0.01 mg to 20 mg stearic acid, from 0.01 mg to 20 mg magnesium stearate, and from 0.01 mg to 20 mg silicon dioxide. In further embodiments, the formulation comprises from 2 mg to 10 mg (S)-amlodipine succinate, from 100 mg to 110 mg mannitol, from 0.1 mg to 6 mg croscarmellose sodium, from 0.5 mg to 7 mg stearic acid, from 0.1 mg to 5 mg magnesium stearate, and from 0.1 mg to 5 mg silicon dioxide. In preferred embodiments, the formulation comprises from 4 mg to 8 mg (S)-amlodipine succinate, from 103 mg to 107 mg mannitol, from 0.1 mg to 4 mg croscarmellose sodium, from 1 mg to 5 mg stearic acid, from 0.1 mg to 3 mg magnesium stearate, and from 0.1 mg to 3 mg silicon dioxide. In further preferred embodiments, the formulation comprises approximately 6 mg or 7 mg (S)-amlodipine succinate, approximately 105 mg or 106 mg mannitol, approximately 2 mg or 3 mg croscarmellose sodium, approximately 3 mg stearic acid, approximately 1 mg magnesium stearate, and approximately 1 mg silicon dioxide. In more preferred embodiments, the formulation comprises approximately 6.44 mg (S)-amlodipine succinate, approximately 105.45 mg mannitol, approximately 2.40 mg croscarmellose sodium, approximately 3.17 mg stearic acid, approximately 1.27 mg magnesium stearate, and approximately 1.27 mg silicon dioxide. In some embodiments, the formulation comprises from 1 % to 30% (S)-amlodipine succinate, from 70% to 95% mannitol, from 0% to 10% croscarmellose sodium, from 0.01% to 10% stearic acid, from 0.01 % to 10% magnesium stearate, and from 0.01% to 10% silicon dioxide, by weight, based on the total weight of the composition. In further embodiments, the formulation comprises from 2% to 20% (S)-amlodipine succinate, from 77% to 93% mannitol, from 0% to 7% croscarmellose sodium, from 0.1% to 7% stearic acid, from 0.1 % to 5% magnesium stearate, and from 0.1 % to 5% silicon dioxide, by weight, based on the total weight of the composition. In preferred embodiments, the formulation comprises from 4% to 12% (S)- amlodipine succinate, from 82% to 90% mannitol, from 0% to 4% croscarmellose sodium, from 0.1% to 4% stearic acid, from 0.1% to 2% magnesium stearate, and from 0.1% to 2% silicon dioxide, by weight, based on the total weight of the composition. In further preferred embodiments, the formulation comprises approximately 5% (S)-amlodipine succinate, approximately 88% mannitol, approximately 2% croscarmellose sodium, approximately 3% stearic acid, approximately 1% magnesium stearate, and approximately 1 % colloidal silica, by weight, based on the total weight of the composition. In other further preferred embodiments, the formulation comprises approximately 10% or 11% (S)-amlodipine succinate, approximately 85% mannitol, approximately 2% or 3% stearic acid, approximately 1% magnesium stearate, and approximately 1% colloidal silica, by weight, based on the total weight of the composition.

[0070] Advantageously, it has been found that this formulation has strong chemical stability and good manufacturing properties.

[0071] In other embodiments of the present invention, the formulation further comprises microcrystalline cellulose, dibasic calcium hydrogenphosphate dihydrate, sodium starch glycolate and magnesium stearate.

[0072] In some embodiments, the formulation comprises from 1 mg to 20 mg (S)-amlodipine succinate, from 5 mg to 100 mg microcrystalline cellulose, from 10 mg to 50 mg dibasic calcium hydrogenphosphate dihydrate, from 0.01 mg to 20 mg sodium starch glycolate, and from 0.01 mg to 20 mg magnesium stearate. In further embodiments, the formulation comprises from 2 mg to 10 mg (S)-amlodipine succinate, from 7 mg to 80 mg microcrystalline cellulose, from 25 mg to 45 mg dibasic calcium hydrogenphosphate dihydrate, from 0.1 mg to 6 mg sodium starch glycolate, and from 0.1 mg to 6 mg magnesium stearate. In preferred embodiments, the formulation comprises from 4 mg to 8 mg (S)-amlodipine succinate, from 10 mg to 75 mg microcrystalline cellulose, from 35 mg to 39 mg dibasic calcium hydrogenphosphate dihydrate, from 0.1 mg to 4 mg sodium starch glycolate, and from 0.1 mg to 4 mg magnesium stearate. In further preferred embodiments, the formulation comprises approximately 6 mg or 7 mg (S)-amlodipine succinate, approximately 71 mg microcrystalline cellulose, approximately 38 mg dibasic calcium hydrogenphosphate dihydrate, approximately 2 mg or 3 mg sodium starch glycolate, and approximately 2 mg or 3 mg magnesium stearate. In more preferred embodiments, the formulation comprises approximately 6.44 mg (S)- amlodipine succinate, approximately 71.03 mg microcrystalline cellulose, approximately 37.74 mg dibasic calcium hydrogenphosphate dihydrate, approximately 2.40 mg sodium starch glycolate, and approximately 2.40 mg magnesium stearate.

[0073] In some embodiments, the formulation comprises from 1 mg to 20 mg (S)-amlodipine succinate, from 5 mg to 20 mg microcrystalline cellulose type 101 , from 40 mg to 70 mg microcrystalline cellulose type 102, from 10 mg to 50 mg dibasic calcium hydrogenphosphate dihydrate, from 0.01 mg to 20 mg sodium starch glycolate, and from 0.01 mg to 20 mg magnesium stearate. In further embodiments, the formulation comprises from 2 mg to 10 mg (S)-amlodipine succinate, from 7 mg to 17 mg microcrystalline cellulose type 101 , from 50 mg to 66 mg microcrystalline cellulose type 102, from 25 mg to 45 mg dibasic calcium hydrogenphosphate dihydrate, from 0.1 mg to 6 mg sodium starch glycolate, and from 0.1 mg to 6 mg magnesium stearate. In preferred embodiments, the formulation comprises from 4 mg to 8 mg (S)-amlodipine succinate, from 10 mg to 14 mg microcrystalline cellulose type 101 , from 56 mg to 60 mg microcrystalline cellulose type 102, from 35 mg to 39 mg dibasic calcium hydrogenphosphate dihydrate, from 0.1 mg to 4 mg sodium starch glycolate, and from 0.1 mg to 4 mg magnesium stearate. In further preferred embodiments, the formulation comprises approximately 6 mg or 7 mg (S)-amlodipine succinate, approximately 12 mg microcrystalline cellulose type 101 , approximately 59 mg microcrystalline cellulose type 102, approximately 38 mg dibasic calcium hydrogenphosphate dihydrate, approximately 2 mg or 3 mg sodium starch glycolate, and approximately 2 mg or 3 mg magnesium stearate. In more preferred embodiments, the formulation comprises approximately 6.44 mg (S)-amlodipine succinate, approximately 12.18 mg microcrystalline cellulose type 101 , approximately 58.85 mg microcrystalline cellulose type 102, approximately 37.74 mg dibasic calcium hydrogenphosphate dihydrate, approximately 2.40 mg sodium starch glycolate, and approximately 2.40 mg magnesium stearate.

[0074] In some embodiments, the formulation comprises from 1 % to 30% (S)-amlodipine succinate, from 2% to 85% microcrystalline cellulose, from 10% to 50% dibasic calcium hydrogenphosphate dihydrate, from 0.01% to 10% sodium starch glycolate, and from 0.01% to 10% magnesium stearate, by weight, based on the total weight of the composition. In further embodiments, the formulation comprises from 2% to 20% (S)-amlodipine succinate, from 10% to 70% microcrystalline cellulose, from 25% to 35% dibasic calcium hydrogenphosphate dihydrate, from 0.1 % to 5% sodium starch glycolate, and from 0.1% to 5% magnesium stearate, by weight, based on the total weight of the composition. In preferred embodiments, the formulation comprises from 4% to 12% (S)-amlodipine succinate, from 30% to 67% microcrystalline cellulose, from 28% to 34% dibasic calcium hydrogenphosphate dihydrate, from 0.1 % to 3% sodium starch glycolate, and from 0.1 % to 3% magnesium stearate, by weight, based on the total weight of the composition. In further preferred embodiments, the formulation comprises approximately 5% or 6% (S)-amlodipine succinate, approximately 59% microcrystalline cellulose, approximately 31% dibasic calcium hydrogenphosphate dihydrate, approximately 2% sodium starch glycolate, and approximately 2% magnesium stearate, by weight, based on the total weight of the composition.

[0075] In some embodiments, the formulation comprises from 1 % to 30% (S)-amlodipine succinate, from 2% to 40% microcrystalline cellulose type 101 , from 30% to 70% microcrystalline cellulose type 102, from 10% to 50% dibasic calcium hydrogenphosphate dihydrate, from 0.01% to 10% sodium starch glycolate, and from 0.01% to 10% magnesium stearate, by weight, based on the total weight of the composition. In further embodiments, the formulation comprises from 2% to 20% (S)-amlodipine succinate, from 5% to 15% microcrystalline cellulose type 101 , from 45% to 55% microcrystalline cellulose type 102, from 25% to 35% dibasic calcium hydrogenphosphate dihydrate, from 0.1 % to 5% sodium starch glycolate, and from 0.1 % to 5% magnesium stearate, by weight, based on the total weight of the composition. In preferred embodiments, the formulation comprises from 4% to 12% (S)- amlodipine succinate, from 7% to 13% microcrystalline cellulose type 101 , from 46% to 52% microcrystalline cellulose type 102, from 28% to 34% dibasic calcium hydrogenphosphate dihydrate, from 0.1% to 3% sodium starch glycolate, and from 0.1% to 3% magnesium stearate, by weight, based on the total weight of the composition. In further preferred embodiments, the formulation comprises approximately 5% or 6% (S)-amlodipine succinate, approximately 10% microcrystalline cellulose type 101 , approximately 49% microcrystalline cellulose type 102, approximately 31% dibasic calcium hydrogenphosphate dihydrate, approximately 2% sodium starch glycolate, and approximately 2% magnesium stearate, by weight, based on the total weight of the composition.

[0076] Advantageously, it has been found that this formulation has very strong chemical stability and very good manufacturing properties. In addition, this formulation forms fewer additional impurities than other tested formulations, as shown in Figure 6.

[0077] The developed formulations were found to be chemically stable during the requested shelf lie and in the given packaging material. The formulations were also simple and non- costly and avoided the use of uncommon and expensive stabilisers.

[0078] Brief Description of the Figures

[0079] Figure 1 shows the XRPD of (S)-amlodipine succinate. Figure 2 shows the effect of reaction temperature on isomeric purity and yield of (S)- amlodipine (L)-hemitartrate DMF-solvate produced by reacting racemic amlodipine with 0.25 equivalents of (L)-tartaric acid in a mixture of DMF and water.

[0080] Figure 3 shows the solubility of (S)-amlodipine free base in different solvents.

[0081] Figure 4 shows the solubility of (S)-amlodipine succinate in different solvents.

[0082] Figure 5 shows the purification effect of the toluene / MeOH solvent system on the residual content of (R)-amlodipine when starting from (S)-amlodipine (L)-hemitartrate DMF- solvate, (S)-amlodipine (D)-hemitartrate hemiurea cocrystal and (S)-amlodipine (D)- hemitartrate DMSO-solvate.

[0083] Figure 6 shows the degradation kinetics of (S)-amlodipine succinate and amlodipine besylate under 40°C / 75%RH on the basis of the main degradant, impurity D.

[0084] The present invention is now described in more detail by, but is not limited to, the following Examples.

[0085] Examples

[0086] Reference example 1 : Production of (S)-amlodipine succinate from racemic amlodipine base using urea cocrystal

[0087] Reference example 1 demonstrates the production of (S)-amlodipine succinate from racemic amlodipine base using urea cocrystal.

[0088] Racemic amlodipine base (270 g) was added to a reactor along with urea (99.15 g). Acetone (1080 ml) and water (175 ml) were added. The mixture was stirred at room temperature for approximately 0.5 hours. In a separate side vessel, a solution of (D)-tartaric acid (25.0 g) in water (270 ml) was prepared. The reaction mixture in the main reactor was seeded with the step product ((S)-amlodipine (D)-hemitartrate hemiurea cocrystal), and the solution of (D)- tartaric acid was gradually added to the reactor with intensive stirring. This dosing process at room temperature lasted for 1 hour, during which a suspension formed.

[0089] After the addition was complete, the side vessel was rinsed with water (95 ml), and the rinsing was added to the suspension. The reaction mixture was then stirred at room temperature for an additional hour. The resulting slurry was subsequently cooled to 20°C and maintained at this temperature with stirring for 2-3 hours. The crystalline product was then isolated, washed with cooled acetone, and dried under reduced pressure. This process yielded 128.3 g of (S)- amlodipine (D)-hemitartrate hemiurea cocrystal with a 75.6% step yield (with regard to the initial (S)-amlodipine present) and an enantiomeric excess (ee) of 92.6%.

[0090] The obtained (S)-amlodipine (D)-hemitartrate hemiurea cocrystal was subsequently converted to (S)-amlodipine succinate following the same procedure as described in Example 3, Step 3.

[0091] Chemical Formula: C20H25CIN2O5

[0092] Molecular Weight: 408.88

[0093] Chemical Formula: C20H25CIN2O5 Chemical Formula: CH4N2O

[0094] Molecular Weight: 408.88 Molecular Weight: 60.06

[0095] 5) cooling; isolation

[0096] Chemical Formula: C20H25CIN2O5

[0097] Molecular Weight: 408.88

[0098] Reference example 2: Production of (S)-amlodipine succinate from (S)-amlodipine (L)- hemitartrate DMF-solvent

[0099] Reference example 2 demonstrates the production of (S)-amlodipine succinate from (S)- amlodipine (L)-hemitartrate DMF-solvent.

[0100] A 10 L reactor was charged with 800 g of (S)-amlodipine (L)-hemitartrate DMF-solvate (prepared according to Gotrane, D. M. et al, Organic Process Research & Development. 2010, 14, 640-643), 4.4 L of toluene, and 800 ml of water. Under stirring, a solution of NaOH (27.6 g in 800 ml of water; 0.48 equiv.) was added dropwise to the mixture over 10-20 minutes while maintaining the temperature at approximately 18-28°C. Subsequently, a solution of K2CO3 (119.1 g in 800 ml of water; 0.6 equiv.) was added to the mixture, followed by an additional 800 ml of water. The resulting emulsion was stirred vigorously at 28-36°C for approximately 30 minutes. Stirring was then stopped, and the phases were allowed to separate. The aqueous phase was discharged, and the organic phase was washed with 1.6 L of water.

[0101] The organic phase, containing (S)-amlodipine base, was transferred to a vessel through a filter and diluted with 400 ml of MeOH. The 10 L reactor was charged with 171 .2 g of succinic acid and 2 L of MeOH, and stirring was initiated. Upon the dissolution of the succinic acid, approximately 40-60% of the (S)-amlodipine base solution was added dropwise over 10-25 minutes while maintaining the temperature at 21-28°C. The reaction mixture was seeded with 2 g of (S)-amlodipine succinate, followed by the slow addition (over 30-50 minutes) of the remaining (S)-amlodipine base solution at a temperature of 23-29°C. The vessel that contained the (S)-amlodipine base was rinsed with 400 ml of MeOH, and the rinsing was added to the reactor at once. The mixture was then cooled to 0°C over 60-90 minutes and stirred for an additional hour at that temperature.

[0102] The product was filtered off and subsequently washed with 640 ml of cold MeOH and 640 ml of cold acetone. The wet product was dried under reduced pressure at 40°C, yielding 680 g (89.9% yield) of pure (S)-amlodipine succinate with API-compliant purity.

[0103] Example 3: Production of (S)-amlodipine succinate from racemic amlodipine besylate Example 3 demonstrates the production of (S)-amlodipine succinate from racemic amlodipine besylate.

[0104] Step 1 : Isolation of racemic amlodipine base in MeOH / water

[0105] Racemic amlodipine besylate (1600 g) was added to a reactor and was diluted with MeOH (4 L) and water (2 L) at room temperature. A solution of NaOH (116.3 g) in water (2.40 L) was prepared in an auxiliary vessel under stirring. The solution of NaOH was slowly added to the solution of racemic amlodipine under stirring at room temperature and the reaction mass was seeded with racemic amlodipine base at approximately 75 % of the addition. The auxiliary vessel and piping was washed with water (1.2 L). After approximately 20 minutes of stirring, the resulting suspension was slowly cooled to 0-6°C under stirring over 1.5 hours. The suspension was stirred for an additional hour at that temperature. The solid phase was isolated and washed with cooled water. The main reactor was rinsed with cooled MTBE (1.0 L) and the rinsing was used to wash the isolated crystals. After drying under reduced pressure and slightly increased temperature, 1.1 kg of racemic amlodipine base was obtained (step yield 96 %).

[0106] 1H NMR (DMSO-cfe, 500 MHz): 5 1.09 (t, 3H, J = 7.0 Hz), 2.30 (s, 3H), 2.70 (m, 2H), 3.43 (m, 2H), 3.50 (s, 3H), 3.96 (m, 2H), 4.56 (d, 1 H, J = 15.3 Hz), 4.65 (d, 1 H, J = 15.3 Hz), 5.29 (s, 1 H), 7.11 (td, 1 H, J = 7.9 and 1.7 Hz), 7.22 (td, 1 H, J = 7.6 and 1.2 Hz), 7.26 (dd, 1 H, J = 7.9 and 1.2 Hz), 7.34 (dd, 1 H, J = 7.6 and 1.7 Hz).

[0107] 13C NMR (DMSO-cfe, 125 MHz): 5 14.1 , 18.0, 36.7, 40.9, 50.5, 59.2, 66.7, 73.1 , 101.4, 101.9, 127.4, 127.7, 128.9, 131.0, 131.1 , 145.6, 146.0, 146.4, 166.4, 167.2.

[0108] All NMR-spectra were measured using BRLIKER AVANCE 500 spectrometer at 500.13 and 125.76 MHz, respectively. Spectra were recorded in DMSO-cfe at 25 °C and chemical shifts are referenced to the residual DMSO-signals as follows:1H b(DMSO) = 2.50 ppm, for13C b(DMSO) = 39.50 ppm.

[0109] Chemical Formula: C20H25CIN2O5

[0110] Molecular Weight: 408.88

[0111] Chemical Formula: CeHeOsS 4) washing with MTBE

[0112] Chemical Formula: C26H31CIN2O8S

[0113] Molecular Weight: 567.05 + Ph-SO3Na (aq)

[0114] Step 2: Preparation of (S)-Amlodipine (D)-hemitartrate DMSO-solvate

[0115] The dried racemic amlodipine base (1.1 kg) was added to a reactor with DMSO (1.1 L) and acetone (1.65 L) at room temperature. The solid dissolved after a short period of stirring. A solution of (D)-tartaric Acid (102.96 g) in DMSO (440 ml) was prepared in a side vessel and the solution was stirred at room temperature for 0.5 hours. The solution of racemic amlodipine base was seeded with approximately 3 g of the step product ((S)-amlodipine (D)-hemitartrate DMSO-solvate). The solution of (D)-tartaric acid in DMSO was then added slowly into the agitated solution of the racemic amlodipine base in the main reactor over a period of 1 .5-2 hours at 24-29°C. The side vessel and the piping was rinsed with DMSO (110 ml) and the rinsing was added to the reaction mixture. The resulting suspension was stirred at25-30°C for approximately 1.5 hours and then slowly cooled to 18-22°C. The suspension was stirred at 20°C for 1 hour and the product was isolated. The wet crystals were washed twice with cold acetone (2 x 600 ml) previously used to rinse the reactor. The washed crystals were dried under reduced pressure to yield 0.57 kg of (S)-amlodipine (D)-hemitartrate DMSO-solvate (step yield 38 %). The (S)-amlodipine (D)-hemitartrate DMSO-solvate was isolated in 99.30 % ee.

[0116] 1H NMR (DMSO-cfe, 500 MHz): 5 1.10 (t, 3H, J = 7.0 Hz), 2.31 (s, 3H), 2.54 (s, 6H), 2.94 (bs, 2H), 3.50 (s, 3H), 3.57 (bs, 2H), 3.80 (s, 1 H), 3.9 (bs), 3.97 (m, 2H), 4.56 (d, 1 H, J = 14.2 Hz), 4.68 (d, 1 H, J = 14.2 Hz), 5.29 (s, 1 H), 7.11 (td, 1 H, J = 7.6 and 1.5 Hz), 7.22 (t, 1 H, J = 7.6 Hz), 7.26 (d, 1 H, J = 7.9 Hz), 7.34 (dd, 1 H, J = 7.9 and 1.5 Hz), 8.9 (bs).

[0117] 13C NMR (DMSO-cfe, 125 MHz): 5 14.1 , 18.2, 36.6, 39.1 , 40.4, 50.5, 59.3, 66.6, 69.0, 71.5, 101.85, 101.91 , 127.4, 127.8, 128.9, 131.0, 131.1 , 145.2, 145.5, 145.8, 166.3, 167.2, 174.8.

[0118] Chemical Formula: C20H25CIN2O5

[0119] Molecular Weight: 408.88

[0120] Chemical Formula: C20H25CIN2O5 Chemical Formula: C2H6OS

[0121] Molecular Weight: 408.88 Molecular Weight: 78.13

[0122] Step 3: Preparation of (S)-amlodipine succinate The dried (S)-amlodipine (D)-hemitartrate DMSO-solvate (0.57 kg) was added to a reactor with toluene (3.14 L) followed by water (570 ml). The mixture was stirred at room temperature for approximately 10 minutes. NaOH (19.47 g) was dissolved in water (570 ml) in a side vessel. A solution of K2CO3 (84.14 g) in water (570 ml) was prepared in another side vessel. (S)- amlodipine base was released by slow addition of the NaOH solution into the agitated reaction mixture followed by addition of the K2CO3 solution, both at room temperature. The side vessels and tubing were rinsed with 570 ml of water and the rinsing was added to the reaction mixture. The resulting emulsion was then heated to 35°C and stirred for 0.5 hours. The aqueous phase was then removed after separation of the phases. The organic phase was washed with 1.14 L of water and the aqueous phase was removed after 0.5 hours of stirring at 30-35°C. The organic phase was filtered and the apparatus was rinsed with 0.29 L of MeOH, and the rinsing was filtered as well and added to the organic phase. Succinic acid (120.96 g) was added to a reactor with 1.425 L of MeOH. A solution resulted after a short time of stirring at room temperature. The filtered organic extract containing (S)-amlodipine base was then slowly added into the agitated solution of succinic acid at 20-30°C, and the reaction mixture was seeded at approximately 50 % of the addition. The side vessels and tubing were rinsed with 0.285 L of MeOH and the rinsing was added to the resulting suspension. The suspension of product was then stirred at 23-29°C for 0.5 hours. It was then slowly cooled to 0-4°C over a period of 1.5 hours under stirring and stirred for an additional hour at that temperature. The crystalline product was isolated at 0-4°C and the crystals were washed with cooled MeOH (0.46 L) and then with cooled acetone (0.46 L). The product was dried under vacuum at slightly increased temperature. (S)-amlodipine succinate (0.48 kg, step yield 90 %) was isolated as white crystals. The (S)-amlodipine succinate was isolated in 99.68 % ee with API-compliant purity. The overall yield was 33 %.

[0123] 1H NMR (DMSO-cfe, 500 MHz): 5 1.09 (t, 3H, J = 7.1 Hz), 2.29 (s, 4H), 2.30 (s, 3H), 3.01 (td, 2H, J = 5.1 and 2.1 Hz), 3.50 (s, 3H), 3.62 (m, 2H), 3.98 (m, 2H), 4.57 (d, 1 H, J = 14.0 Hz), 4.69 (d, 1 H, J = 14.0 Hz), 5.30 (s, 1 H), 7.12 (td, 1 H, J = 7.6 and 1.5 Hz), 7.22 (td, 1 H, J = 7.6 and 1 .1 Hz), 7.27 (dd, 1 H, J = 7.8 and 1 .1 Hz), 7.34 (dd, 1 H, J = 7.8 and 1 .5 Hz), 8.0-11 .0 (bs).

[0124] 13C NMR (DMSO-cfe, 125 MHz): 5 14.1 , 18.2, 31.9, 36.6, 38.8, 50.5, 59.4, 66.6, 67.8, 101.9, 102.0, 127.4, 127.8, 129.0, 131.0, 131.1 , 144.9, 145.4, 145.8, 166.3, 167.1 , 175.4.

[0125] Chemical Formula: C20H25CIN2O5 Chemical Formula: C2H6OS

[0126] Molecular Weight: 408.88 Molecular Weight: 78.13

[0127] Chemical Formula: C20H25CIN2O5

[0128] Molecular Weight: 408.88

[0129] Example 4: Production of (S)-amlodipine succinate from racemic amlodipine base

[0130] Example 4 demonstrates the production of (S)-amlodipine succinate from racemic amlodipine base.

[0131] Racemic amlodipine base (120 g) was added to a 0.5 L reactor together with 11 .05 g of (D)- tartaric acid. The solids were added with DMSO (180 ml) and the resulting thick slurry was stirred for 1 hour at 22-28°C. The suspension was then diluted by slow addition of acetone (240 ml) over 0.5 hours, cooled slowly to 19-21 °C, stirred for 4 hours and filtered off. The isolated crystals were washed with acetone and dried under reduced pressure. 60.5 g of (S)- amlodipine (D)-hemitartrate DMSO-solvate was obtained in 37 % yield. The (S)-amlodipine (D)-hemitartrate DMSO-solvate was isolated in 98.36 % ee.

[0132] The dried (S)-amlodipine (D)-hemitartrate DMSO-solvate (60 g) was added to a reactor with toluene (330 ml) followed by water (60 ml). The mixture was stirred at room temperature for approximately 10 minutes. NaOH (2.05 g) was dissolved in water (90 ml) in a side vessel. A solution of K2CO3 (8.86 g) in water (90 ml) was prepared in another side vessel. (S)-amlodipine base was released by slow addition of the NaOH solution into the agitated reaction mixture followed by addition of the K2CO3 solution, both at room temperature. The resulting emulsion was then heated to 35°C and stirred for 0.5 hours. The aqueous phase was then removed after separation of the phases. The organic phase was washed with 120 ml of water and the aqueous phase was removed after 0.5 hours of stirring at 30-35°C. The apparatus was rinsed with 30 ml of MeOH, and the rinsing was added to the organic phase in a side vessel. Succinic acid (12.73 g) was added to a side vessel with 150 ml of MeOH. A clear solution resulted after a short time of stirring at room temperature. The solution of succinic acid was then slowly added into the filtered organic extract containing (S)-amlodipine base in the main reactor at 20-30°C, and the reaction mixture was seeded at approximately 50 % of the addition. The side vessel was rinsed with 30 ml of MeOH and the rinsing was added to the resulting suspension. The suspension of product was then stirred at 23-29°C for 0.5 hours. It was then slowly cooled to 0-5°C over a period of 1.5 hours under stirring and stirred for an additional hour at that temperature. The crystalline product was isolated at 0-4 °C and the crystals were washed with cooled MeOH and then with cooled acetone. The product was dried under vacuum. (S)- amlodipine succinate (50.5 g, step yield 90 %) was isolated as white crystals. The (S)- amlodipine succinate was isolated in 99.42 % ee. The overall yield was 33 %.

[0133] 1H NMR (DMSO-cfe, 500 MHz): 5 1.09 (t, 3H, J = 7.1 Hz), 2.29 (s, 4H), 2.30 (s, 3H), 3.01 (td, 2H, J = 5.1 and 2.1 Hz), 3.50 (s, 3H), 3.62 (m, 2H), 3.98 (m, 2H), 4.57 (d, 1 H, J = 14.0 Hz), 4.69 (d, 1 H, J = 14.0 Hz), 5.30 (s, 1 H), 7.12 (td, 1 H, J = 7.6 and 1.5 Hz), 7.22 (td, 1 H, J = 7.6 and 1 .1 Hz), 7.27 (dd, 1 H, J = 7.8 and 1 .1 Hz), 7.34 (dd, 1 H, J = 7.8 and 1 .5 Hz), 8.0-11 .0 (bs).

[0134] 13C NMR (DMSO-cfe, 125 MHz): 5 14.1 , 18.2, 31.9, 36.6, 38.8, 50.5, 59.4, 66.6, 67.8, 101.9, 102.0, 127.4, 127.8, 129.0, 131.0, 131.1 , 144.9, 145.4, 145.8, 166.3, 167.1 , 175.4.

[0135] Example 5: (S)-amlodipine salt screening

[0136] Example 5 demonstrates extensive screening of (S)-amlodipine salts to find a suitable salt for a pharmaceutical formulation.

[0137] The following acids were screened as possible counterions to (S)-amlodipine: acetic acid, ascorbic acid, benzoic acid, citric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrochloric acid, hippuric acid, lactic acid, L-malic acid, malonic acid, methanesulfonic acid, naphtalene-2-sulfonic acid, oxalic acid dihydrate, (S)-mandelic acid, salicylic acid, succinic acid and p-toluenesulfonic acid monohydrate. The screening procedure involved mixing methanol solutions of (S)-amlodipine and an acid followed by slow evaporation. The most promising salts where selected based on ease of crystallisation and melting point. These salts were prepared again by the same procedure but in larger amount (1-2 g) for further characterisation. The data for the most promising salts compared with the maleate salt and the besylate salt are summarised in Tables 1a-b below.

[0138] Table 1a

[0139] Table 1b

[0140] The (S)-amlodipine impurities are summarised in Table 2 below.

[0141] Table 2

[0142] The data from the screening were compared to the properties of racemic amlodipine besylate. (S)-amlodipine salts besylate, hippurate and mesylate were eliminated after the screening for further formulation development based on their undesirable physicochemical properties, specifically melting point, hygroscopicity and physical and chemical stability. The remaining five salts (maleate, succinate, oxalate, malonate and L-malate) were chosen as the most promising salts for further characterisation.

[0143] Example 6: Formulation stress tests

[0144] The most promising salts from the screening were prepared for formulation by crystallisation starting from 5 g of (S)-amlodipine base and 1.1 molar equivalent of the salt. An example of the crystallisation procedure is as follows:

[0145] 1) dissolving (S)-amlodipine base in a flask in 10 ml of MeOH (or EtOH or acetone - depending on the salt);

[0146] 2) filtering the solution through silica;

[0147] 3) transferring the filtered solution to an EasyMax reactor;

[0148] 4) dissolving the acid in a different flask in 10 ml of MeOH;

[0149] 5) transferring the acid solution to a dropping funnel;

[0150] 6) adding the acid solution dropwise to the solution of (S)-amlodipine base while stirring; 7) filtrating and washing with MeOH (or EtOH or acetone - depending on the salt); and

[0151] 8) drying under reduced pressure at 40 °C.

[0152] The salts were formulated as tablets with the composition of marketed racemic amlodipine. The composition comprises amlodipine salt, microcrystalline cellulose, dibasic calcium hydrogenphosphate dihydrate, sodium starch glycolate and magnesium stearate. The tablets were prepared and subjected to the stress tests, as summarised in Table 3 below.

[0153] The amount of (S)-amlodipine salt listed in Tables 3-8 as 5 mg refers specifically to the weight amount of (S)-amlodipine free base present in the formulation. The amount does not represent the actual weight amount of the particular salts themselves.

[0154] Table 3

[0155] It was found that (S)-amlodipine maleate was very unstable in the tested formulation, yielding high amounts of the (S)-amlodipine aspartate impurity. The tablets containing the oxalate salt were also quite unstable, but the degradation pathway in this case was mainly the oxidation reaction into impurity D. The best performance in terms of the chemical purity was attributed to the usage of the succinate or L-malate salts.

[0156] In order to confirm the utility of the final candidates, the preliminary prediction of stability was performed as a continuation of the already performed stress tests (these data were also incorporated in the prediction). (S)-amlodipine maleate has not been included in this study due to the formation of impurities, namely, the Michael addition product ((S)-amlodipine aspartate) and impurity D. The chemical purity results of the extended stress tests were shown in Tables 4-6. Tables 4a-b show the results obtained under the 30 °C stress tests, Table 5 shows the results obtained under the 40 °C stress tests and Tables 6a-b show the results obtained under the 50 °C stress tests.

[0157] The results of the stability predictions were calculated. It was found that the highest probability of passing the stability study under 25C / 60%RH for 2 years in PVDC packaging material with respect to impurity D was achieved when the succinate salt was used in the formulation (94.26%), compared with 66.07% for L-malate, 82.67% for malonate and 8.77% for oxalate. The lowest stability was proved by the oxalate salt which would likely not pass the requested shelf-life (2 years) in the PVDC packaging material.

[0158] Table 4a

[0159] Table 4b Table 5

[0160] Table 6a Table 6b

[0161] All stressed samples were unchanged in terms of polymorphic stability. From the point of view of physical stability, it was not possible to choose a preferential (S)-amlodipine salt because they were all the same after stresses. The quantification of water was very similar for all salts.

[0162] The results are shown in Table 7 and Table 8. In particular, Table 7 shows the stress test conditions and polymorphic results of the tested (S)-amlodipine salts and Table 8 shows the quantification of water before stresses (TO). Table 7

[0163] Table 8

[0164] Example 7: (S)-amlodipine succinate stress tests in formulation (S)-amlodipine succinate was selected as the most successful salt from the screening. Another composition was prepared and found to have satisfactory results. Table 9 shows the qualitative composition of Batch A and Tables 10-12 show the chemical purity results of the stress tests. In particular, Table 10 shows the results obtained under the 30 °C stress tests, Tables 11a-b show the results obtained under the 40 °C stress tests, Tables 12a-b show the results obtained under the 50 °C stress tests and Table 13 shows the results obtained under the 60 °C stress tests.

[0165] The amount of (S)-amlodipine succinate salt listed in Tables 10-13 as 5 mg refers specifically to the weight amount of (S)-amlodipine free base present in the formulation. The amount does not represent the actual weight amount of the succinate salt itself.

[0166] Table 9

[0167] Table 10

[0168] Table 11a

[0169] Table 11 b Table 12a

[0170] Table 12b Table 13

[0171] The prediction of stability performed on the basis of the abovementioned data for PVDC packaging material resulted in very high probability of passing the 2-year shelf-life under the 25°C / 60%RH regime (99.90%).

[0172] In addition to strong chemical stability, the formulation of Batch A composition also performed very well from a manufacturing point of view. The I PC parameters of the batch complied with desired set limits. The results are shown in Table 14 below. Table 14

[0173] The Batch A composition has also been subjected to stability testing using two grades of PVDC packaging material (PVDC 40 and PVDC 120). Three-month stability data under 25°C / 25%RH and 40°C / 75%RH conditions are available and shown in Tables 15 and 16. In particular, Table 15 shows the three-month (3M) stability results in PVDC 40 packaging material and Table 16 shows the 3M stability results in PVDC 120 packaging material.

[0174] Table 15

[0175] Table 16

[0176] Example 8: Final prototype formulation A final prototype based on the Batch B composition was selected due to its higher stability compared to the Batch A composition. Additionally, the prediction of stability studies indicated that the Batch A composition formed a number of additional impurities. To avoid such issues, the decision was made to proceed with the development of the Batch B composition. The final composition of Batch B is shown in Table 17. These tablets were subjected to prediction of stability studies under various temperature and humidity conditions, with the chemical purity results shown in Tables 18-22. Table 18 shows the results obtained under the 30 °C stress tests, Tables 19a-b show the results obtained under the 40 °C stress tests, Tables 20a-c show the results obtained under the 50 °C stress tests and Tables 21a-b show the results obtained under the 60 °C stress tests.

[0177] The amount of (S)-amlodipine succinate salt listed in Tables 18-21b as 5 mg refers specifically to the weight amount of (S)-amlodipine free base present in the formulation. The amount does not represent the actual weight amount of the succinate salt itself.

[0178] Table 17 Table 18

[0179] Table 19a

[0180] Table 19b

[0181] Table 20a Table 20b

[0182] Table 20c

[0183] Table 21a

[0184] Table 21b

[0185] The prediction of stability performed on the basis of the abovementioned data for both PVC and PVDC packaging materials resulted in very high probability of passing the 2-year shelflife under the 25°C / 60%RH regime (99.06% for PVC and 99.51% for PVDC).

[0186] The chemical purity results and the degradation kinetics with respect to the impurity D were comparable among the (S)-amlodipine succinate batches, as well as with the degradation behaviour of the Amlodipine besylate product (Figure 6).

[0187] The final prototype with the Batch B composition also performed very well from a manufacturing point of view. The I PC parameters of the batch were comparable to those of the Batch A composition and complied with desired set limits. Notably, the friability and disintegration results of the Batch B composition were lower, indicating better performance compared to the Batch A composition. The results are shown in Table 22 below. Table 22

[0188] The Batch B composition has also been subjected to stability testing using two grades of PVDC packaging material (PVDC 40 and PVDC 120). Three-month stability data under 25°C / 25%RH and 40°C / 75%RH conditions are available and shown in Tables 23 and 24. In particular, Table 23 shows the 3M stability results in PVDC 40 packaging material and Table 24 shows the 3M stability results in PVDC 120 packaging material. The chemical purity results have shown significantly less creation of unknown impurities compared to the results of Batch A composition.

[0189] Table 23 Table 24 Example 9: Stability tests

[0190] The (S)-amlodipine succinate tablets were subjected to stability testing.

[0191] Table 25a shows composition of the 1.25 mg strength tablet, and Table 25b shows the composition of the 2.5 mg and 5 mg strength tablets. The amount or strength of (S)-amlodipine succinate salt listed in this example as 1 .25 mg, 2.5 mg or 5 mg refers specifically to the weight amount of (S)-amlodipine free base present in the formulation. The 1.25 mg, 2.5 mg and 5 mg amount or strength does not represent the actual weight amount of the succinate salt itself.

[0192] The results of the stability tests are shown in Tables 26-28 below. In particular, Table 26 shows the results for the 1 .25 mg strength tablets sorted in blister PVC250 / PVDC120 / white / / AI 0.020 packaging and at25°C / 60 % RH conditions, Table 27 shows the results for the 2.5 mg strength tablets stored in LDPE transparent / container packaging and at 25°C / 60 % RH conditions, and Table 28 shows the results for the 5 mg strength tablets stored in LDPE transparent / container packaging and at 25°C / 60 % RH conditions.

[0193] The methods listed in T ables 26-28 as “Ph. Eur.” refer to the corresponding methods disclosed in European Pharmacopoeia version 11.6.

[0194] Table 25a

[0195] Table 25b Table 26

[0196] Table 27 Table 28

Claims

- 38 -CLAIMS:1 . A method for producing (S)-amlodipine succinate comprising: a) reacting (S)-amlodipine (D)-hemitartrate or a solvate thereof with a first base in the presence of a two-phase solvent system comprising a first non-polar organic solvent and water to produce (S)-amlodipine base; b) removing the water layer; and c) reacting (S)-amlodipine base with succinic acid to produce (S)-amlodipine succinate.

2. The method of claim 1 , wherein the (S)-amlodipine (D)-hemitartrate or a solvate thereof is (S)-amlodipine (D)-hemitartrate DMSO-solvate.

3. The method of claims 1 or 2, wherein the first base is selected from a hydroxide base or a carbonate base or a combination thereof.

4. The method of any one of claims 1 to 3, wherein the first non-polar organic solvent is selected from toluene, isopropyl acetate, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBUK), or a combination thereof.

5. The method of any one of claims 1 to 4, wherein the (S)-amlodipine base is reacted with succinic acid in the presence of a second organic solvent.

6. The method of claim 5, wherein the second organic solvent is selected from methanol (MeOH), ethanol (EtOH), acetone, diethyl ether, tetrahydrofuran (THF), dichloromethane (DCM), toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate, methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBUK), 2-methyltetrahydrofuran (2-MeTHF), or a combination thereof.

7. The method of any one of claims 1 to 6, wherein the method for producing (S)- amlodipine succinate from (S)-amlodipine (D)-hemitartrate or a solvate thereof is carried out in situ without the isolation and / or purification of any of the intermediate products.

8. The method of any one of claims 1 to 7, wherein the (S)-amlodipine (D)-hemitartrate or a solvate thereof is produced by reacting racemic amlodipine base with (D)-tartaric acid.- 39 -9. The method of claim 8, wherein the racemic amlodipine base is reacted with (D)- tartaric acid in the presence of a solvent mixture comprising dimethyl sulfoxide (DMSO).

10. The method of claims 8 or 9, wherein the racemic amlodipine base is produced by reacting racemic amlodipine besylate with a second base.

11. The method of claim 10, wherein the racemic amlodipine besylate is reacted with a second base in the presence of a solvent mixture comprising a third organic solvent and water.

12. (S)-amlodipine succinate obtainable by the method of any one of claims 1 to 11.

13. A formulation comprising an amount of (S)-amlodipine succinate which provides the same amount of (S)-amlodipine as from 1 mg to 10 mg of (S)-amlodipine free base.

14. The formulation of claim 13, wherein the formulation further comprises mannitol, croscarmellose sodium, stearic acid, magnesium stearate and silicon dioxide.

15. The formulation of claim 14, wherein the formulation comprises from comprises from 4% to 12% (S)-amlodipine succinate, from 82% to 90% mannitol, from 0% to 4% croscarmellose sodium, from 0.1 % to 4% stearic acid, from 0.1 % to 2% magnesium stearate, and from 0.1% to 2% silicon dioxide, by weight, based on the total weight of the composition.

16. The formulation of claim 13, wherein the formulation further comprises microcrystalline cellulose, dibasic calcium hydrogenphosphate dihydrate, sodium starch glycolate and magnesium stearate.

17. The formulation of claim 16, wherein the formulation comprises from 4% to 12% (S)- amlodipine succinate, from 30% to 67% microcrystalline cellulose, from 28% to 34% dibasic calcium hydrogenphosphate dihydrate, from 0.1 % to 3% sodium starch glycolate, and from 0.1% to 3% magnesium stearate, by weight, based on the total weight of the composition.

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