SNOONIAN JOHN R (US)
WILKINSON HAROLD SCOTT (US)
BALANOV ANNA (US)
US20210061759A1 | 2021-03-04 | |||
US20190167635A1 | 2019-06-06 | |||
US20190169123A1 | 2019-06-06 | |||
US20200165200A1 | 2020-05-28 | |||
US20210315860A1 | 2021-10-14 |
What is claimed is: 1. A method of preparing an enantiomerically pure crystalline form of (R)-(+)- amisulpride comprising the steps of: (a) coupling, in the presence of a tertiary amine and an acid activating reagent, 4- amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and (R)-(1-ethylpyrrolidin-2- yl) methanamine to form a reaction mixture; and (b) isolating from the reaction mixture of step (a), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°; wherein step (b) does not comprise formation of a solvate of (R)-(+)-amisulpride. 2. The method of claim 1, wherein the coupling of step (a) comprises the steps of: (a1) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with the tertiary amine and the acid activating reagent to form a first reaction mixture; and (a2) adding (R)-(1-ethylpyrrolidin-2-yl)methanamine to the first reaction mixture. 3. A method of preparing an enantiomerically pure crystalline form of (S)-(-)- amisulpride comprising the steps of: (a) coupling, in the presence of a tertiary amine and an acid activating reagent, 4- amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and (S)-(1-ethylpyrrolidin-2- yl) methanamine to form a reaction mixture; and (b) isolating from the reaction mixture of step (a), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°; wherein the step (b) does not comprise formation of a solvate of (S)-(-)-amisulpride. 4. The method of claim 3, wherein the coupling of step (a) comprises the steps of: (a1) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with the tertiary amine and the acid activating reagent to form a first reaction mixture; and (a2) adding (S)-(1-ethylpyrrolidin-2-yl)methanamine to the first reaction mixture. 5. The method of any one of claims 1-4, wherein step (b) comprises step (b1): concentrating the reaction mixture of step (a) to give a mixture of step (b1). 6. The method of claim 5, further comprising step (b2): treating the mixture of step (b1) with a base and the isolation reagent to form a step (b2) mixture. 7. The method of claim 6, wherein the base is an aqueous solution of an inorganic base. 8. The method of claim 7, wherein the base is an aqueous solution of potassium carbonate. 9. The method of any one of claims 6-8, further comprising step (b3): separating the step (b2) mixture to obtain an organic phase. 10. The method of claim 9, further comprising step (b4): concentrating the organic phase to a first concentrated solution having less than about 2 wt% water. 11. The method of claim 10, wherein the first concentrated solution has about 1.0 wt% to about 0.001 wt% water. 12. The method of claim 11, wherein the first concentrated solution has about 1.0 wt% to about 0.01 wt% water. 13. The method of claim 12, wherein the first concentrated solution has about 0.5 wt% to about 0.01 wt% water. 14. The method of any one of claims 10-13, further comprising step (b5): concentrating the first concentrated solution to a second concentrated solution, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 15 wt% to about 65 wt% of the second concentrated solution. 15. The method of claim 14, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 35 wt% to about 40 wt% of the second concentrated solution. 16. The method of claim 14, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 33 wt% to about 38 wt% of the second concentrated solution. 17. The method of claim 14, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 35 wt% of the second concentrated solution. 18. The method of any one of claims 14-17, further comprising adding S5, wherein S5 is a solvent, to the second concentrated solution. 19. The method of claim 18, wherein S5 is methyl tert-butyl ether. 20. The method of any one of claims 14-19, further comprising step (b6): adding a seed amount of a crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to the second concentrated solution to form a seeded mixture. 21. The method of any one of claims 14-19, further comprising step (b6): adding a seed amount of a crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to the second concentrated solution to form a seeded mixture. 22. The method of claim 20 or 21, wherein the seed amount has a total weight that is about 0.001 wt% to about 15 wt% of the second concentrated solution. 23. The method of claim 20 or 21, wherein the seed amount has a total weight that is about 0.1 wt% to about 10 wt% of the second concentrated solution. 24. The method of claim 20 or 21, wherein the seed amount has a total weight that is about 0.1 wt% to about 5 wt% of the expected yield of the (R)-(+)-amisulpride or (S)-(-)- amisulpride present in the second concentrated solution. 25. The method of claim 20 or 21, wherein the seed amount has a total weight that is about 0.1 wt% to about 2.0 wt% of the expected yield of the (R)-(+)-amisulpride or (S)-(-)- amisulpride present in the second concentrated solution. 26. The method of claim 20 or 21, wherein the seed amount has a total weight that is about 0.4 wt%, about 1.4 wt%, or about 2.0 wt% of the expected yield of the (R)-(+)- amisulpride or (S)-(-)-amisulpride present in the second concentrated solution. 27. The method of claim 20 or 21, wherein the seed amount has a total weight that is about 0.75 wt% of the expected yield of the (R)-(+)-amisulpride or (S)-(-)-amisulpride present in the second concentrated solution. 28. The method of any one of claims 20-27, further comprising step (b7): filtering the seeded mixture of step (b6) to obtain a product solid. 29. The method of claim 28, further comprising step (b8): drying the product solid to obtain a crude product. 30. The method of claim 29, further comprising step (b9): recrystallizing the crude product in the presence of the isolation reagent. 31. The method of claim 30, wherein the recrystallizing comprises (i) dissolving the crude product with the isolation reagent to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution, and (iii) adding a seed amount of a crystalline form of (R)-(+)-amisulpride or a crystalline form of (S)-(-)-amisulpride. 32. The method of claim 30, wherein the recrystallizing comprises (i) heating the crude product in the presence of an isolation reagent at a first elevated temperature to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution to form a concentrated recrystallization solution; (iii) adding S5, wherein S5 is a solvent, to the concentrated recrystallization solution; (iv) adding a seed amount of a crystalline form of (R)- (+)-amisulpride or a crystalline form of (S)-(-)-amisulpride to the concentrated recrystallization solution of step (iii) to form a seeded recrystallization solution; and (v) cooling the seeded recrystallization solution. 33. The method of claim 32, wherein the first elevated temperature is from about 50 °C to about 55 °C. 34. The method of claim 32 or 33, wherein the cooling comprises cooling to a first reduced temperature over a first period of time, and then cooling to a second reduced temperature over a second period of time. 35. The method of claim 34, wherein the first reduced temperature is from about 38 °C to about 42 °C. 36. The method of claim 34 or 35, wherein the first period of time is about 120 min. 37. The method of any one of claims 34-36, wherein the second reduced temperature is from about 10 °C to about 15 °C. 38. The method of any one of claims 34-37, wherein the second period of time is about 60 min. 39. The method of any one of claims 34-38, wherein the cooling over the first period of time is performed at a first cooling rate. 40. The method of any one of claims 34-39, wherein the cooling over the second period of time is performed at a second cooling rate. 41. The method of claim 40, wherein the second cooling rate is greater than the first cooling rate. 42. The method of claim 39, wherein the first cooling rate is about 0.1 °C/min. 43. The method of claim 40, wherein the second cooling rate is about 0.5 °C/min. 44. A method of preparing an enantiomerically pure crystalline form of (R)-(+)- amisulpride comprising the steps of: (a) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with a tertiary amine and an acid activating reagent to form a reaction mixture; (b) adding a (R)-(1-ethylpyrrolidin-2-yl)methanamine salt to the reaction mixture to form a mixture of step (b); and (c) isolating from the mixture of step (b), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. 45. The method of claim 44, wherein step (c) does not comprise formation of a solvate of (R)-(+)-amisulpride. 46. The method of claim 44 or 45, wherein the isolating of step (c) comprises (d1) adding the isolation reagent to the mixture of step (b), followed by an aqueous base solution to form a mixture of step (d1), (d2) separating the mixture of step (d1) to obtain an organic phase; (d3) concentrating the organic phase of step (d2) to produce a product solution having about 5.0 wt% to about 0.001 wt% water; (d4) adding to the product solution a seed amount of a crystalline form of (R)-(+)- amisulpride, characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to form a seeded mixture; (d5) filtering the seeded mixture of step (d4) to obtain a product solid; and (d6) drying the product solid of step (d5) to produce the enantiomerically pure crystalline form of (R)-(+)-amisulpride. 47. The method of any one of claims 44-46, further comprising recrystallizing the enantiomerically pure crystalline form of (R)-(+)-amisulpride of step (d6). 48. The method of claim 47, wherein the recrystallizing comprises (i) heating the enantiomerically pure crystalline form of (R)-(+)-amisulpride of step (d6) in the presence of an isolation reagent at a first elevated temperature to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution to form a concentrated recrystallization solution; (iii) adding S5, wherein S5 is a solvent, to the concentrated recrystallization solution; (iv) adding a seed amount of a crystalline form of (R)-(+)- amisulpride to the concentrated recrystallization solution of step (iii) to form a seeded recrystallization solution; and (v) cooling the seeded recrystallization solution. 49. The method of claim 48, wherein the first elevated temperature is from about 50 °C to about 55 °C. 50. The method of claim 48 or 49, wherein the cooling comprises cooling to a first reduced temperature over a first period of time, and then cooling to a second reduced temperature over a second period of time. 51. The method of claim 50, wherein the first reduced temperature is from about 38 °C to about 42 °C. 52. The method of claim 50 or 51, wherein the first period of time is about 120 min. 53. The method of any one of claims 50-52, wherein the second reduced temperature is from about 10 °C to about 15 °C. 54. The method of any one of claims 50-53, wherein the second period of time is about 60 min. 55. The method of any one of claims 48-54, wherein S5 is an ether solvent. 56. The method of any one of claims 48-54, wherein S5 is methyl tert-butyl ether. 57. The method of any one of claims 48-56, wherein the method further comprises isolating and drying the crystalline form of (R)-(+)-amisulpride. 58. A method of preparing an enantiomerically pure crystalline form of (S)-(-)- amisulpride comprising the steps of: (a) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with a tertiary amine and an acid activating reagent to form a reaction mixture; (b) adding a (S)-(1-ethylpyrrolidin-2-yl)methanamine salt to the reaction mixture of step (a) to form a mixture of step (b); and (c) isolating from the mixture of step (b), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at least at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. 59. The method of claim 58, wherein step (c) does not comprise formation of a solvate of (S)-(-)-amisulpride. 60. The method of claim 58 or 59, wherein the isolating of step (c) comprises: (d1) adding the isolation reagent to the mixture of step (b), followed by an aqueous base solution to form a mixture of step (d1); (d2) separating the mixture of step (d1) to obtain an organic phase; (d3) concentrating the organic phase of step (d2) to produce a product solution with about 5.0 wt% to about 0.01 wt% water; (d4) adding to the product solution of step (d3) with a seed amount of a crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to form a seeded mixture; (d5) filtering the seeded mixture of step (d4) to obtain a product solid; and (d6) drying the product solid of step (d5) to produce the enantiomerically pure crystalline form of (S)-(-)-amisulpride. 61. The method of any one of claims 58-60, further comprising recrystallizing the enantiomerically pure crystalline form of (S)-(-)-amisulpride of step (d6). 62. The method of claim 61, wherein the recrystallizing comprises (i) heating the enantiomerically pure crystalline form of (S)-(-)-amisulpride of step (d6) in the presence of an isolation reagent at a first elevated temperature to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution to form a concentrated recrystallization solution; (iii) adding S5, wherein S5 is a solvent, to the concentrated recrystallization solution; (iv) adding a seed amount of a crystalline form of (S)-(-)- amisulpride to the concentrated recrystallization solution of step (iii) to form a seeded recrystallization solution; and (v) cooling the seeded recrystallization solution. 63. The method of claim 61 or 62, wherein the first elevated temperature is from about 50 °C to about 55 °C. 64. The method of claim 61 or 62, wherein the cooling comprises cooling to a first reduced temperature over a first period of time, and then cooling to a second reduced temperature over a second period of time. 65. The method of claim 64, wherein the first reduced temperature is from about 38 °C to about 42 °C. 66. The method of claim 64 or 65, wherein the first period of time is about 120 min. 67. The method of any one of claims 64-66, wherein the second reduced temperature is from about 10 °C to about 15 °C. 68. The method of any one of claims 64-67, wherein the second period of time is about 60 min. 69. The method of any one of claims 62-68, wherein S5 is an ether solvent. 70. The method of any one of claims 62-68, wherein S5 is methyl tert-butyl ether. 71. The method of claim 46 or 60, wherein the product solution of step (d3) has about 0.001 wt% to about 0.5 wt% water. 72. The method of any one of claims 1-71, wherein the tertiary amine is of the formula wherein: (i) R1, R2 and R3 are each independently C1-6 alkyl , C3-6 cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycloalkyl, or 5-10 membered monocyclic heteroaryl; or (ii) R1 is C1-6 alkyl , C3-6 cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycloalkyl, or 5-10 membered monocyclic heteroaryl, and R2 and R3 together with the N atom to which they are attached form a 3-10 membered monocyclic or bicyclic heterocycloalkyl or a 5-10 membered monocyclic heteroaryl. 73. The method of claim 72, wherein R2 and R3 together with the N atom to which they are attached form a 3-10 membered monocyclic or bicyclic heterocycloalkyl or a 5-10 membered monocyclic heteroaryl. 74. The method of any one of claims 1-73, wherein the tertiary amine is triethyl amine. 75. The method of any one of claims 1-73, wherein the tertiary amine is 4- methylmorpholine. 76. The method of any one of claims 1-75, wherein the acid activating reagent is of the formula wherein Rx is halogen and Ry is C1-5 alkyl. 77. The method of any one of claims 1-75, wherein the acid activating reagent is ethyl chloroformate. 78. The method of any one of claims 1-77, wherein the isolation reagent is of the formula wherein R4 is C1-6 alkyl; and R5 is C1-5 alkyl or C1-5 alkoxide. 79. A method of preparing an enantiomerically pure crystalline form of (R)-(+)- amisulpride comprising the steps of: (a) heating (R)-(+)-amisulpride in the presence of an isolation reagent to a first elevated temperature to form a crystallization mixture; (b) adding a seed amount of Form A of (R)-(+)-amisulpride to the crystallization mixture to form a seeded mixture; (c) cooling the seeded mixture to a first reduced temperature over a first period of time; (d) cooling the seeded mixture from step (c) to a second reduced temperature over a second period of time; and (e) filtering the seeded mixture from step (d) to provide an enantiomerically pure crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. 80. A method of preparing an enantiomerically pure crystalline form of (S)-(-)-amisulpride comprising the steps of: (a) heating (S)-(-)-amisulpride in the presence of an isolation reagent to a first elevated temperature to form a crystallization mixture; (b) adding a seed amount of Form A’ of (S)-(-)-amisulpride to the crystallization mixture to form a seeded mixture; (c) cooling the seeded mixture to a first reduced temperature over a first period of time; (d) cooling the seeded mixture from step (c) to a second reduced temperature over a second period of time; and (e) filtering the seeded mixture from step (d) to provide an enantiomerically pure crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. 81. The method of claim 79 or 80, wherein the first elevated temperature is from about 50 °C to about 55 °C. 82. The method of any one of claims 79-81, wherein the first reduced temperature is from about 38 °C to about 42 °C. 83. The method of any one of claims 79-82, wherein the first period of time is about 120 min. 84. The method of any one of claims 79-83, wherein the second reduced temperature is from about 10 °C to about 15 °C. 85. The method of any one of claims 79-84, wherein the second period of time is about 60 min. 86. The method of any one of claims 79-85, wherein the heating of step (a) is further performed in the presence of S5, wherein S5 is an ether solvent. 87. The method of claim 86, wherein S5 is methyl tert-butyl ether. 88. The method of any one of claims 1-87, wherein the isolation reagent is of the formula wherein R4 is C3-6 alkyl; and R5 is C1-5 alkyl. 89. The method of any one of claims 1-88, wherein the isolation reagent is not ethyl acetate. 90. The method of any one of claims 1-88, wherein the isolation reagent is isopropyl acetate. 91. The method of any one of claims 1-87, wherein the isolation reagent is of the formula wherein R4 is C1-6 alkyl; and R5 is C1-5 alkoxide. 92. The method of any one of claims 1-87, wherein the isolation reagent is diethyl carbonate or dimethyl carbonate. 93. The method of any one of claims 1-87, wherein the isolation reagent is of the formula R6COR7, where each of R6 and R7 is independently C1-5 alkyl. 94. The method of any one of claims 44-57, 71-78, and 88-93, wherein the (R)-(1- ethylpyrrolidin-2-yl)methanamine salt is a bis tartrate salt of (R)-(1-ethylpyrrolidin-2- yl)methanamine. 95. The method of any one of claims 44-57, 71-78, and 88-93, wherein the (R)-(1- ethylpyrrolidin-2-yl)methanamine salt is a bis L-tartrate salt of (R)-(1-ethylpyrrolidin-2- yl)methanamine. 96. The method of any one of claims 58-78 and 88-93, wherein the (S)-(1-ethylpyrrolidin- 2-yl)methanamine salt is a bis tartrate salt of (S)-(1-ethylpyrrolidin-2-yl)methanamine. 97. The method of any one claims 58-78 and 88-93, wherein the (S)-(1-ethylpyrrolidin-2- yl)methanamine salt is a bis D-tartrate salt of (S)-(1-ethylpyrrolidin-2-yl)methanamine. 98. The method of any one of claims 1-87, further comprising recrystallizing the enantiomerically pure crystalline form of (R)-(+)-amisulpride or the enantiomerically pure crystalline form of (S)-(-)-amisulpride in the presence of isopropyl acetate. 99. The method of any one of claims 20, 22-43, 46-57, 71-78, 79, 81-95, and 98, wherein the seed amount of a crystalline form of (R)-(+)-amisulpride has a greater than about 95% chemical purity and a greater than about 95% enantiomeric purity. 100. The method of any one of claims 20, 22-43, 46-57, 71-78, 79, 81-95, and 98, wherein the seed amount of a crystalline form of (R)-(+)-amisulpride has a greater than about 98% chemical purity and a greater than about 98% enantiomeric purity. 101. The method of any one of claims 21-43, 60-78, 80-93, and 96-98, wherein the seed amount of a crystalline form of (S)-(-)-amisulpride has a greater than about 95% chemical purity and a greater than about 95% enantiomeric purity. 102. The method of any one of claims 21-43, 60-78, 80-93, and 96-98, wherein the seed amount of a crystalline form of (S)-(-)-amisulpride has a greater than about 98% chemical purity and a greater than about 98% enantiomeric purity. 103. The method of any one of claims 1, 2, 5-57, 71-79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)-amisulpride has a greater than about 95% chemical purity. 104. The method of any one of claims 1, 2, 5-57, 71-79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)-amisulpride has a greater than about 98% chemical purity. 105. The method of any one of claims 1, 2, 5-57, 71-79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)-amisulpride has a greater than about 99% chemical purity. 106. The method of any one of claims 1, 2, 5-57, 71-79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)-amisulpride has a greater than about 95% enantiomeric purity. 107. The method of any one of claims 1, 2, 5-57, 71-79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)-amisulpride has a greater than about 98% enantiomeric purity. 108. The method of any one of claims 1, 2, 5-57, 71-79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)-amisulpride has a greater than about 99% enantiomeric purity. 109. The method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)-amisulpride has a greater than about 95% chemical purity. 110. The method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)-amisulpride has a greater than about 98% chemical purity. 111. The method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)-amisulpride has a greater than about 99% chemical purity. 112. The method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)-amisulpride has a greater than about 95% enantiomeric purity. 113. The method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)-amisulpride has a greater than about 98% enantiomeric purity. 114. The method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)-amisulpride has a greater than about 99% enantiomeric purity. 115. An enantiomerically pure crystalline form of (R)-(+)-amisulpride, wherein the crystalline form of (R)-(+)-amisulpride has a particle size distribution D10 value of about 2 to about 10 µm; a particle size distribution D50 value of about 15 to about 30 µm; and a particle size distribution D90 value of about 75 to about 100 µm, as measured by a laser diffraction particle size analyzer. 116. An enantiomerically pure crystalline form of (S)-(-)-amisulpride, wherein the crystalline form of (S)-(-)-amisulpride has a particle size distribution D10 value of about 2 to about 10 µm; a particle size distribution D50 value of about 15 to about 30 µm; and a particle size distribution D90 value of about 75 to about 100 µm, as measured by a laser diffraction particle size analyzer. 117. An enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)- amisulpride prepared by the method of any one of claims 1-114, comprising less than about 1.0 wt% of a compound of the following formula: 118. An enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)- amisulpride prepared by the method of any one of claims 1-114, comprising less than about 0.2 wt% of a compound of the following formula: 119. An enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)- amisulpride prepared by the method of any one of claims 1-114, comprising less than about 1.0 wt% of a compound of the following formula: 120. An enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)- amisulpride prepared by the method of any one of claims 1-114, comprising less than about 0.2 wt% of a compound of the following formula: 121. An enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)- amisulpride prepared by the method of any one of claims 1-114, comprising less than about 1.0 wt% of a compound of the following formula: 122. An enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)- amisulpride prepared by the method of any one of claims 1-114, comprising less than about 0.2 wt% of a compound of the following formula: 123. An enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, comprising less than about 1.0 wt% of a compound of the following formula: 124. An enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, comprises less than about 0.2 wt% of a compound of the following formula: 125. An enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, comprising less than about 1.0 wt% of a compound of the following formula: 126. An enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, comprises less than about 0.2 wt% of a compound of the following formula: 127. An enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, comprising less than about 1.0 wt% of a compound of the following formula: 128. An enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, comprises less than about 0.2 wt% of a compound of the following formula: 129. An enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 1.0 wt% of a compound of the following formula: 130. An enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 0.2 wt% of a compound of the following formula: . 131. An enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 1.0 wt% of a compound of the following formula: 132. An enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 0.2 wt% of a compound of the following formula: 133. An enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 1.0 wt% of a compound of the following formula: 134. An enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 0.2 wt% of a compound of the following formula: 135. A pharmaceutical composition comprising the enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, and a pharmaceutically acceptable carrier. 136. A pharmaceutical composition comprising the enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96- 98, 101, 102, and 110-114, and a pharmaceutically acceptable carrier. 137. A pharmaceutical composition comprising: (i) the enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of claims 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108; (ii) the enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of claims 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114; and (iii) a pharmaceutically acceptable carrier, wherein the crystalline form of (R)-(+)-amisulpride and the crystalline form of (S)-(-)-amisulpride are in a ratio of about 65:35 to about 88:12 by weight of free base. 138. The pharmaceutical composition of claim 137, wherein the crystalline form of (R)- (+)-amisulpride and the crystalline form of (S)-(-)-amisulpride are in a ratio of about 75:25 to about 88:12 by weight of free base. 139. The pharmaceutical composition of claim 137 or 138, wherein the crystalline form of (R)-(+)-amisulpride and the crystalline form of (S)-(-)-amisulpride are in a ratio of about 80:20 to about 88:12 by weight of free base. 140. The pharmaceutical composition of any one of claims 137-139, wherein the crystalline form of (R)-(+)-amisulpride and the crystalline form of (S)-(-)-amisulpride are in a ratio of about 85:15 by weight of free base. 141. The pharmaceutical composition of any one of claims 135-140, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 142. The pharmaceutical composition of any one of claims 135-140, comprising less than about 0.2 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 143. The pharmaceutical composition of any one of claims 135-142, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 144. The pharmaceutical composition of any one of claims 135-142, comprising less than about 0.2 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 145. The pharmaceutical composition of any one of claims 135-144, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 146. The pharmaceutical composition of any one of claims 135-144, comprising less than about 0.2 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 147. The pharmaceutical composition of any one of claims 135-146, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 148. The pharmaceutical composition of any one of claims 135-147, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 149. The pharmaceutical composition of any one of claims 135-148, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 150. The pharmaceutical composition of any one of claims 135-149, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 151. The pharmaceutical composition of any one of claims 135-150, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 152. The pharmaceutical composition of any one of claims 135-151, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. 153. A method of treating a psychiatric disorder in a subject comprising administering to the subject an enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)- amisulpride prepared by any one of claims 1-114, or an enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)-amisulpride of any one of claims 115-134, or a pharmaceutical composition of any one of claims 135-152. 154. The method according to claim 153, wherein the psychiatric disorder is a depressive order. 155. The method according to claim 153, wherein the psychiatric disorder is bipolar disorder. 156. The method according to claim 153, wherein the psychiatric disorder is bipolar depression. 157. The method according to claim 153, wherein the psychiatric disorder is major depressive disorder (MDD). 158. The method according to claim 153, wherein the psychiatric disorder is major depressive disorder with mixed features (MDD-MF). 159. The method according to claim 153, wherein the psychiatric disorder is treatment resistant depression (TRD). 160. The method according to claim 153, wherein the psychiatric disorder is schizophrenia. |
Scheme 1A [000238] Example 4, Step 1: (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase): First 30.0 kg of 4-amino-5- ethylsulfonyl)-2-methoxybenzoic acid and 159 kg of acetone were charged to a 400 L reactor. The mixture was cooled to -10 °C and 14 kg of ethyl chloroformate and 7 kg of acetone rinse was added to the mixture. Then 15 kg of 4-methylmorpholine and a 4 kg acetone rinse was slowly charged to the reactor (reaction is exothermic) while maintaining the temperature below 0 °C. Then 15.9 kg of (S)-(1-ethylpyrrolidin-2-yl)methanamine was slowly added to the reactor while maintaining the temperature below 5 °C. The reaction was stirred at 5 °C for 1h and then heated to 22 °C. The mixture was stirred for another 12h at 20 °C and concentrated under reduced pressure to 60 L. The temperature was then adjusted to 22 °C and a solution of 26 wt% potassium carbonate (142 kg) and 150 kg isopropyl acetate was added to the mixture. The reaction mixture was stirred for about 10 min, the stirring stopped, and the layers allowed to separate. The aqueous layer was removed, and 60.0 kg of water added to the organic layer. The reaction mixture was stirred for 10 min, the stirring stopped, and the layers allowed to separate. The aqueous layer was removed, and 60.0 kg of water added to the organic layer. The reaction mixture was stirred for 10 min, the stirring stopped, and the layers allowed to separate. The aqueous layer was removed and the reactor was equipped with a Dean Stark apparatus. The solution was then stirred at reflux with the Dean Stark apparatus removing water. The reactor temperature reached 91.8 °C as the water was removed. After the removal was almost completed, the solution was concentrated to a 45wt% solution. The reaction temperature was adjusted to 45 °C and the water content was measured and found to be <0.2% by Karl Fischer titration. Then 25 kg of isopropyl acetate was added and the solution was stirred at 45 °C and seeded with 0.3 kg of (S)-amisulpride of Form A’. The mixture was stirred for 30 min at 45 °C and the resulting slurry was cooled to 15 °C over 3.5h. The slurry was then stirred at 15 °C for 2h and filtered. The mother liquors from the filtration were recirculated through the reactor and filter. The isolated solid was washed with 36 kg of isopropyl acetate at 15 °C. The solid was dried in a filter dryer at 35 °C to yield 35.2 kg of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)- 2-methoxybenzamide (crude freebase). [000239] Example 4, Step 2 (recrystallization): (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A’): The 35.2 kg of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide (crude freebase) and 141 kg of isopropyl acetate were charged to a 400 L reactor. The mixture was heated to 60 °C and filtered. The reactor and filter were rinsed with 17.6 kg of isopropyl acetate and the combined isopropyl acetate mixture was concentrated to 98 L under reduced pressure. The temperature was adjusted to 50 °C and seeded with 0.67 kg of (S)-amisulpride of Form A’. The mixture was then stirred at 50 °C for 90 min and slowly cooled to 15 °C over 6h, and the slurry was stirred 15 °C for 1h and then isolated by filtration in a filter dryer. The mother liquors were recirculated to the reactor and filter dryer and the solid was washed with 35.2 kg of isopropyl acetate at 15 °C. The isolated solid was transferred to a filter dryer and dried until dry (loss on drying <0.5%). This yielded 26.1 kg of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A’. Analysis by titration and analysis by mass balance indicated that the product was greater than about 99.8 wt% chemically pure. Chiral HPLC indicated that the product was greater than about 99.5 % enantiomerically pure. XRPD characterization is shown in FIG 6B and Table 8-1. [000240] Example 5: (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A; Scheme 1B Scale-Up: Scheme 1B [000241] Example 5, Step 1: (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase): First 29.7 kg of 4-amino-5- ethylsulfonyl)-2-methoxybenzoic acid and 158 kg of acetone were charged to a 400 L reactor. The mixture was cooled to -10 °C and 14 kg of ethyl chloroformate and 7 kg of acetone rinse was added to the mixture. Then 15 kg of 4-methylmorpholine and a 4 kg acetone rinse were slowly charged to the reactor (reaction is exothermic) while maintaining the temperature below 0 °C. Then 15.78 kg of (R)-(1-ethylpyrrolidin-2-yl)methanamine was slowly added to the reactor while maintaining the temperature below 5 °C and the reaction was stirred at 5 °C for 1h and then heated to 22 °C. The mixture was stirred for another 11h at 20 °C and concentrated under reduced pressure to 59 L. The temperature was then adjusted to 22 °C and solution of 26 wt% potassium carbonate (141 kg) and 149 kg isopropyl acetate was added to the mixture. The reaction mixture was stirred for 11 min, the stirring stopped, and the layers allowed to separate. The aqueous layer was removed and 59.5 kg of water added to the organic layer. The reaction mixture was stirred for 10 min, the stirring stopped, and the layers allowed to separate. The aqueous layer was removed, and 59.5 kg of water added to the organic layer. The reaction mixture was stirred for 10 min, the stirring stopped, and the layers allowed to separate. The aqueous layer was removed and the reactor was equipped with a Dean Stark apparatus. The solution was stirred at reflux with the Dean Stark apparatus removing water. The reactor temperature reached 91.8 °C as the water was removed, and the solution was concentrated to 100 L. The reaction temperature was reduced to 45 °C and the water content was measured and found to be 0.2% by Karl Fischer titration. The solution was stirred at 45 °C and seeded with 0.6 kg of (R)-amisulpride of Form A. The mixture was stirred for 30 min at 45 °C and the resulting slurry was cooled to 15 °C over 3.5h. The slurry was stirred at 15 °C for 6.5h and filtered. The mother liquors from the filtration were recirculated through the reactor and filter and the isolated solid was washed with 36 kg of isopropyl acetate at 15 °C. The solid was dried in a vacuum oven at 35 °C to yield 33.3 kg of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide (crude freebase). [000242] Example 5, Step 2 (recrystallization): (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A’): The 33.3 kg of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide (crude freebase) and 133 kg of isopropyl acetate were charged to a 400 L reactor. The mixture was heated to 60 °C and filtered. The reactor and filter were rinsed with 16.7 kg of isopropyl acetate and the combined isopropyl acetate mixture was concentrated to 93 L under reduced pressure at 50 to 60 °C. The temperature was adjusted to 50 °C and seeded with 0.5 kg of (R)-amisulpride of Form A. The mixture was stirred at 50 °C for 90 min and slowly cooled to 15 °C over 6.5h, and the slurry was stirred at 15 °C for 2h and then isolated by filtration in a filter dryer. The mother liquors were recirculated to the reactor and filter dryer and the solid was washed with 33.5 kg of isopropyl acetate at 15 °C. The isolated solid was transferred to a drying oven and dried under high vacuum until dry (loss on drying <0.5%). This yielded 24.4 kg of (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A. Analysis by titration and analysis by mass balance indicated that the product was greater than about 99.8 wt% chemically pure. Chiral HPLC indicated that the product was greater than about 99.5 % enantiomerically pure. XRPD characterization is shown in FIG 6A and Table 8-1. [000243] Example 6: General Method of Making (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ using a tertiary amine salt: Scheme 2A [000244] Without being held to theory, it is believed that 4-amino-5-(ethylsulfonyl)-2- methoxybenzoic acid reacts with ethyl chloroformate to form an anhydride intermediate (structure shown below) after Step A in Scheme 2A. Anhydride Intermediate [000245] To a mixture of 4-amino-5-(ethanesulfonyl)-2-methoxybenzoic acid in acetone at -13 °C is added ethyl chloroformate, followed by triethylamine. The mixture is stirred at - 10 °C for 1h. Then (S)-1-ethylpyrrolidin-2-yl)methanamine bis D-tartrate salt, acetone, and triethylamine are added and the mixture is stirred for 1h at 0 °C. The mixture is then stirred at 20 °C for 16h and concentrated under reduced pressure. The residue is then diluted with isopropyl acetate and aqueous potassium carbonate. The aqueous layer is removed and the organic layer is washed with water twice. The water in the resulting organic layer is removed via azeotropic distillation to give an organic solution with the water content below 0.5 wt%. This organic solution is concentrated to approximately 35 wt%. This mixture is heated to 45 °C and seeded with (S)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A’, stirred at 45 °C for 30 min, then cooled to 15 °C over 180 min. The resulting slurry is stirred at 15 °C for 1h and filtered to give a solid. This solid is washed with cold isopropyl acetate and dried under vacuum to yield of (S)-4-amino-N-[(1- ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenz amide substantially of Form A’. [000246] Example 7: General Method of Making (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A using a tertiary amine salt: Scheme 2B [000247] Without being held to theory, it is believed that an anhydride intermediate (structure shown below) is formed after Step A in Scheme 2B. Anhydride Intermediate [000248] To a mixture of 4-amino-5-(ethanesulfonyl)-2-methoxybenzoic acid in acetone at -13±5 °C, is added ethyl chloroformate, followed by triethylamine. The mixture is stirred at -10 °C for 1h. Then (R)-(1-ethylpyrrolidin-2-yl)methanamine bis L-tartrate salt, acetone, and triethylamine are added and the mixture is stirred for 1h at 0 °C. The mixture is allowed to warm and stirred at 20 °C for 16h and concentrated under reduced pressure. The residue is then diluted with isopropyl acetate and aqueous potassium carbonate. The aqueous layer is removed and the organic layer was washed with water twice. The water in the resulting organic layer is removed via azeotropic distillation to give an organic solution with the water content below 0.5 wt%. The organic solution is concentrated to give a mixture of about 35 wt% of the organic solution. The mixture is heated to 45 °C and seeded with about 1 wt% (R)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2-methoxybenzamide of Form A, stirred at 45 °C for 30 min, then cooled to 15 °C over 180 min. The resulting slurry is stirred at 15 °C for 1h, filtered to give a solid. This solid is washed with cold (15 °C) isopropyl acetate and dried under vacuum to yield of (R)-4-amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially of Form A. [000249] Example 8: (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A using a tertiary amine salt; Scheme 2B Lab Scale : Scheme 2B [000250] First 25 g of 4-amino-5-(ethanesulfonyl)-2-methoxybenzoic acid and 132 g of acetone were placed into a 500 mL flask. The mixture was cooled to -13 °C and 12 g of ethylchloroformate was added. Then 12.5 g of triethylamine was added and the mixture was stirred at -10 °C for 1h. Then 44.2 g of (R)-(1-ethylpyrrolidin-2-yl)methanamine bis L- tartrate salt, 18 g of acetone, and 44 g of triethylamine were added and the mixture was stirred for 1h at 0 °C. The mixture was allowed to warm and stirred at 20 °C for 16h and concentrated under reduced pressure. The residue was then diluted with 125 g of isopropyl acetate and 119 g of 26 wt% aqueous potassium carbonate. The mixture was stirred and the phases separated. The aqueous layer was removed and the organic layer was washed with 50 g of water twice. The organic layer was then dried by azeotropic drying via a Dean-Stark trap until the water separation substantially stops. The organic solution was then concentrated to yield a mixture of 35 wt% of the organic solution. The mixture was heated to 45 °C and seeded with 0.5 g of (R)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A. The mixture was then stirred at 45 °C for 30 min, then cooled to 15 °C over 180 min. The resulting slurry was then stirred at 15 °C for 1h, filtered to give a solid. This solid is washed with 31 g of cooled (15 °C) isopropyl acetate and dried under vacuum to yield 23.9 g of (R)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide substantially of Form A. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11 (t, J=7.24 Hz, 3 H) 1.24 (t, J=7.43 Hz, 3 H) 1.55 - 1.77 (m, 3 H) 1.79 - 1.91 (m, 1 H) 2.13 - 2.27 (m, 2 H) 2.51 - 2.71 (m, 1 H) 2.73 - 2.94 (m, 1 H) 3.07 - 3.28 (m, 4 H) 3.68 (ddd, J=13.60, 7.34, 2.93 Hz, 1 H) 3.93 (s, 3 H) 5.55 (s, 2 H) 6.22 (s, 1 H) 8.05 (br d, J=4.70 Hz, 1 H) 8.51 (s, 1 H). 13 C NMR (101 MHz, CHLOROFORM-d) δ ppm 7.24, 14.24, 22.91, 28.44, 41.33, 47.92, 49.66, 53.65, 56.02, 62.24, 98.47, 112.27, 112.77, 136.33, 150.57, 162.42, 164.09. XRPD characterization is shown in FIG.9 and Table 8-2 in Example 9. [000251] Example 9: Characterization of Crystalline Amisulpride Enantiomers Made Substantially According to Example 4 and Example 5. This example presents characterization and other data on (S)-amisulpride of Form A’ made by the method described in Example 4, and on (R)-amisulpride of Form A made by the method described in Example 5. [000252] Table 6 summarizes various properties and data on Form A’ crystalline form of (S)-amisulpride prepared from Example 4 and Form A crystalline form of (R)-amisulpride prepared from Example 5 made substantially by the methods of, respectively, Examples 1-5. The FIG. references in Table 6 are to figures in the present application. TABLE 6 [000253] Prior to analysis, the Form A’ crystals of (S)-amisulpride and Form A crystals of (R)-amisulpride were separately pre-sieved through a 30 mesh screen. All material was passed through screen during this pre-sieving step including aggregates. [000254] Particle size distribution (PSD) measurements were measured by laser diffraction using a Malvern Instruments Mastersizer 3000 particle size analyzer instrument operated with the instrumentation and parameters described in Table 7. TABLE 7 PSD Instrument and Data Collection Parameters [000255] The samples were first sieved through a 30 mesh screen prior to suspension. Approximately 400 mg of the sieved sample was weighed into a 50 ml beaker and 40 ml of a 0.2% v/v Span 85 (Sorbitan trioleate) in hexanes dispersant solution (e.g., a dispersant solution prepared by dissolving 2 mL of Span 85 (Sorbitan trioleate) in 1L of hexanes) added. The overhead stirrer impeller was placed slightly above the bottom of the beaker (about 1 to 1.5 cm) and stirred at 500 rpm. After 1 minute, a disposable graduated transfer pipette was used to remove about 3 mL of the sample suspension from the center position of the beaker between impeller shaft and beaker side, and midway between top of vortex and beaker bottom. The entire contents of the pipette were added to the Malvern sample cell without inverting the pipette and the pipette rinsed twice with the circulating dispersant from the sample cell. The obscuration should be between 7% and 15%, if the obscuration was less than 7%, another aliquot of sample was added, making sure to transfer the entire aliquot taken up in the transfer pipette to the instrument, in order to avoid, e.g., potential artifacts due to settling of the suspension within the pipette. If the obscuration was greater than 15%, the instrument was drained and rinsed, and the measurement performed using a smaller sample suspension aliquot. After a sample cell with acceptable obscuration was obtained, the sample was circulated in the Mastersizer Hydro MV circulation system for two minutes and the sample dispersion measured. [000256] Polarized light microscopy (PLM) measurements were made using a Nikon Microphot polarizing light microscope. Samples were prepared in Isopar G with 3% Lecithin and observed using cross-polarized light and imaged using cross-polarized light with a quarter wave plate. [000257] Scanning electron microscope (SEM) measurements were conducted by Au sputter-coating samples using the Denton Desk II SEM coating system and the coated samples were imaged using the JEOL 6560 scanning electron microscope equipped with a tungsten filament at an accelerating voltage of 3 kV. The SEM showed small aggregates and fine particles coating the surfaces for both the (S)-amisulpride and (R)-amisulpride crystal batches. [000258] XRPD analysis was performed using a Rigaku MiniFlex II Desktop X-Ray diffractometer using Cu radiation. The tube voltage and amperage were set to 30 kV and 15 mA, respectively. The scattering slit was fixed at 1.25° and the receiving slit was fixed at 0.3 mm. Diffracted radiation was detected by a NaI scintillation detector. A θ-2θ continuous scan at 1.0°/min with a step size of 0.02-0.05° from 3 to 45° 2θ was used. Data were collected and analyzed using Jade 8.5.4. Each sample was prepared for analysis by placing it in a low background, round, 0.1 mm indent sample holder. [000259] Dynamic vapor sorption (DVS) isotherms were generated using a VTI SGA- 100 Symmetric Vapor Sorption Analyzer. Analysis included pre-analysis drying at 25°C with equilibrium criteria of 0.0000 wt% change in 5 minutes or a maximum of 180 minutes. Equilibrium criteria were the lesser of 0.01 wt% change in 5 minutes or 180 minutes at each RH step. Temperature was fixed at 25 °C and the relative humidity steps (25 to 95% to 25%) were made in 5% increments. Analysis was repeated for each sample in consecutive analyses (i.e., the sample was not removed from analyzer between analyses). [000260] Specific surface area (SSA) was measured using a Quantachrome Quadrasorb SI surface area analyzer performed at six-points over the relative pressure range of 0.1000 to 0.3500 in 0.0500 increments. Approximately 1.3 to 4.6 grams of sample were used per analysis and were weighed into bulb tubes. Samples in bulb tubes were degassed 2 hours at 40°C under vacuum using the Quantachrome FlowVac degasser prior to surface area analysis. Nitrogen gas was used as the gas for the surface area analyses. The surface area was found to be in the range 0.5-0.7 m 2 /g for the samples analyzed. [000261] Differential scanning calorimetry (DSC) analyses was performed using TA Instruments Q100 differential scanning calorimeter. Samples were analyzed in an aluminum pan with crimped lid. Each sample was heated under a 50 mL/min nitrogen purge at a heating rate of 10°C/min, from a starting temperature of 25°C up to a final temperature of 150°C. TABLE 8-1 XRPD Peak List of FIGS.6A and 6B TABLE 8-2 XRPD Peak List of FIG.9 TABLE 9A DVS Water Sorption Isotherm (R)-Amisulpride Data of FIG.7 TABLE 9B DVS Water Sorption Isotherm (S)-Amisulpride Data of FIG.7 [000262] Tables 9A and 9B presents the DVS water sorption for crystalline enantiomeric amisulpride of Form A and Form A’ shown in FIG.7A. As can be seen, both crystalline (S)-amisulpride Form A’ and crystalline (R)-amisulpride Form A are substantially non-hygroscopic, exhibiting a maximum mass change of less than 0.15%. [000263] Example 10. Alternative General Procedure: (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A’) [000264] Scheme 1A, Step 1: (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase): To a mixture of 4-amino-5- (ethylsulfonyl)-2-methoxybenzoic acid in acetone at 20±5 °C was added ethyl chloroformate. The mixture was cooled. 4-Methylmorpholine was added followed by (S)-(1-ethyl pyrrolidin-2-yl)methanamine. The mixture was warmed to about 20-25 °C, and after stirring for about 2 hours, the reaction mixture was concentrated and diluted with aqueous potassium carbonate and isopropyl acetate. The aqueous layer was removed and the organic layer was further diluted with isopropyl acetate. The organic layer was then washed with water twice. The isopropyl acetate solution (i.e., the organic layer) was dried via azeotropic distillation until the water content of the isopropyl acetate solution was below 0.3 wt%. The solution was concentrated to approximately 39 wt% followed by addition of methyl t-butyl ether. The temperature was adjusted to 45 °C. The solution was seeded at 45 °C with (S)-4-Amino- N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-metho xybenzamide in crystalline Form A’ and stirred at 45 °C for 45 minutes. The mixture was cooled to 15 °C and stirred for 1h. The suspension was then filtered and the product cake was washed with isopropyl acetate and methyl t-butyl ether. The wet-cake was dried under vacuum at 40 °C ± 5 °C to a constant weight to yield (S)-4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide (crude freebase). [000265] Scheme 1A, Step 2 (recrystallization): (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A’): Isopropyl acetate was added to (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase from Step 1) and the mixture was heated to about 55 °C to achieve dissolution. The resulting solution was then passed through a filter. The filtrate was concentrated by distillation followed by methyl t-butyl ether addition. The resulting solution was cooled to 50 °C and seeded with Form A’. The resulting slurry was stirred at 50 °C for 1 hour and then slowly cooled to 15 °C. The suspension was then filtered and the product cake was washed with isopropyl acetate and methyl t-butyl ether. The wet-cake was dried under vacuum at 35 °C ±5 °C to constant weight to yield (S)- 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl) -2-methoxybenzamide, substantially as Form A’. [000266] Example 11. Alternative Lab Scale Procedure: (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A’) [000267] Scheme 1A, Step 1: (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase): To a mixture of 55 g of 4-amino-5- (ethylsulfonyl)-2-methoxybenzoic acid in 292 g of acetone at 20 ±5 °C was added 24 g of ethyl chloroformate. The mixture was cooled to 0 °C and 27.5 g of 4-methylmorpholine was added at < 25 °C. The mixture was cooled to 10 °C and 28.6 g of (S)-(1-ethyl pyrrolidin-2- yl)methanamine was added. The reaction mixture was warmed to 20-25 °C and stirred for 2 hours. Subsequently, the reaction mixture was concentrated to approximately 110 mL. The mixture was diluted with 233 g of 29 wt% aqueous potassium carbonate and 165 g of isopropyl acetate. The mixture was stirred for 10 min and the aqueous layer was removed. 110g of DI water was added to the organic along with 138 g of isopropyl acetate. The mixture was stirred for 10 min and the aqueous layer was removed. 110 g of DI water was added to the organic layer, the mixture was stirred for 10 min, and the aqueous layer was removed. The isopropyl acetate solution (i.e., the organic layer) was dried via azeotropic distillation. The isopropyl acetate solution was further concentrated until the water content was below 0.3% by weight.27.5 grams of methyl t-butyl ether was added and the system was prepared for seeding. The solution was seeded at 45 °C with (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ and stirred at 45 °C for 45 min. The mixture was slowly cooled to 15 °C and stirred for 1 h. The suspension was then filtered and the product cake was washed with 44 g isopropyl acetate and 44 g of methyl t-butyl ether. The wet-cake was dried under vacuum at 40 °C ±5 °C to constant weight to yield approximately 62 g of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A’ (crude freebase). [000268] Scheme 1A, Step 2 (recrystallization): (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A’): Isopropyl acetate (242 g) was added to 60.5 g of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide and the mixture was heated to 55 °C to achieve dissolution. The resulting solution was then passed through a filter and rinsed with 34 g of isopropyl acetate. The filtrate was concentrated by distillation to about a 39 wt% solution and 24 g of methyl t-butyl ether were added. The resulting solution was adjusted to 50 °C and seeded with 0.45 g of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]- 5-(ethylsulfonyl)-2-methoxybenzamide substantially of Form A’, and the mixture was stirred for 1 h. The mixture was cooled to about 38 °C at a rate of about -0.1 °C/min. Then, the mixture was cooled to about 10-15 °C at a rate of about -0.5 °C/min. The resulting slurry was stirred at 10-15 °C for 1 h. Then, the resulting slurry was filtered and the product cake was washed with 61 g of isopropyl acetate and 25 g of methyl t-butyl ether. The wet-cake was dried under vacuum at 35 °C ±5 °C to constant weight to yield 54.6 g of (S)-4-Amino-N-[(1- ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenz amide substantially as Form A’. [000269] Example 12. Alternative General Procedure: (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A) [000270] Scheme 1A, Step 1: (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase): To a mixture of 4-amino-5- (ethylsulfonyl)-2-methoxybenzoic acid in acetone at 20±5 °C was added ethyl chloroformate. The mixture was cooled. 4-Methylmorpholine was added followed by (R)-(1-ethyl pyrrolidin-2-yl)methanamine. The mixture was warmed to about 20-25 °C and stirred for about 2 h, then the reaction mixture was concentrated and diluted with aqueous potassium carbonate and isopropyl acetate. The aqueous layer was removed and the organic layer was further diluted with isopropyl acetate and washed with water twice. The water was removed via azeotropic distillation (until the water content of the isopropyl acetate solution was below about 0.3 wt%). The solution was concentrated to approximately 39 wt% followed by addition of methyl t-butyl ether. The temperature was adjusted to 45 °C. The solution was seeded at 45 °C with about 1.5 wt% (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A and stirred at 45 °C for 45 minutes. The mixture was cooled to 15 °C and stirred for 1 h. The suspension was then filtered and the product cake was washed with isopropyl acetate and methyl t-butyl ether. The wet-cake was dried under vacuum at 40 °C ± 5 °C to constant weight to yield (R)-4-amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A (crude freebase). [000271] Scheme 1A, Step 2 (recrystallization): (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A): Isopropyl acetate was added to (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase) and the mixture was heated to 55 °C to achieve dissolution. The resulting solution was then passed through a filter. The filtrate was concentrated by distillation followed by methyl t-butyl ether addition. The resulting solution was cooled to 50 °C and seeded with Form A. The resulting slurry was stirred at 50 °C for 1 hour and then slowly cooled to 15 °C. The suspension was then filtered and the product cake was washed with isopropyl acetate and methyl t-butyl ether. The wet-cake was dried under vacuum at 35 °C ±5 °C to constant weight to yield (R)-4-amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially of Form A. [000272] Example 13. Alternative Lab Scale Procedure: (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A [000273] Scheme 1B, Step 1: (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase): To a mixture of 75 g of 4-amino-5- (ethylsulfonyl)-2-methoxybenzoic acid in 393 g of acetone at about 20 °C was added 33 g of ethyl chloroformate. The mixture was cooled to about 0 °C and 37.5 g of 4- methylmorpholine was added at less than 25 °C. The mixture was cooled to about 5 °C and 39 g of (R)-(1-ethyl pyrrolidin-2-yl)methanamine was added. The reaction mixture was warmed to about 20-25 °C and stirred for 2 hours. Subsequently, the reaction mixture was concentrated to approximately 150 mL. The mixture was diluted with 315 g of 29 wt% aqueous potassium carbonate and 225 g of isopropyl acetate. The mixture was stirred for 10 min and the aqueous layer was removed.150 g of DI water was added to the organic along with 188 g of isopropyl acetate. The mixture was stirred for 10 min and the aqueous layer was removed. 150 g of DI water was added to the organic layer and the mixture was stirred for 10 min. The aqueous layer was removed. The isopropyl acetate solution (i.e., the organic layer) was dried via azeotropic distillation. The isopropyl acetate solution was further concentrated until the water content was below 0.3% by weight. Methyl t-butyl ether (38 g) was added and the system was prepared for seeding. The solution was seeded at about 45 °C with (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A and stirred at about 45 °C for 45 min. The mixture was slowly cooled to about 15 °C and stirred for 1 h. The suspension was then filtered and the product cake was washed with 60 g isopropyl acetate and 60 g of methyl t-butyl ether. The wet-cake was dried under vacuum at about 40 °C to constant weight to yield approximately 85.5 g of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A (crude freebase). [000274] Scheme 1B, Step 2 (recrystallization): (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A): Isopropyl acetate (337g) was added to 83.6 g of (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide and the mixture was heated to about 55 °C to achieve dissolution. The resulting solution was then passed through a filter and rinsed with approximately 42 g of isopropyl acetate. The filtrate was concentrated by distillation to about 39 wt% solution and methyl t-butyl ether (33 g) was added. The resulting solution was adjusted to about 50 °C and seeded with (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially of Form A, and the mixture was stirred for 1 h. The resulting slurry was cooled to about 15 °C and stirred for 1 h at this temperature. The suspension was then filtered and the product cake was washed with isopropyl acetate (84 g) and 34 g methyl t-butyl ether (34 g). The wet-cake was dried under vacuum at about 35 °C to constant weight to yield 76.8 g of (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially as Form A. [000275] Example 14. Alternative Procedure: (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’; Scheme 1A (Scaled-Up) [000276] Scheme 1A, Step 1: (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide (crude freebase): 200 kg of 4-amino-5-ethylsulfonyl-2- methoxybenzoic acid and 1,060 kg of acetone were charged to a 750 gallon reactor. While mixing at 20 °C, 88 kg of ethyl chloroformate and 7 kg of acetone rinse was added to the mixture. After cooling to 0 °C, 100 kg of 4-methylmorpholine and a 7 kg acetone rinse was slowly charged to the reactor while maintaining the temperature below 25 °C. After cooling to 10 °C, 104 kg of (S)-(1-ethylpyrrolidin-2-yl)methanamine was added and the reaction was stirred at 22 °C for 8 h. The mixture was concentrated under reduced pressure to about 400 L. The temperature was then adjusted to 25 °C and a solution of 29 wt% potassium carbonate (848 kg) and 600 kg isopropyl acetate was added to the mixture. The phases were mixed, the stirring stopped, and the layers were allowed to separate. The aqueous layer was removed and 400 kg of water along with 500 kg of isopropyl acetate were added to the organic layer. The reaction mixture was mixed, the stirring stopped, and the layers allowed to separate. The aqueous layer was removed and 400 kg of water added to the organic layer. The reaction mixture was stirred for 10 min, the stirring stopped, and the layers were allowed to separate. The aqueous layer was removed and the reactor was equipped with a Dean-Stark apparatus. The solution was then stirred at reflux with the Dean Stark apparatus removing water. After the water content was reduced, the mixture was then concentrated to not less than 40 wt%. The water content was measured and found to be not more than 0.3% by Karl Fischer titration. The system was diluted with isopropyl acetate as required, then the temperature was adjusted to 55 °C and methyl t-butyl ether (100 kg) was added. The temperature was adjusted to 45 °C and seeded with 4 kg of (S)-amisulpride of Form A’. The mixture was stirred for 45 min at 45 °C and the resulting slurry was cooled to 15 °C over 2.5 h. The slurry was then stirred at 15 °C for 3 h and filtered. The isolated solid was washed with 160 kg of isopropyl acetate and 160 kg of methyl t-butyl ether at 15 °C. The solid was dried in a filter dryer at 40 °C to yield 230 kg of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ (crude freebase). [000277] Scheme 1A, Step 2 (recrystallization): (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide substantially (Form A’): 230 kg of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2-methoxybenzamide (crude freebase) and 922 kg of isopropyl acetate were charged to a 750 gal reactor. The mixture was heated to NLT 55 °C and filtered. The reactor and filter were rinsed with 115 kg of isopropyl acetate and the combined isopropyl acetate mixture was concentrated to approximately 600 L under reduced pressure. The temperature was adjusted to 55 °C and 95 kg of methyl t-butyl ether was added. The mixture was cooled to 50 °C and seeded with 3.5 kg of (S)-amisulpride of Form A’. The mixture was then stirred at 50 °C for 90 min. The mixture was cooled to about 38 °C at a rate of about -0.1 °C/min. Then, the mixture was cooled to about 10-15 °C at a rate of about -0.5 °C/min. The resulting slurry was stirred at 10- 15 °C for 1 h and then isolated by filtration in a filter dryer. The mother liquors were recirculated to the reactor and filter dryer and the solid was washed with 230 kg of isopropyl acetate and 94 kg of methyl t-butyl ether at 10-15 °C. The isolated solid was dried until loss on drying less than 0.5%. This yielded 207.5 kg of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide, Form A’. Analysis by titration and analysis by mass balance indicated that the product was greater than about 99.8 wt% chemically pure. Chiral HPLC indicated that the product was greater than about 99.5 % enantiomerically pure. XRPD characterization was consistent with Form A’. [000278] Example 15. Alternative Scaled-Up Procedure: (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A; Scheme 1B (Scaled- Up) [000279] (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide Form A can also be prepared according in a method analogous to the alternative procedure of Example 14, using (R)-(1-ethylpyrrolidin-2-yl)methanamine in place of (S)-(1-ethylpyrrolidin-2-yl)methanamine. [000280] Example 16. Formulations of Form A’ and Form A prepared by the procedure of Example 14 [000281] The particle size distribution (PSD) of crystalline products prepared by the foregoing examples were examined. FIG.10 presents a plot of the cooling profile comparison between the cooling profile X, using the recrystallization procedure of, e.g., Example 14, with cooling profile Y, using the recrystallization procedure of, e.g., Example 4 (Step 2). Recrystallization using the cooling methods of Example 14 (cooling method X) provided Form A’ having a smaller particle size distribution (e.g., D 50 and D 90 values) than Form A’ prepared by the methods of Example 4 (cooling method Y), as shown in the table below. [000282] PSD data was obtained using a Malvern Instruments Mastersizer particle size analyzer instrument. PSD Instrument and data collection parameters are provided below. PSD Instrument and Data Collection Parameters [000283] Crystalline (S)-amisulpride prepared using the method of Example 14, using cooling profile X, provided crystalline products having narrower and smaller particle size distributions (PSD). In the tablet manufacturing process, it was found that the granulation speed for crystalline amisulpride with larger PSD was significantly faster than that with smaller PSD. Spray was used to add a binder solution during the granulation process. However, faster granulation speeds increased the concentration of the polyvinyl alcohol binder solution used in the formulation. FIG.11 shows a plot of the cumulative frequency versus particle size. If crystalline material having higher PSD was used, then it was necessary to use higher concentration of polyvinyl alcohol solution in the granulation process. Using crystalline amisulpride with smaller PSD allowed for a lower concentration of the polyvinyl alcohol binder, which allowed for more control in the tablet manufacturing process compared to crystalline amisulpride having larger PSD. [000284] In addition, it was found that crystalline products having smaller PSD have higher hardness values, compared to tablets containing crystalline products having larger PSD. Controlled release tablets comprising (R)- and (S)-amisulpride can be prepared according to the processes provided in U.S. Patent No.11,160,758. [000285] The PSD of the crystalline amisulpride used in the various formulations are provided below. Amisulpride corresponding to “small PSD” can be prepared using the recrystallization and cooling methods of, e.g., Examples 14 and 15 (i.e., cooling profile X of FIG.10). Amisulpride corresponding to “large PSD” can be prepared using the recrystallization methods of Examples 1 and 3 (i.e., cooling profile Y of FIG.10). The PSDs were measured using a Mastersizer 2000 particle size analyzer instrument as described above. [000286] The details of the tablet compositions are provided below. q.s: quantum sufficiat *1 Partial saponification (saponification value: 85.0-89.0 mol %, viscosity: 4.6-6.0 mPa•s) *2 It is not included in the total because it was removed in the drying process. *3 Substitution Type: 2208, Viscosity: 100 mPa•s [000287] A summary of the physical properties of the core tablets is provided in FIG. 12. A plot of the correlation between tablet thickness and hardness of the 200 mg tablets is provided in FIG.13A. A plot of the correlation between tablet thickness and hardness of the 100 mg tablets is provided in FIG.13B. [000288] In addition, Impurity AA of the following formula may be observed in crystalline (S)-amisulpride Form A’ prepared from Example 2 or 4, and/or crystalline (R)- amisulpride Form A prepared from Example 5 or 8: Impurity AA 1H NMR (400 MHz, DMSO-d ) δ ppm 1.07 (t, J=7.24 Hz, 3H) 3.13 (q, J=7.30 Hz, 2H) 3.30 13 (s, 3H) 6.48 (s, 3H) 7.37 (br d, J=9.00 Hz, 2H) 8.10 (s, 1H); C NMR (100 MHz, DMSO-d ) δ ppm 7.57, 48.78, 56.43, 98.48, 111.00, 111.10, 135.70, 151.94, 162.63, 165.11. Impurity AA may also be observed in crystalline (S)-amisulpride Form A’ prepared from Example 10, 11, 14, 15, or 16, and/or crystalline (R)-amisulpride Form A prepared from Example 5, 8, 12, 13, or 15. It may be found as a degradant in any of the products prepared from Examples 2, 4, 5, and 8 after a certain period of time (e.g., over at least one month at room temperature or an elevated temperature, or 0.01 wt% to 0.03 wt% over 6 months at 40 °C, 75% relative humidity). Likewise, Impurity AA may be found as a degradant in any of the products prepared from Examples 10-16. In certain embodiments, Impurity AA may be present in about 0.001 wt% to about 0.3 wt% of any of the products prepared from Examples 2, 4, 5, and 8. In certain embodiments, Impurity AA may be present in about 0.01 wt% to about 0.2 wt% of any of the products prepared from Examples 2, 4, 5, and 8. In certain embodiments, Impurity AA may be present in about 0.001 wt% to about 0.3 wt% (e.g.0.01 wt% to about 0.2 wt%) of any of the products prepared from Examples 2, 4, 5, and 8 over at least two months at room temperature or an elevated temperature (e.g. at least three months, at least four months, at least five months, at least six months, at least twelve months). In certain embodiments, Impurity AA may be present in about 0.01 wt% to about 0.03 wt% of any of the products prepared from Examples 2, 4, 5, and 8 over at least six months at 40 °C with 75% relative humidity. In certain embodiments, the amount of Impurity AA is less than about 1.0 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A prepared from Examples 5 and 8. In certain embodiments, the amount of Impurity AA is less than about 1.0 wt% of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 4. In certain embodiments, the amount of Impurity AA is less than about 0.2 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2-methoxybenzamide of Form A prepared from Examples 5 and 8. In certain embodiments, the amount of Impurity AA is less than about 0.2 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 4. In certain embodiments, Impurity AA may be present in about 0.001 wt% to about 0.3 wt% of any of the products prepared from Examples 1-8 or 10-15. In certain embodiments, Impurity AA may be present in about 0.01 wt% to about 0.2 wt% of any of the products prepared from Examples 1-8 or 10-15. In certain embodiments, Impurity AA may be present in about 0.001 wt% to about 0.3 wt% (e.g.0.01 wt% to about 0.2 wt%) of any of the products prepared from Examples 1-8 or 10-15 over at least two months at room temperature or an elevated temperature (e.g. at least three months, at least four months, at least five months, at least six months, at least twelve months). In certain embodiments, Impurity AA may be present in about 0.01 wt% to about 0.03 wt% of any of the products prepared from Examples 1-8 or 10- 15 over at least six months at 40 °C with 75% relative humidity. In certain embodiments, the amount of Impurity AA is less than about 1.0 wt% of (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Examples 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity AA is less than about 1.0 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A’ prepared from Examples 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity AA is less than about 0.2 wt% of (R)-4-Amino-N-[(1- ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenz amide of Form A prepared from Examples 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity AA is less than about 0.2 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Examples 1, 2, 4, 6, 10, 11, or 14. [000289] In addition, Impurity BB-(i) of the following formula may be present in any of the products prepared from Example 5 or 8: Impurity BB-(i) Impurity BB-(i) may also be present in any of the products prepared from Examples 13, 5, 7, 8, 12, 13, or 15. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.04 - 1.09 (m, 3 H) 1.26 (t, J=7.04 Hz, 3 H) 1.74 (br d, J=8.61 Hz, 1 H) 1.82 - 1.92 (m, 1 H) 1.94 - 2.07 (m, 2 H) 3.05 - 3.17 (m, 4 H) 3.20 - 3.31 (m, 2 H) 3.40 (dt, J=14.87, 2.74 Hz, 1 H) 3.49 - 3.58 (m, 1 H) 3.77 - 3.81 (m, 3 H) 3.81 - 3.88 (m, 1 H) 6.45 (s, 1 H) 6.52 (s, 2 H) 8.07 (s, 1 H) 9.67 (br d, J=4.70 Hz, 1 H). 13 C NMR (100 MHz, CHLOROFORM-d) δ ppm 7.24, 9.44, 20.25, 25.39, 37.72, 49.56, 56.17, 61.87, 66.96, 73.54, 98.38, 111.80, 112.18, 136.13, 151.08, 162.65, 164.52. In certain embodiments, the amount of Impurity BB-(i) is less than about 1.0 wt% of (R)-4-Amino-N- [(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxy benzamide of Form A prepared from Example 5 or 8. In certain embodiments, the amount of Impurity BB is less than about 0.2 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A prepared from Example 5 or 8. In certain embodiments, the amount of Impurity BB-(i) is less than about 1.0 wt% of (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity BB is less than about 0.2 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. [000290] In addition, Impurity BB-(ii) of the following formula may be present in any of the products prepared from Example 2 or 4: Impurity BB-(ii) It may also be present in any of the products from Examples 1, 2, 4, 6, 10, 11, or 14. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (t, J=7.24 Hz, 3 H) 1.41 (t, J=7.04 Hz, 3 H) 1.86 (br dd, J=10.17, 2.35 Hz, 1 H) 2.04 (br dd, J=8.80, 4.50 Hz, 1 H) 2.15 - 2.24 (m, 1 H) 2.29 (br s, 1 H) 3.04 - 3.29 (m, 4 H) 3.38 - 3.51 (m, 2 H) 3.56 - 3.66 (m, 2 H) 3.87 (s, 3 H) 4.06 - 4.14 (m, 1 H) 5.83 (s, 2 H) 6.23 (s, 1 H) 8.41 (s, 1 H) 8.90 - 8.97 (m, 1 H). 13 C NMR (100 MHz, CHLOROFORM-d) δ ppm 7.22, 9.42, 20.28, 25.34, 37.69, 49.57, 56.14, 61.93, 67.04, 73.49, 98.34, 111.89, 112.34, 136.14, 150.95, 162.61, 164.45. In certain embodiments, the amount of Impurity BB-(ii) is less than about 1.0 wt% of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 2 or 4. In certain embodiments, the amount of Impurity BB-(ii) is less than about 0.2 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2- methoxybenzamide of Form A’ prepared from Example 2 or 4. In certain embodiments, the amount of Impurity BB-(ii) is less than about 1.0 wt% of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity BB-(ii) is less than about 0.2 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. [000291] In addition, Impurity CC-(i) of the following formula may be present in any of the products prepared from Examples 3, 5, 7, 8, 12, 13, or 15: Impurity CC-(i) In certain embodiments, the amount of Impurity CC-(i) is less than about 1.0 wt% of (R)-4- Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2 -methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity CC-(i) is less than about 0.2 wt% of (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity CC-(i) is less than about 0.15 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity CC-(i) is less than about 0.05 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. [000292] In addition, Impurity CC-(ii) of the following formula may be present in any of the products prepared from Example 1, 2, 4, 6, 10, 11, or 14. Impurity CC-(ii) In certain embodiments, the amount of Impurity CC-(ii) is less than about 1.0 wt% of (S)-4- Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2 -methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity CC-(ii) is less than about 0.2 wt% of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity CC-(ii) is less than about 0.15 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity CC-(ii) is less than about 0.05 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. [000293] In addition, Impurity DD-(i) of the following formula may be present in any of the products prepared from Example 3, 5, 7, 8, 12, 13, or 15: Impurity DD-(i) In certain embodiments, the amount of Impurity DD-(i) is less than about 1.0 wt% of (R)-4- Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2 -methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity DD-(i) is less than about 0.2 wt% of (R)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity DD-(i) is less than about 0.15 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity DD-(i) is less than about 0.05 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. [000294] In addition, Impurity DD-(ii) of the following formula may be present in any of the products prepared from Example 1, 2, 4, 6, 10, 11, and 14: Impurity DD-(ii) In certain embodiments, the amount of Impurity DD-(ii) is less than about 1.0 wt% of (S)-4- Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2 -methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity DD-(ii) is less than about 0.2 wt% of (S)-4-Amino-N-[(1-ethyl-2- pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity DD-(ii) is less than about 0.15 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity DD-(ii) is less than about 0.05 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo nyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. [000295] In addition, Impurity EE of the following formula may be present in any of the products prepared from the examples: Impurity EE In certain embodiments, the amount of Impurity EE is less than about 1.0 wt% of (R)-4- Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2 -methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity EE is less than about 0.2 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]- 5-(ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity EE is less than about 0.15 wt% of (R)- 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl) -2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity EE is less than about 0.05 wt% of (R)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]- 5-(ethylsulfonyl)-2-methoxybenzamide of Form A prepared from Example 3, 5, 7, 8, 12, 13, or 15. In certain embodiments, the amount of Impurity EE is less than about 1.0 wt% of (S)- 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl) -2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity EE is less than about 0.2 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5- (ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity EE is less than about 0.15 wt% of (S)-4- Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2 -methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. In certain embodiments, the amount of Impurity EE is less than about 0.05 wt% of (S)-4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]- 5-(ethylsulfonyl)-2-methoxybenzamide of Form A’ prepared from Example 1, 2, 4, 6, 10, 11, or 14. [000296] In addition, isopropyl acetate may be observed in any of the products of the examples. In certain embodiments, isopropyl acetate may be present in any of the products prepared from the examples in an amount that is less than about 5,000 ppm. In certain embodiments, isopropyl acetate may be present in any of the products prepared from the examples in an amount that is less than about 1,000 ppm. In certain embodiments, isopropyl acetate may be present in any of the products prepared from the examples in an amount that is less than about 500 ppm. In certain embodiments, isopropyl acetate may be present in any of the products prepared from the examples in an amount that is from about 200 ppm to about 300 ppm. In certain embodiments, isopropyl acetate may be present in any of the products prepared from the examples in an amount that is less than about 100 ppm. In certain embodiments, isopropyl acetate may be present in any of the products prepared from the examples in an amount that is less than about 50 ppm. [000297] In addition, methyl tert-butyl ether may be observed in any of the products prepared from the examples. In certain embodiments, methyl tert-butyl ether may be present in any of the products prepared from the examples in an amount that is less than about 5,000 ppm. In certain embodiments, methyl tert-butyl ether may be present in any of the products prepared from the examples in an amount that is less than about 1,000 ppm. In certain embodiments, methyl tert-butyl ether may be present in any of the products prepared from the examples in an amount that is less than about 500 ppm. In certain embodiments, methyl tert- butyl ether may be present in any of the products prepared from the examples in an amount that is less than about 200 ppm. In certain embodiments, methyl tert-butyl ether may be present in any of the products prepared from the examples in an amount that is from about 75 ppm to about 125 ppm. In certain embodiments, methyl tert-butyl ether may be present in any of the products prepared from the examples in an amount that is less than about 100 ppm. In certain embodiments, methyl tert-butyl ether may be present in any of the products prepared from the examples in an amount that is less than about 50 ppm. In certain embodiments, methyl tert-butyl ether may be present in any of the products prepared from the examples in an amount that is less than about 10 ppm. [000298] Additional Embodiments [000299] Embodiment 1. A method of preparing an enantiomerically pure crystalline form of (R)-(+)-amisulpride comprising the steps of: (a) coupling, in the presence of a tertiary amine and an acid activating reagent, 4- amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and (R)-(1-ethylpyrrolidin-2- yl) methanamine to form a reaction mixture; and (b) isolating from the reaction mixture of step (a), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuKα radiation, at least approximate peak positions (2θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°; (c) wherein step (b) does not comprise formation of a solvate of (R)-(+)- amisulpride. [000300] Embodiment 2. The method of embodiment 1, wherein the coupling of step (a) comprises the steps of: (a1) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with the tertiary amine and the acid activating reagent to form a first reaction mixture; and (a2) adding (R)-(1-ethylpyrrolidin-2-yl)methanamine to the first reaction mixture. [000301] Embodiment 3. A method of preparing an enantiomerically pure crystalline form of (S)-(-)-amisulpride comprising the steps of: (a) coupling, in the presence of a tertiary amine and an acid activating reagent, 4- amino-5-(ethylsulfonyl)-2-methoxybenzoic acid and (S)-(1-ethylpyrrolidin-2- yl) methanamine to form a reaction mixture; and (b) isolating from the reaction mixture of step (a), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°; (c) wherein the step (b) does not comprise formation of a solvate of (S)-(-)- amisulpride. [000302] Embodiment 4. The method of embodiment 3, wherein the coupling of step (a) comprises the steps of: (a1) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with the tertiary amine and the acid activating reagent to form a first reaction mixture; and (a2) adding (S)-(1-ethylpyrrolidin-2-yl)methanamine to the first reaction mixture. [000303] Embodiment 5. The method of any one of embodiments 1-4, wherein step (b) comprises step (b1): concentrating the reaction mixture of step (a) to give a mixture of step (b1). [000304] Embodiment 6. The method of embodiment 5, further comprising step (b2): treating the mixture of step (b1) with a base and the isolation reagent to form a step (b2) mixture. [000305] Embodiment 7. The method of embodiment 6, wherein the base is an aqueous solution of an inorganic base. [000306] Embodiment 8. The method of embodiment 7, wherein the base is an aqueous solution of potassium carbonate. [000307] Embodiment 9. The method of any one of embodiments 6-8, further comprising step (b3): separating the step (b2) mixture to obtain an organic phase. [000308] Embodiment 10. The method of embodiment 9, further comprising step (b4): concentrating the organic phase to a first concentrated solution having less than about 2 wt% water. [000309] Embodiment 11. The method of embodiment 10, wherein the first concentrated solution has about 1.0 wt% to about 0.001 wt% water. [000310] Embodiment 12. The method of embodiment 11, wherein the first concentrated solution has about 1.0 wt% to about 0.01 wt% water. [000311] Embodiment 13. The method of embodiment 12, wherein the first concentrated solution has about 0.5 wt% to about 0.01 wt% water. [000312] Embodiment 14. The method of any one of embodiments 10-13, further comprising step (b5): concentrating the first concentrated solution to a second concentrated solution, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 15 wt% to about 65 wt% of the second concentrated solution. [000313] Embodiment 15. The method of embodiment 14, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 35 wt% to about 40 wt% of the second concentrated solution. [000314] Embodiment 16. The method of embodiment 14, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 33 wt% to about 38 wt% of the second concentrated solution. [000315] Embodiment 17. The method of embodiment 14, wherein the second concentrated solution has a total weight of (R)-(+)-amisulpride or (S)-(-)-amisulpride that is about 35 wt% of the second concentrated solution. [000316] Embodiment 18. The method of any one of embodiments 14-17, further comprising adding S5, wherein S5 is an ether solvent, to the second concentrated solution. [000317] Embodiment 19. The method of embodiment 18, wherein S5 is methyl tert-butyl ether. [000318] Embodiment 20. The method of any one of embodiments 14-19, further comprising step (b6): adding a seed amount of a crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to the second concentrated solution to form a seeded mixture. [000319] Embodiment 21. The method of any one of embodiments 14-19, further comprising step (b6): adding a seed amount of a crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to the second concentrated solution to form a seeded mixture. [000320] Embodiment 22. The method of embodiment 20 or 21, wherein the seed amount has a total weight that is about 0.001 wt% to about 15 wt% of the second concentrated solution. [000321] Embodiment 23. The method of embodiment 20 or 21, wherein the seed amount has a total weight that is about 0.1 wt% to about 10 wt% of the second concentrated solution. [000322] Embodiment 24. The method of embodiment 20 or 21, wherein the seed amount has a total weight that is about 0.1 wt% to about 5 wt% of the expected yield of the (R)-(+)-amisulpride or (S)-(-)-amisulpride present in the second concentrated solution. [000323] Embodiment 25. The method of embodiment 20 or 21, wherein the seed amount has a total weight that is about 0.1 wt% to about 2.0 wt% of the expected yield of the (R)-(+)-amisulpride or (S)-(-)-amisulpride present in the second concentrated solution. [000324] Embodiment 26. The method of embodiment 20 or 21, wherein the seed amount has a total weight that is about 0.4 wt%, about 1.4 wt%, or about 2.0 wt% of the expected yield of the (R)-(+)-amisulpride or (S)-(-)-amisulpride present in the second concentrated solution. [000325] Embodiment 27. The method of embodiment 20 or 21, wherein the seed amount has a total weight that is about 0.75 wt% of the expected yield of the (R)-(+)- amisulpride or (S)-(-)-amisulpride present in the second concentrated solution. [000326] Embodiment 28. The method of any one of embodiments 20-27, further comprising step (b7): filtering the seeded mixture of step (b6) to obtain a product solid. [000327] Embodiment 29. The method of embodiment 28, further comprising step (b8): drying the product solid to obtain a crude product. [000328] Embodiment 30. The method of embodiment 29, further comprising step (b9): recrystallizing the crude product in the presence of the isolation reagent. [000329] Embodiment 31. The method of embodiment 30, wherein the recrystallizing comprises (i) dissolving the crude product with the isolation reagent to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution, and (iii) adding a seed amount of a crystalline form of (R)-(+)-amisulpride or a crystalline form of (S)-(-)-amisulpride. [000330] Embodiment 32. The method of embodiment 30, wherein the recrystallizing comprises (i) heating the crude product in the presence of an isolation reagent at a first elevated temperature to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution to form a concentrated recrystallization solution; (iii) adding S5, wherein S5 is a solvent, to the concentrated recrystallization solution; (iv) adding a seed amount of a crystalline form of (R)-(+)-amisulpride or a crystalline form of (S)-(-)-amisulpride to the concentrated recrystallization solution of step (iii) to form a seeded recrystallization solution; and (v) cooling the seeded recrystallization solution. [000331] Embodiment 33. The method of embodiment 32, wherein the first elevated temperature is from about 50 °C to about 55 °C. [000332] Embodiment 34. The method of embodiment 32 or 33, wherein the cooling comprises cooling to a first reduced temperature over a first period of time, and then cooling to a second reduced temperature over a second period of time. [000333] Embodiment 35. The method of embodiment 34, wherein the first reduced temperature is from about 38 °C to about 42 °C. [000334] Embodiment 36. The method of embodiment 34 or 35, wherein the first period of time is about 120 min. [000335] Embodiment 37. The method of any one of embodiments 34-36, wherein the second reduced temperature is from about 10 °C to about 15 °C. [000336] Embodiment 38. The method of any one of embodiments 34-37, wherein the second period of time is about 60 min. [000337] Embodiment 39. The method of any one of embodiments 34-38, wherein the cooling over the first period of time is performed at a first cooling rate. [000338] Embodiment 40. The method of any one of embodiments 34-39, wherein the cooling over the second period of time is performed at a second cooling rate. [000339] Embodiment 41. The method of embodiment 40, wherein the second cooling rate is greater than the first cooling rate. [000340] Embodiment 42. The method of embodiment 39, wherein the first cooling rate is about 0.1 °C/min. [000341] Embodiment 43. The method of embodiment 40, wherein the second cooling rate is about 0.5 °C/min. [000342] Embodiment 44. A method of preparing an enantiomerically pure crystalline form of (R)-(+)-amisulpride comprising the steps of: (a) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with a tertiary amine and an acid activating reagent to form a reaction mixture; (b) adding a (R)-(1-ethylpyrrolidin-2-yl)methanamine salt to the reaction mixture to form a mixture of step (b); and (c) isolating from the mixture of step (b), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. [000343] Embodiment 45. The method of embodiment 44, wherein step (c) does not comprise formation of a solvate of (R)-(+)-amisulpride. [000344] Embodiment 46. The method of embodiment 44 or 45, wherein the isolating of step (c) comprises (d1) adding the isolation reagent to the mixture of step (b), followed by an aqueous base solution to form a mixture of step (d1), (d2) separating the mixture of step (d1) to obtain an organic phase; (d3) concentrating the organic phase of step (d2) to produce a product solution having about 5.0 wt% to about 0.001 wt% water; (d4) adding to the product solution a seed amount of a crystalline form of (R)-(+)- amisulpride, characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to form a seeded mixture; (d5) filtering the seeded mixture of step (d4) to obtain a product solid; and (d6) drying the product solid of step (d5) to produce the enantiomerically pure crystalline form of (R)-(+)-amisulpride. [000345] Embodiment 47. The method of any one of embodiments 44-46, further comprising recrystallizing the enantiomerically pure crystalline form of (R)-(+)-amisulpride of step (d6). [000346] Embodiment 48. The method of embodiment 47, wherein the recrystallizing comprises (i) heating the enantiomerically pure crystalline form of (R)-(+)- amisulpride of step (d6) in the presence of an isolation reagent at a first elevated temperature to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution to form a concentrated recrystallization solution; (iii) adding S5, wherein S5 is a solvent, to the concentrated recrystallization solution; (iv) adding a seed amount of a crystalline form of (R)-(+)-amisulpride to the concentrated recrystallization solution of step (iii) to form a seeded recrystallization solution; and (v) cooling the seeded recrystallization solution. [000347] Embodiment 49. The method of embodiment 48, wherein the first elevated temperature is from about 50 °C to about 55 °C. [000348] Embodiment 50. The method of embodiment 48 or 49, wherein the cooling comprises cooling to a first reduced temperature over a first period of time, and then cooling to a second reduced temperature over a second period of time. [000349] Embodiment 51. The method of embodiment 50, wherein the first reduced temperature is from about 38 °C to about 42 °C. [000350] Embodiment 52. The method of embodiment 50 or 51, wherein the first period of time is about 120 min. [000351] Embodiment 53. The method of any one of embodiments 50-52, wherein the second reduced temperature is from about 10 °C to about 15 °C. [000352] Embodiment 54. The method of any one of embodiments 50-53, wherein the second period of time is about 60 min. [000353] Embodiment 55. The method of any one of embodiments 48-54, wherein S5 is an ether solvent. [000354] Embodiment 56. The method of any one of embodiments 48-54, wherein S5 is methyl tert-butyl ether. [000355] Embodiment 57. The method of any one of embodiments 48-56, wherein the method further comprises isolating and drying the crystalline form of (R)-(+)- amisulpride. [000356] Embodiment 58. A method of preparing an enantiomerically pure crystalline form of (S)-(-)-amisulpride comprising the steps of: (a) reacting 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid with a tertiary amine and an acid activating reagent to form a reaction mixture; (b) adding a (S)-(1-ethylpyrrolidin-2-yl)methanamine salt to the reaction mixture of step (a) to form a mixture of step (b); and (c) isolating from the mixture of step (b), in the presence of an isolation reagent, an enantiomerically pure crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at least at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. [000357] Embodiment 59. The method of embodiment 58, wherein step (c) does not comprise formation of a solvate of (S)-(-)-amisulpride. [000358] Embodiment 60. The method of embodiment 58 or 59, wherein the isolating of step (c) comprises: (d1) adding the isolation reagent to the mixture of step (b), followed by an aqueous base solution to form a mixture of step (d1); (d2) separating the mixture of step (d1) to obtain an organic phase; (d3) concentrating the organic phase of step (d2) to produce a product solution with about 5.0 wt% to about 0.01 wt% water; (d4) adding to the product solution of step (d3) with a seed amount of a crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ), at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2° to form a seeded mixture; (d5) filtering the seeded mixture of step (d4) to obtain a product solid; and (d6) drying the product solid of step (d5) to produce the enantiomerically pure crystalline form of (S)-(-)-amisulpride. [000359] Embodiment 61. The method of any one of embodiments 58-60, further comprising recrystallizing the enantiomerically pure crystalline form of (S)-(-)-amisulpride of step (d6). [000360] Embodiment 62. The method of embodiment 61, wherein the recrystallizing comprises (i) heating the enantiomerically pure crystalline form of (S)-(-)- amisulpride of step (d6) in the presence of an isolation reagent at a first elevated temperature to form a recrystallization solution, (ii) filtering and concentrating the recrystallization solution to form a concentrated recrystallization solution; (iii) adding S5, wherein S5 is a solvent, to the concentrated recrystallization solution; (iv) adding a seed amount of a crystalline form of (S)-(-)-amisulpride to the concentrated recrystallization solution of step (iii) to form a seeded recrystallization solution; and (v) cooling the seeded recrystallization solution. [000361] Embodiment 63. The method of embodiment 61 or 62, wherein the first elevated temperature is from about 50 °C to about 55 °C. [000362] Embodiment 64. The method of embodiment 61 or 62, wherein the cooling comprises cooling to a first reduced temperature over a first period of time, and then cooling to a second reduced temperature over a second period of time. [000363] Embodiment 65. The method of embodiment 64, wherein the first reduced temperature is from about 38 °C to about 42 °C. [000364] Embodiment 66. The method of embodiment 64 or 65, wherein the first period of time is about 120 min. [000365] Embodiment 67. The method of any one of embodiments 64-66, wherein the second reduced temperature is from about 10 °C to about 15 °C. [000366] Embodiment 68. The method of any one of embodiments 64-67, wherein the second period of time is about 60 min. [000367] Embodiment 69. The method of any one of embodiments 62-68, wherein S5 is an ether solvent. [000368] Embodiment 70. The method of any one of embodiments 62-68, wherein S5 is methyl tert-butyl ether. [000369] Embodiment 71. The method of embodiment 46 or 60, wherein the product solution of step (d3) has about 0.001 wt% to about 0.5 wt% water. [000370] Embodiment 72. The method of any one of embodiments 1-71, wherein the tertiary amine is of the formula wherein: (i) R 1 , R 2 and R 3 are each independently C 1-6 alkyl , C 3-6 cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycloalkyl, or 5-10 membered monocyclic heteroaryl; or (ii) R 1 is C 1-6 alkyl , C 3-6 cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycloalkyl, or 5-10 membered monocyclic heteroaryl, and R 2 and R 3 together with the N atom to which they are attached form a 3-10 membered monocyclic or bicyclic heterocycloalkyl or a 5-10 membered monocyclic heteroaryl. [000371] Embodiment 73. The method of embodiment 72, wherein R 2 and R 3 together with the N atom to which they are attached form a 3-10 membered monocyclic or bicyclic heterocycloalkyl or a 5-10 membered monocyclic heteroaryl. [000372] Embodiment 74. The method of any one of embodiments 1-73, wherein the tertiary amine is triethyl amine. [000373] Embodiment 75. The method of any one of embodiments 1-73, wherein the tertiary amine is 4-methylmorpholine. [000374] Embodiment 76. The method of any one of embodiments 1-75, wherein the acid activating reagent is of the formula wherein R x is halogen and R y is C 1-5 alkyl. [000375] Embodiment 77. The method of any one of embodiments 1-75, wherein the acid activating reagent is ethyl chloroformate. [000376] Embodiment 78. The method of any one of embodiments 1-77, wherein the isolation reagent is of the formula 4 5 wherein R is C 1-6 alkyl; and R is C 1-5 alkyl or C 1-5 alkoxide. [000377] Embodiment 79. A method of preparing an enantiomerically pure crystalline form of (R)-(+)-amisulpride comprising the steps of: (a) heating (R)-(+)-amisulpride in the presence of an isolation reagent to a first elevated temperature to form a crystallization mixture; (b) adding a seed amount of Form A of (R)-(+)-amisulpride to the crystallization mixture to form a seeded mixture; (c) cooling the seeded mixture to a first reduced temperature over a first period of time; (d) cooling the seeded mixture from step (c) to a second reduced temperature over a second period of time; and (e) filtering the seeded mixture from step (d) to provide an enantiomerically pure crystalline form of (R)-(+)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. [000378] Embodiment 80. A method of preparing an enantiomerically pure crystalline form of (S)-(-)-amisulpride comprising the steps of: (a) heating (S)-(-)-amisulpride in the presence of an isolation reagent to a first elevated temperature to form a crystallization mixture; (b) adding a seed amount of Form A’ of (S)-(-)-amisulpride to the crystallization mixture to form a seeded mixture; (c) cooling the seeded mixture to a first reduced temperature over a first period of time; (d) cooling the seeded mixture from step (c) to a second reduced temperature over a second period of time; and (e) filtering the seeded mixture from step (d) to provide an enantiomerically pure crystalline form of (S)-(-)-amisulpride characterized by an x-ray powder diffraction pattern (XRPD) comprising, when measured using CuK α radiation, at least approximate peak positions (2 θ) at 7.0±0.2° and 9.7±0.2°, and further peaks at 15.4±0.2° and/or 19.4±0.2°. [000379] Embodiment 81. The method of embodiment 79 or 80, wherein the first elevated temperature is from about 50 °C to about 55 °C. [000380] Embodiment 82. The method of any one of embodiments 79-81, wherein the first reduced temperature is from about 38 °C to about 42 °C. [000381] Embodiment 83. The method of any one of embodiments 79-82, wherein the first period of time is about 120 min. [000382] Embodiment 84. The method of any one of embodiments 79-83, wherein the second reduced temperature is from about 10 °C to about 15 °C. [000383] Embodiment 85. The method of any one of embodiments 79-84, wherein the second period of time is about 60 min. [000384] Embodiment 86. The method of any one of embodiments 79-85, wherein the heating of step (a) is further performed in the presence of S5, wherein S5 is an ether solvent. [000385] Embodiment 87. The method of embodiment 86, wherein S5 is methyl tert-butyl ether. [000386] Embodiment 88. The method of any one of embodiments 1-87, wherein the isolation reagent is of the formula 4 5 , wherein R is C 3-6 alkyl; and R is C 1-5 alkyl. [000387] Embodiment 89. The method of any one of embodiments 1-88, wherein the isolation reagent is not ethyl acetate. [000388] Embodiment 90. The method of any one of embodiments 1-88, wherein the isolation reagent is isopropyl acetate. [000389] Embodiment 91. The method of any one of embodiments 1-87, wherein the isolation reagent is of the formula , wherein R 4 is C 1-6 alkyl; and R 5 is C 1-5 alkoxide. [000390] Embodiment 92. The method of any one of embodiments 1-87, wherein the isolation reagent is diethyl carbonate or dimethyl carbonate. [000391] Embodiment 93. The method of any one of embodiments 1-87, wherein the isolation reagent is of the formula R 6 COR 7 , where each of R 6 and R 7 is independently C 1-5 alkyl. [000392] Embodiment 94. The method of any one of embodiments 44-57, 71-78, and 88-93, wherein the (R)-(1-ethylpyrrolidin-2-yl)methanamine salt is a bis tartrate salt of (R)-(1-ethylpyrrolidin-2-yl)methanamine. [000393] Embodiment 95. The method of any one of embodiments 44-57, 71-78, and 88-93, wherein the (R)-(1-ethylpyrrolidin-2-yl)methanamine salt is a bis L-tartrate salt of (R)-(1-ethylpyrrolidin-2-yl)methanamine. [000394] Embodiment 96. The method of any one of embodiments 58-78 and 88- 93, wherein the (S)-(1-ethylpyrrolidin-2-yl)methanamine salt is a bis tartrate salt of (S)-(1- ethylpyrrolidin-2-yl)methanamine. [000395] Embodiment 97. The method of any one embodiments 58-78 and 88-93, wherein the (S)-(1-ethylpyrrolidin-2-yl)methanamine salt is a bis D-tartrate salt of (S)-(1- ethylpyrrolidin-2-yl)methanamine. [000396] Embodiment 98. The method of any one of embodiments 1-87, further comprising recrystallizing the enantiomerically pure crystalline form of (R)-(+)-amisulpride or the enantiomerically pure crystalline form of (S)-(-)-amisulpride in the presence of isopropyl acetate. [000397] Embodiment 99. The method of any one of embodiments 20, 22-43, 46- 57, 71-78, 79, 81-95, and 98, wherein the seed amount of a crystalline form of (R)-(+)- amisulpride has a greater than about 95% chemical purity and a greater than about 95% enantiomeric purity. [000398] Embodiment 100. The method of any one of embodiments 20, 22-43, 46- 57, 71-78, 79, 81-95, and 98, wherein the seed amount of a crystalline form of (R)-(+)- amisulpride has a greater than about 98% chemical purity and a greater than about 98% enantiomeric purity. [000399] Embodiment 101. The method of any one of embodiments 21-43, 60-78, 80-93, and 96-98, wherein the seed amount of a crystalline form of (S)-(-)-amisulpride has a greater than about 95% chemical purity and a greater than about 95% enantiomeric purity. [000400] Embodiment 102. The method of any one of embodiments 21-43, 60-78, 80-93, and 96-98, wherein the seed amount of a crystalline form of (S)-(-)-amisulpride has a greater than about 98% chemical purity and a greater than about 98% enantiomeric purity. [000401] Embodiment 103. The method of any one of embodiments 1, 2, 5-57, 71- 79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)- amisulpride has a greater than about 95% chemical purity. [000402] Embodiment 104. The method of any one of embodiments 1, 2, 5-57, 71- 79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)- amisulpride has a greater than about 98% chemical purity. [000403] Embodiment 105. The method of any one of embodiments 1, 2, 5-57, 71- 79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)- amisulpride has a greater than about 99% chemical purity. [000404] Embodiment 106. The method of any one of embodiments 1, 2, 5-57, 71- 79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)- amisulpride has a greater than about 95% enantiomeric purity. [000405] Embodiment 107. The method of any one of embodiments 1, 2, 5-57, 71- 79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)- amisulpride has a greater than about 98% enantiomeric purity. [000406] Embodiment 108. The method of any one of embodiments 1, 2, 5-57, 71- 79, 81-95, and 98-100, wherein the enantiomerically pure crystalline form of (R)-(+)- amisulpride has a greater than about 99% enantiomeric purity. [000407] Embodiment 109. The method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)- amisulpride has a greater than about 95% chemical purity. [000408] Embodiment 110. The method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)- amisulpride has a greater than about 98% chemical purity. [000409] Embodiment 111. The method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)- amisulpride has a greater than about 99% chemical purity. [000410] Embodiment 112. The method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)- amisulpride has a greater than about 95% enantiomeric purity. [000411] Embodiment 113. The method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)- amisulpride has a greater than about 98% enantiomeric purity. [000412] Embodiment 114. The method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, and 102, wherein the enantiomerically pure crystalline form of (S)-(-)- amisulpride has a greater than about 99% enantiomeric purity. [000413] Embodiment 115. An enantiomerically pure crystalline form of (R)-(+)- amisulpride, wherein the crystalline form of (R)-(+)-amisulpride has a particle size distribution D 10 value of about 2 to about 10 µm; a particle size distribution D 50 value of about 15 to about 30 µm; and a particle size distribution D 90 value of about 75 to about 100 µm, as measured by a laser diffraction particle size analyzer. [000414] Embodiment 116. An enantiomerically pure crystalline form of (S)-(-)- amisulpride, wherein the crystalline form of (S)-(-)-amisulpride has a particle size distribution D 10 value of about 2 to about 10 µm; a particle size distribution D 50 value of about 15 to about 30 µm; and a particle size distribution D 90 value of about 75 to about 100 µm, as measured by a laser diffraction particle size analyzer. [000415] Embodiment 117. An enantiomerically pure crystalline form of (R)-(+)- amisulpride or (S)-(-)-amisulpride prepared by the method of any one of embodiments 1-114, comprising less than about 1.0 wt% of a compound of the following formula: [000416] Embodiment 118. An enantiomerically pure crystalline form of (R)-(+)- amisulpride or (S)-(-)-amisulpride prepared by the method of any one of embodiments 1-114, comprising less than about 0.2 wt% of a compound of the following formula: [000417] Embodiment 119. An enantiomerically pure crystalline form of (R)-(+)- amisulpride or (S)-(-)-amisulpride prepared by the method of any one of embodiments 1-114, comprising less than about 1.0 wt% of a compound of the following formula: [000418] Embodiment 120. An enantiomerically pure crystalline form of (R)-(+)- amisulpride or (S)-(-)-amisulpride prepared by the method of any one of embodiments 1-114, comprising less than about 0.2 wt% of a compound of the following formula: [000419] Embodiment 121. An enantiomerically pure crystalline form of (R)-(+)- amisulpride or (S)-(-)-amisulpride prepared by the method of any one of embodiments 1-114, comprising less than about 1.0 wt% of a compound of the following formula: [000420] Embodiment 122. An enantiomerically pure crystalline form of (R)-(+)- amisulpride or (S)-(-)-amisulpride prepared by the method of any one of embodiments 1-114, comprising less than about 0.2 wt% of a compound of the following formula: [000421] Embodiment 123. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, comprising less than about 1.0 wt% of a compound of the following formula: [000422] Embodiment 124. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, comprises less than about 0.2 wt% of a compound of the following formula: [000423] Embodiment 125. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, comprising less than about 1.0 wt% of a compound of the following formula: [000424] Embodiment 126. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, comprises less than about 0.2 wt% of a compound of the following formula: [000425] Embodiment 127. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, comprising less than about 1.0 wt% of a compound of the following formula: [000426] Embodiment 128. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, comprises less than about 0.2 wt% of a compound of the following formula: [000427] Embodiment 129. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 1.0 wt% of a compound of the following formula: [000428] Embodiment 130. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 0.2 wt% of a compound of the following formula: [000429] Embodiment 131. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 1.0 wt% of a compound of the following formula: [000430] Embodiment 132. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 0.2 wt% of a compound of the following formula: [000431] Embodiment 133. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 1.0 wt% of a compound of the following formula: [000432] Embodiment 134. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, comprising less than about 0.2 wt% of a compound of the following formula: [000433] Embodiment 135. A pharmaceutical composition comprising the enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108, and a pharmaceutically acceptable carrier. [000434] Embodiment 136. A pharmaceutical composition comprising the enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, and a pharmaceutically acceptable carrier. [000435] Embodiment 137. A pharmaceutical composition comprising: (i) the enantiomerically pure crystalline form of (R)-(+)-amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98-100, and 103-108; (ii) the enantiomerically pure crystalline form of (S)-(-)-amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114; and (iii) a pharmaceutically acceptable carrier, wherein the crystalline form of (R)-(+)-amisulpride and the crystalline form of (S)-(-)-amisulpride are in a ratio of about 65:35 to about 88:12 by weight of free base. [000436] Embodiment 138. The pharmaceutical composition of embodiment 137, wherein the crystalline form of (R)-(+)-amisulpride and the crystalline form of (S)-(-)- amisulpride are in a ratio of about 75:25 to about 88:12 by weight of free base. [000437] Embodiment 139. The pharmaceutical composition of embodiment 137 or 138, wherein the crystalline form of (R)-(+)-amisulpride and the crystalline form of (S)-(-)- amisulpride are in a ratio of about 80:20 to about 88:12 by weight of free base. [000438] Embodiment 140. The pharmaceutical composition of any one of embodiments 137-139, wherein the crystalline form of (R)-(+)-amisulpride and the crystalline form of (S)-(-)-amisulpride are in a ratio of about 85:15 by weight of free base. [000439] Embodiment 141. The pharmaceutical composition of any one of embodiments 135-140, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000440] Embodiment 142. The pharmaceutical composition of any one of embodiments 135-140, comprising less than about 0.2 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000441] Embodiment 143. The pharmaceutical composition of any one of embodiments 135-142, comprising less than about 1.0 wt% of a compound of the following formula: , wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000442] Embodiment 144. The pharmaceutical composition of any one of embodiments 135-142, comprising less than about 0.2 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000443] Embodiment 145. The pharmaceutical composition of any one of embodiments 135-144, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000444] Embodiment 146. The pharmaceutical composition of any one of embodiments 135-144, comprising less than about 0.2 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000445] Embodiment 147. The pharmaceutical composition of any one of embodiments 135-146, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000446] Embodiment 148. The pharmaceutical composition of any one of embodiments 135-147, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000447] Embodiment 149. The pharmaceutical composition of any one of embodiments 135-148, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000448] Embodiment 150. The pharmaceutical composition of any one of embodiments 135-149, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000449] Embodiment 151. The pharmaceutical composition of any one of embodiments 135-150, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000450] Embodiment 152. The pharmaceutical composition of any one of embodiments 135-151, comprising less than about 1.0 wt% of a compound of the following formula: wherein the recited wt% is calculated relative to the total amount of (R)-(+)-amisulpride and (S)-(-)-amisulpride that is present in the pharmaceutical composition. [000451] Embodiment 153. A method of treating a psychiatric disorder in a subject comprising administering to the subject an enantiomerically pure crystalline form of (R)-(+)- amisulpride or (S)-(-)-amisulpride prepared by any one of embodiments 1-114, or an enantiomerically pure crystalline form of (R)-(+)-amisulpride or (S)-(-)-amisulpride of any one of embodiments 115-134, or a pharmaceutical composition of any one of embodiments 135-152. [000452] Embodiment 154. The method according to embodiment 153, wherein the psychiatric disorder is a depressive order. [000453] Embodiment 155. The method according to embodiment 153, wherein the psychiatric disorder is bipolar disorder. [000454] Embodiment 156. The method according to embodiment 153, wherein the psychiatric disorder is bipolar depression. [000455] Embodiment 157. The method according to embodiment 153, wherein the psychiatric disorder is major depressive disorder (MDD). [000456] Embodiment 158. The method according to embodiment 153, wherein the psychiatric disorder is major depressive disorder with mixed features (MDD-MF). [000457] Embodiment 159. The method according to embodiment 153, wherein the psychiatric disorder is treatment resistant depression (TRD). [000458] Embodiment 160. The method according to embodiment 153, wherein the psychiatric disorder is schizophrenia. [000459] Embodiment 161. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, wherein the crystalline form of (R)-(+)-amisulpride has a greater than about 95% chemical purity and about 95% enantiomeric purity. [000460] Embodiment 162. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, wherein the crystalline form of (R)-(+)-amisulpride has a greater than about 98% chemical purity and about 98% enantiomeric purity. [000461] Embodiment 163. An enantiomerically pure crystalline form of (R)-(+)- amisulpride prepared by the method of any one of embodiments 1, 2, 5-57, 71-79, 81-95, 98- 100, and 103-108, wherein the crystalline form of (R)-(+)-amisulpride has a greater than about 99% chemical purity and about 99% enantiomeric purity. [000462] Embodiment 164. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, wherein the crystalline form of (S)-(-)-amisulpride has a greater than about 95% chemical purity and about 95% enantiomeric purity. [000463] Embodiment 165. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared by the method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, wherein the crystalline form of (S)-(-)-amisulpride has a greater than about 98% chemical purity and about 98% enantiomeric purity. [000464] Embodiment 166. An enantiomerically pure crystalline form of (S)-(-)- amisulpride prepared method of any one of embodiments 3-43, 58-78, 80-93, 96-98, 101, 102, and 110-114, wherein the crystalline form of (S)-(-)-amisulpride has a greater than about 99% chemical purity and about 99% enantiomeric purity. [000465] Although the invention has been described with reference to a specific embodiments this description is not meant to be construed in a limiting sense. The invention being thus described, it is apparent that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications, alternatives, and equivalents as would be apparent to those skilled in the art are intended to be included within the scope of the appended claims.