Method for resolution of baclofen salts

Abstract

The invention relates to the field of resolution of chiral compounds existing in the form of two optical antipodes (enantiomers), such as Baclofen. More particularly, the invention relates to the production of the pure enantiomer (R)(−) Baclofen, of chemical nomenclature (R)-4-amino-3-(4-chlorophenyl)-butanoic acid, and the hydrogen maleate salt thereof. More specifically, the invention relates to the resolution of hydrogen maleate salts of racemic Baclofen by preferential crystallisation and particularly by the AS3PC method (auto-seeded and programmed polythermal preferential crystallisation).

Claims

1. A racemic salt of baclofen hydrogen maleate (Bahma), wherein said racemic salt of baclofen hydrogen maleate has a melting/decomposition point of 164±1° C.

2. A process for resolving the (S) and (R) enantiomers of baclofen comprising the resolution of a baclofen hydrogen maleate salt as defined in claim 1.

3. The process as claimed in claim 2, wherein racemic baclofen is transformed into racemic baclofen hydrogen maleate salt in the presence of maleic acid, and in that said salt is then resolved by preferential crystallization to separate the two (S) and (R) enantiomers.

4. The process as claimed in claim 3, wherein the resolution of the racemic salt is performed by auto-seeded preferential crystallization or by seeded preferential crystallization.

5. The process as claimed in claim 4, wherein the resolution of the racemic salt is performed by auto-seeded preferential crystallization.

6. The process as claimed in claim 3, wherein the preferential crystallization is performed with a solvent selected from the group consisting of an alcoholic solvent, an aqueous solution, an acidic aqueous solution and mixtures thereof.

7. The process as claimed in claim 3, wherein the preferential crystallization is performed with an acidic aqueous solution, the acid being selected from the group consisting of hydrochloric acid, acetic acid and nitric acid.

8. The process as claimed in claim 7, wherein the preferential crystallization is performed with an aqueous hydrochloric acid solution.

9. The process as claimed in claim 7, wherein the preferential crystallization is performed with an aqueous 2 mol/L hydrochloric acid solution.

10. The process as claimed in claim 3, wherein the preferential crystallization is auto-seeded and in that it comprises the following steps: a) a volume V of a saturated solution of racemic Bahma salt in a solvent is prepared at a temperature T.sub.L; b) at least 5% by weight of the first Bahma enantiomer to be recovered relative to the weight of the racemic Bahma salt is added; c) the mixture is heated to a temperature T.sub.B=T.sub.L+3° C.; d) a cooling programming law is applied to the mixture from T.sub.B to T.sub.F, T.sub.F being below T.sub.B, such that the mixture maintains a low supersaturation which favors the growth of the first Bahma enantiomer present in the form of crystals, while prohibiting the spontaneous nucleation of the second Bahma enantiomer dissolved in the solution; e) the crystals of the first Bahma enantiomer are harvested at the temperature T.sub.F; f) substantially the same mass of racemic Bahma salt as the mass of the harvest made in the preceding step is added to the mixture, the difference is made up with solvent to reach the volume V and the new combined mixture is brought to the temperature T.sub.B; g) the temperature T.sub.B is maintained for a time t so as to allow the system to return to thermodynamic equilibrium; h) the same cooling programming law as in step (d) is applied to the mixture prepared in step (g) containing the second Bahma enantiomer, so that the mixture maintains a low supersaturation during the crystallization so as to promote the growth of the second Bahma enantiomer present in the form of crystals while at the same time prohibiting the spontaneous nucleation of the first Bahma enantiomer present in the solution; i) the crystals of the second Bahma enantiomer are harvested at the temperature T.sub.F; j) substantially the same mass of racemic Bahma salt as the mass of the harvest made in the preceding step is added to the mixture, the difference is made up with solvent to reach the volume V and the new combined mixture is brought to the temperature T.sub.B; k) the temperature T.sub.B is maintained for a time t so as to allow the system to return to thermodynamic equilibrium; l) steps (d) to (k) are repeated to successively obtain one and then the other of the two enantiomers.

11. The process as claimed in claim 10, wherein the temperature T.sub.L ranges from 30 to 70° C.

12. The process as claimed in claim 11, wherein the temperature T.sub.L ranges from 40 to 60° C.

13. The process as claimed in claim 10, wherein the temperature T.sub.L is 50° C.

14. A process for the enantiomeric purification of baclofen hydrogen maleate (Bahma) salts, comprising the recrystallization of the Bahma salts in a solvent.

Description

FIGURES

(1) FIG. 1 is an optical microscopy image of a single crystal with an enantiomeric excess of 98.6% derived from a racemic salt of Bahma prepared in example 1.

(2) FIG. 2 is the binary phase diagram of Bahma obtained by differential scanning calorimetry (DSC) (the liquidus curve is not present, given that the Bahma salt decomposes during or after melting).

(3) FIG. 3 is a theoretical binary phase diagram of a conglomerate having a partial solid solution.

(4) FIG. 4 is a theoretical binary phase diagram of a baclofen salt other than the Bahma salt with the usual presence of a stoichiometric racemic compound.

(5) FIG. 5 represents the calibration curve plotted by varying the concentration (C) of a pure Bahma enantiomer and by measuring the specific optical rotation (a) at a wavelength of 365 nm in the water/n-propanol azeotrope at 25° C.

(6) FIG. 6 represents the XRD diffractogram calculated and measured for the racemic salt of Bahma of example 1.

(7) FIG. 7 represents the ternary isobaric isotherm of the system {Bahma (R) enantiomer—Bahma (S) enantiomer—Solvent} illustrating the enantiomeric purification process of the present invention.

(8) FIG. 8 is a comparison of the diffractograms, obtained by x-ray diffraction analysis, of the B form of (R)(−)-baclofen and of Test 1 of example 5.

(9) FIG. 9 corresponds to the .sup.1H NMR spectrum of Test 1 of example 5 in deuterated DMSO.

(10) FIG. 10 is a comparison of the diffractograms, obtained by x-ray diffraction analysis, of the B form of (R)(−)-baclofen and of Test 2 of example 5.

(11) FIG. 11 corresponds to the .sup.1H NMR spectrum of Test 2 of example 5 in deuterated DMSO.

(12) FIG. 12 is a comparison of the diffractograms, obtained by x-ray diffraction analysis, of the B form of (R)(−)-baclofen and of Test 3 of example 5.

(13) FIG. 13 corresponds to the .sup.1H NMR spectrum of Test 3 of example 5 in deuterated DMSO.

(14) FIG. 14 corresponds to the .sup.1H NMR spectrum of the baclofen hydrogen maleate salt in deuterated water.

(15) FIG. 15 corresponds to the .sup.1H NMR spectrum of baclofen in deuterated water.

(16) FIG. 16 corresponds to the .sup.1H NMR spectrum of maleic acid in deuterated water.

ANALYTICAL TECHNIQUES

(17) Determination of the Melting/Decomposition Point and Production of the Binary Phase Diagram by Differential Scanning Calorimetry (DSC)

(18) The differential scanning calorimetry measurements were taken in the following manner: DSC 204 F1 Netzsch equipped with an Intracooler aluminum crucible, closed aluminum lid Atmosphere: helium Heating rate: 5K.min.sup.−1 Data processing: Netzsch Proteus Thermal Analysis software (v.4.8.4)

(19) Following the DSC and chiral HPLC analyses performed on single crystals obtained at 20 and 70° C. (98.3% ee at 70° C. and 98.8% ee at 20° C.), the binary phase diagram of FIG. 1 was established. The enantiomeric excess (% ee) was determined by chiral HPLC according to the method described below.

(20) Determination of the Enantiomeric Excess (% ee) by Chiral HPLC

(21) The chromatographic method originates from that described in Hefnawy, M., Aboul-Enein, H. Talanta, 2003, vol. 61, No. 5, pages 667-673.

(22) The enantiomeric excesses were determined by chiral HPLC chromatography using a Chirobiotic T column (length 15 cm, inside diameter 4.6 mm, 5 μm particles) mounted on a Spectra System HPLC chain equipped with an AS sample changer, a P1000 pump and a UV1000 detector. The experimental conditions were: Solvent: isocratic mixture of methanol, water, acetic acid and triethylamine in 98:2:0.1:0.1 proportions; Flow rate: 1 ml.min.sup.−1; Detector: λ=226 nm; Volume injected: 10 μL

(23) Determination of the Enantiomeric Excess (% ee) by Polarimetry

(24) Between each preferential crystallization, the enantiomeric excesses (% ee) of the precipitates and of the solution were also determined by polarimetry. This technique is faster than chiral HPLC analysis and thus makes it possible to check the correct progress of the resolution process so as to adjust the parameters accordingly (amount of solvent and of racemic Bahma salt to be compensated for before the start of a crystallization).

(25) These analyses were performed on a Perkin-Elmer Model 341 polarimeter equipped with a thermostatically regulated 10 cm measuring cell allowing analysis at various wavelengths. The measurements were taken at 25° C. and the samples were dissolved in the water/n-propanol azeotrope (43.29 mol %). The table below gives the specific optical rotation (α) of a pure Bahma enantiomer at various wavelengths (λ).

(26) TABLE-US-00002 λ (nm) α (°) 365 −0.35 589 −0.11 578 −0.08 546 −0.1 436 −0.19

(27) The wavelength of 365 nm was retained since it had the best deviation of polarized light (−0.35°).

(28) FIG. 5 shows the calibration curve which was plotted by varying the concentration of the pure Bahma enantiomer and by measuring the specific optical rotation at a wavelength of 365 nm. The values are reported in the table below

(29) TABLE-US-00003 C (g/dL) α (°) 2.20 −0.34 1.65 −0.26 1.24 −0.22 0.93 −0.16 0.70 −0.12 0.00 0

(30) It was then possible to deduce the specific optical rotation value for Bahma via the following formula:
α=[α].sub.365nm.sup.25° C.*l*C
in which:
α is the optical rotation of the sample in degrees (°);
C is the concentration of the sample in g.dL.sup.−1;
l is the length of the analysis cell in dm;
[α].sub.365nm.sup.25° C. is the specific optical rotation of Bahma at 25° C. and at 365 nm in the solvent used, expressed in °.dL.g.sup.−1.dm.sup.−1.

(31) The specific optical rotation of Bahma under these conditions is 0.1642°dL.g.sup.−1.dm.sup.−1.

(32) Analysis by Single-Crystal X-Ray Diffraction

(33) The single crystal chosen was bonded to the end of a glass rod and mounted on a goniometric head of the Brüker SMART APEX diffractometer equipped with a two-dimensional detector. Three sets of measurements were recorded (in total 1800 images (frames)) corresponding to 3 ω scans (incrementation of 0.3°), for four different values of ϕ.

(34) The elemental lattice parameters and the orientation matrix were determined using the SMART program. The data integrations and the refinement of the lattice parameters were performed using the SAINT program. The intensities were corrected for the Lorentz polarization factor and for absorption by the SAINT and SADABS programs to obtain the F.sub.O.sup.2.(hkl). The WinGX program was used for determination of the space group, the resolution of the structure and its refinement.

(35) Analysis by Powder X-Ray Diffraction

(36) The powder x-ray diffraction analyses were performed with a D8 Discover diffractometer (Brüker). The instrument is equipped with an x-ray tube containing a copper anticathode (40 kV, 40 mA, radiation Kα1=1.5406 Å, radiation Kα2=1.5444 Å) and is mounted with a Lynx eye angular detector. The analysis program used is a 3 to 30° sweep in 2θ in increments of 0.04° with 0.5 s/step and a rotation of 20 rpm (Phi spinner).

(37) Determination of the Solubility

(38) The solubility of a Bahma salt in a given solvent was calculated, for a given temperature and in a given volume of solvent, via the following formula:

(39) $\frac{m_{\mathrm{Bahma}}}{m_{\mathrm{Bahma}}+\left({\rho }_{\mathrm{solvent}}\times V_{\mathrm{solvent}}\right)}\times 100$
in which
m.sub.Bahma is the mass of the Bahma salt introduced in grams to reach saturation;
ρ.sub.solvent is the density of the solvent in g.mL.sup.−1; and
V.sub.solvent is the volume of the solvent in mL.

(40) Experimental Device for Resolution by Preferential Crystallization

(41) The crystallizations were performed in closed tubes (diameter 3 cm, length 9 cm). Stirring was performed by cruciform magnetic bars and the temperature control was provided by a Lauda ECO RE 415 programmable cryothermostat.

(42) The entrainments were performed by means of the AS3PC process described in patent application WO 1995/008522.

(43) In the course of the entrainments, samples of solutions (10 μL diluted in 1 mL of mobile phase) were collected so as to determine their enantiomeric excess by chromatography according to the method described above.

(44) a) First Crystallization

(45) A volume V of 40 mL of saturated solution of racemic Bahma salt at 50° C. (temperature T.sub.L) in a solvent or a solvent mixture was prepared by filtration of a suspension at this same temperature after an equilibration time of several hours to reach saturation.

(46) At least 5% by weight of excess of a pure Bahma enantiomer (Bahma-100% ee) relative to the weight of the racemic Bahma salt (rac. Bahma) introduced are added to this clear solution. The suspension obtained is then overheated slightly to a temperature T.sub.B=T.sub.L+3° C. Thus, all the seeds of the enantiomer in deficit that might remain at T.sub.L are necessarily dissolved. The starting system is thus a suspension of the enantiomer in excess. The liquid phase of the suspension is saturated in one enantiomer and slightly under-saturated in the other enantiomer. This system has the advantage of being at thermodynamic equilibrium.

(47) A cooling temperature ramp is then applied to the system from T.sub.B to T.sub.F (T.sub.F<T.sub.B), the final temperature at which the system is rapidly filtered without waiting for the thermodynamic equilibrium to be established.

(48) b) Following Crystallizations

(49) At the end of each entrainment, the suspensions were filtered through a sinter funnel. A sample of the filtrates (10 μL of filtrate diluted in 1 mL of mobile phase) was recovered for analysis of the % ee by chiral HPLC and the remainder was set aside to perform the following entrainment. The solid recovered was weighed and 15 mg were then dissolved in 1.5 mL of water/n-propanol azeotrope for analysis of the % ee by polarimetry and 10 μL of this solution were diluted in 1 mL of mobile phase for analysis of the % ee by chiral HPLC.

(50) The filtrate recovered was compensated by adding a mass of racemic Bahma salt substantially equal to that of the crystals recovered in the preceding crystallization. The filtrate was also compensated for the losses of solvent by adding solvent to make up to 40 mL (initial volume of solvent).

(51) The system was then heated again to T.sub.B at which point a new suspension was obtained. After 30 minutes of equilibration at this temperature, the same cooling program was applied, at the end of which a new filtration gives the opposite enantiomer to the preceding one. Successive recycling makes it possible to recover the same enantiomer as the starting one following the odd crystallizations, whereas the other enantiomer is systematically recovered for all the even crystallizations.

(52) By successive recycling, it is then possible to preparatively resolve the two enantiomers of a racemic mixture.

Examples

Example 1: Preparation and Characterization of Bahma Salts

(53) The Bahma salts (racemic or enantiomerically pure) used in the process of the present invention were prepared by evaporation of a suspension of baclofen (racemic or enantiomerically pure) and of maleic acid (1:1 stoichiometric mixture) in acetone.

(54) The single crystals of Bahma salt for the x-ray diffraction analysis were obtained by dissolving 50 mg of racemic Bahma salt in a given volume of solvent: water, methanol or water/n-propanol azeotrope (to achieve a homogeneous solution, the mixture may be heated). After dissolution of the solids, a temperature may be imposed on the solution or it is left at room temperature (about 20° C.). The salt crystals highly enriched in Bahma form by evaporation of the solvent or solvent mixture after a few days for the slowest evaporations; single crystals were thus obtained by evaporation of solutions left at 20, 50 and 70° C.

(55) These single crystals were studied by x-ray diffraction to determine their complete structure. The crystallographic data for a single crystal obtained at 20° C. are reported in table 1.

(56) TABLE-US-00004 TABLE 1 System Monoclinic Space group P2.sub.1 (No. 4) a/Å 5.728(1) b/Å 13.774(1) c/Å 9.618(9) α/° 90 β/° 106.628(1) γ/° 90 Volume/Å.sup.3 727.2(2) Final R.sub.1 (I > 2σ(I)) 0.0287 Final wR(F.sup.2) (I > 2σ(I)) 0.0812 Final R.sub.1 0.0294 Final wR(F.sup.2) 0.0817 Flack parameter −0.02(5) R.sub.1 = Σ(∥F.sub.O| − |F.sub.C∥)/Σ|F.sub.O| wR(F.sup.2) = [Σ[w(F.sub.O.sup.2 − F.sub.C.sup.2).sup.2]/Σ[w(F.sub.O.sup.2).sup.2]].sup.1/2

(57) The space group, the number of molecules in the asymmetric unit, the absence of disorder and the value of the Flack parameter indicate virtually total chiral discrimination in the solid state at room temperature. These observations were correlated by identical behavior up to at least 70° C.

(58) Table 2 below shows the reduced coordinates of the atoms other than hydrogen (×10.sup.4) and the isotropic agitation factor U.sub.eq (Å.sup.2×10.sup.3).

(59) TABLE-US-00005 TABLE 2 Atom x y U.sub.eq C(1) −5631(3) 8817(1) −938(2) 33(1) C(2) −3549(3) 9419(1) −1112(2)  35(1) C(3) −3199(3) 10379(1)  −272(2) 31(1) C(4) −1434(3) 10998(1)  −828(2) 36(1) C(5) −2316(3) 10237(1)  1357(2) 30(1) C(6)  −80(3) 9806(1) 2015(2) 37(1) C(7)  739(3) 9687(1) 3512(2) 39(1) C(8)  −725(4) 9994(1) 4340(2) 39(1) C(9) −2951(3) 10412(1)  3718(2) 41(1) C(10) −3730(3) 10535(1)  2229(2) 35(1) Cl(1)  289(1) 9851(1) 6215(1) 58(1) N(1) −1225(3) 12006(1)  −269(2) 38(1) O(1) −7139(2) 9107(1) −380(2) 46(1) O(2) −5825(2) 7935(1) −1485(1)  39(1) C(1A)  2665(3) 2546(1) 3835(2) 35(1) O(1A)  2173(2) 2425(1) 2502(1) 41(1) O(2A)  4794(3) 2762(2) 4591(2) 67(1) C(2A)  683(3) 2437(1) 4532(2) 35(1) C(3A)  787(3) 2427(2) 5927(2) 37(1) C(4A)  2891(4) 2502(2) 7252(2) 40(1) O(3A)  5022(3) 2668(2) 7127(2) 62(1) O(4A)  2565(3) 2399(1) 8443(2) 60(1)

(60) Table 3 below shows the reduced coordinates of the hydrogen atoms (×10.sup.4) and the isotropic agitation factor U.sub.eq (Å.sup.2×10.sup.3).

(61) TABLE-US-00006 TABLE 3 Atom x y U.sub.eq H(2A) −3817 9558 −2133 41 H(2B) −2063 9042 −787 41 H(3) −4770 10714 −506 38 H(4A) 161 10697 −542 43 H(4B) −1985 11014 −1880 43 H(6) 883 9593 1445 44 H(7) 2245 9406 3947 47 H(9) −3924 10610 4290 49 H(10) −5231 10823 1806 42 H(1A) −2693 12278 −496 56 H(1B) −260 12345 −665 56 H(1C) −598 11999 690 56 H(2) −4657 7823 −1791 58 H(2A1) −867 2364 3894 42 H(3A) −713 2362 6108 44 H(3A1) 4939 2737 6267 93

(62) Table 4 below shows the calculated and measured position and intensity of the characteristic XRD peaks for the racemic Bahma salt. The corresponding XRD diffractograms are shown in FIG. 6.

(63) TABLE-US-00007 TABLE 4 Measured Bahma Miller Calculated Bahma Inten- indices 2θ/ 2θ/ Intensity sity h k l deg d/Å I/rel. deg d/Å (counts) (I/Io %) 0 0 1 9.59 9.22 2.41 9.58 9.223 344 1.8 0 1 1 11.54 7.66 2.72 11.51 7.679 1116 5.8 0 2 0 12.83 6.89 5.77 12.81 6.904 2266 11.8 0 2 1 16.04 5.52 4.96 16.03 5.525 2047 10.6 1 0 0 16.12 5.49 5.4 −1 0 1 16.24 5.45 54.44 16.21 5.462 8893 46.2 1 1 0 17.36 5.1 33.95 17.35 5.108 6557 34 −1 1 1 17.47 5.07 19.97 17.45 5.078 3944 20.5 0 1 2 20.3 4.37 6.49 20.28 4.375 1874 9.7 1 2 0 20.66 4.3 51.05 20.64 4.3 8915 46.3 −1 2 1 20.75 4.28 44.13 20.7 4.288 8204 42.6 1 0 1 21.04 4.22 3.14 21.02 4.224 1696 8.8 0 3 1 21.59 4.11 22.72 21.56 4.119 5218 27.1 1 1 1 22.02 4.03 29.17 21.99 4.039 6216 32.3 −1 1 2 22.28 3.99 17.94 22.24 3.993 2895 15 0 2 2 23.2 3.83 2.46 23.16 3.837 1381 7.2 1 2 1 24.72 3.6 14.87 24.69 3.603 3047 15.8 −1 2 2 24.95 3.57 13.08 24.92 3.57 2218 11.5 1 3 0 25.24 3.53 78.2 25.22 3.528 9331 48.4 −1 3 1 25.32 3.51 7.46 0 4 0 25.82 3.45 100 25.79 3.452 19184 100 0 3 2 27.38 3.25 11.56 27.35 3.258 2470 12.8 0 4 1 27.61 3.23 34.09 27.57 3.233 5707 29.6 1 0 2 28.6 3.12 2.89 28.55 3.124 1238 6.4 1 3 1 28.7 3.11 6.3 28.68 3.11 1618 8.4 −1 3 2 28.9 3.09 4.41 28.87 3.09 1396 7.2 −1 0 3 28.93 3.08 2.51 1 1 2 29.34 3.04 27.72 29.29 3.047 5113 26.5 −1 1 3 29.66 3.01 4.39 0 1 3 29.77 3 17.51 29.71 3.005 3125 16.2

Example 2: Resolution in the n-Propanol/Water Azeotropic Mixture by Auto-Seeded Preferential Crystallization

(64) The solubility of the racemic Bahma salt at various temperatures was determined in the n-propanol/water azeotropic mixture (ρ=0.870 g.mL.sup.−1). The calculated values are presented in the table below.

(65) TABLE-US-00008 Temperature Solubility 20° C. 1.49% 35° C. 2.80% 50° C. 4.81%

(66) Several entrainments were performed in this solvent using a saturated racemic solution at 50° C. and following the experimental device described previously. 1.sup.st Series:

(67) TABLE-US-00009 Initial system: 40 mL saturated at 50° C. (1.7583 g of rac. Bahma in 34.796 g of solvent) and 0.2505 g of Bahma-100% ee Crude harvests Temperature Time Solution Mass ee (° C.) (min) ee (%) (g) (%) Test 1 53 0 −4.71 50 6 −4.44 45 16 −0.40 40 26 4.54 35 36 11.69   32.5 41 15.30 30 46 19.92 0.6682 g −91.08 Compensation 0.6895 g of rac. Bahma and 4 h at 53° C. 2 mL of solvent Test 2 53 0 6.43 35 36 −9.89 30 46 −18.08 0.6587 g +84.29 Compensation 0.6718 g of rac. Bahma and 12 h at 53° C. 2 mL of solvent Test 3 53 0 −5.47 35 36 −3.37 30 46 10.02 0.4971 g −91.03 Compensation 0.4955 g of rac. Bahma and 2 h at 53° C. 2 mL of solvent Test 4 53 0 5.14 35 36 −2.38 30 46 −11.27 0.4156 g +82.72 1 h at 53° C. Compensation 0.4153 g of rac. Bahma Test 5 53 0 −3.07 35 36 12.84 30 46 20.93 0.5608 g −93.78 Compensation 0.555 g of rac. Bahma and 30 min at 53° C. 1.5 mL of solvent Test 6 53 0 9.76 35 36 −5.35 30 46 −13.76 0.5339 g +96.59 2.sup.nd Series:

(68) TABLE-US-00010 Initial system: 40 mL saturated at 50° C. (1.7583 g of rac. Bahma in 34.796 g of solvent) and 0.2445 g de Bahma-100% ee Crude harvests Temperature Time Solution Mass ee (° C.) (min) ee (%) (g) (%) Test 1 53 0 −11.88 35 36 −3.47 30 46 9.75 0.5012 g −94.04% Compensation 0.5120 g of rac. Bahma and 60 min at 53° C. 1.2 mL of solvent Test 2 53 0 5.70 35 36 −9.90 30 46 −17.87 0.4679 g +84.61% Compensation 0.4621 g of rac. Bahma and 30 min at 53° C. 1 mL of solvent Test 3 53 0 −8.86 35 36 6.62 30 46 15.26 0.5496 g −95.07% Compensation 0.5469 g of rac. Bahma and 30 min at 53° C. 1.5 mL of solvent Test 4 53 0 8.16 35 36 −8.64 30 46 −17.34 0.6465 g +92.52% Compensation 0.5122 g of rac. Bahma and 30 min at 53° C. 1.5 mL of solvent Test 5 53 0 −8.02 35 36 9.69 30 46 19.47 0.6463 g −88.51% Compensation 0.5136 g of rac. Bahma and 30 min at 53° C. 1.75 mL of solvent Test 6 53 0 11.09 35 36 −5.15 30 46 −17.59 0.6124 g +91.71% Compensation 0.4975 g of rac. Bahma and 30 min at 53° C. 1.5 mL of solvent Test 7 53 0 −12.35 35 36 −2.47 30 46 12.65 0.5378 g −91.71% Compensation 0.5306 g of rac. Bahma and 30 min at 53° C. 2 mL of solvent Test 8 53 0 7.46 35 36 −4.89 30 46 −14.73 0.5254 g +88.90% Compensation 0.5238 g of rac. Bahma and 30 min at 53° C. 0.5 mL of solvent Test 9 53 0 −6.25 35 36 10.26 30 46 19.42 0.6444 g −89.51% Compensation 0.5183 g of rac. Bahma and 30 min at 53° C. 1 mL of solvent Test 10 53 0 8.00 35 36 −7.59 30 46 −16.49 0.7194 g +87.05%

Example 3: Resolution in Acidified Water by Auto-Seeded Preferential Crystallization

(69) The solubility of the racemic Bahma salt at various temperatures was determined in pure water (ρ=1 g.mL.sup.−1), in aqueous 1M HCl solution (ρ=1.017 g.mL.sup.−1) and in aqueous 2M HCl solution (ρ=1.030 g.mL.sup.−1). The calculated values are presented in the table below.

(70) TABLE-US-00011 Solubility Solubility Solubility Temperature Water 1M HCl 2M HCl 20° C. 0.75% 4.51% 6.48% 35° C. 1.00% 6.86% 11.44% 50° C. 1.78% 12.54% 22.24%

(71) Thus, the use of an acidified aqueous solution advantageously makes it possible to increase the solubility of the racemic Bahma salt, which makes it possible to improve the productivity of the preferential crystallization. For HCl concentrations of 1M and 2M at these temperatures, the solid phases do not contain any hydrochloride.

(72) Entrainment was performed in 1M HCl using a saturated racemic solution at 50° C. and following the experimental device described previously.

(73) TABLE-US-00012 Initial system: 40 mL saturated at 50° C. (5.8326 g of rac. Bahma and 40.68 g of 1M HCl) and 0.1735 g of Bahma-100% ee Crude harvests Temperature Time Solution Mass ee (° C.) (min) ee (%) (g) (%) Test 1 50.25 0 −2.89 47.5 6 −2.81 45 11 −2.03 42.5 16 −0.90 40 21 3.76 37.5 26 11.55 0.8885 −90.56%

(74) Entrainment was performed in 2M HCl using a saturated racemic solution at 50° C. and following the experimental device described previously.

(75) TABLE-US-00013 Initial system: 40 mL saturated at 50° C. (11.7835 g of rac. Bahma in 41.2 g of 2M HCl) and 0.2501 g of Bahma-100% ee Tempera- Crude harvests ture Time Solution Mass ee (° C.) (min) ee (%) (g) (%) Test 1 50.5 0 −3.53 47.5 6 −2.66 45.0 11 −2.09 42.5 16 −5.98 40.0 21 3.74 37.5 26 10.52 1.7437 g −89.94% Compensation: 1.7457 g of rac. Bahma and 60 min at 50.5° C. 2 mL of 2M HCl Test 2 50.5 0 / 40.0 21 −2.77 37.5 26 −11.80 2.1713 g +98.37%

Example 4: Enantiomeric Purification Process According to the Invention

(76) The enantiomeric purification process according to the invention was performed using 0.4239 g of Bahma salt at −50.43% ee, i.e. a mixture of 0.2138 g of (R)-Bahma and 0.2101 g of racemic Bahma mixture, to which a mass of 27.0787 g of water (m.sub.H0=26.7258 g of water, i.e. an excess Δm=1.32% of water) was added.

(77) The system was then left under magnetic stirring at 20° C. overnight and the suspension was filtered.

(78) The solid was then washed twice with water and the harvest was thus able to be analyzed. 0.1905 g of solid (R)-Bahma salt at −98.59% ee is obtained and the filtrate has a measured purity of −11.56% ee.

Example 5: Process for Obtaining Pure Baclofen from Baclofen Hydrogen Maleate Salt

(79) 1 g of enantiomerically pure baclofen hydrogen maleate salt (corresponding to a mass of 0.6480 g of baclofen and 0.3520 g of maleic acid) is dissolved in 10 ml of 1M NaOH solution at 25° C. with stirring.

(80) The pH of the solution is then adjusted by adding a known volume of 37 mass % hydrochloric acid solution. The temperature is controlled in parallel. The addition of hydrochloric acid entrains the precipitation of the B form of baclofen, which is then filtered off, dried, weighed and analyzed by x-ray diffraction and by NMR (nuclear magnetic resonance) analysis.

(81) Three tests were then performed in order to check that the process is viable at various final pH values and various temperatures.

(82) Test 1:

(83) TABLE-US-00014 Volume of HCl Test added Final temperature Final pH Mass harvested Test 1 230 μL 25° C. 9.02 0.5485 g

(84) Test 2:

(85) TABLE-US-00015 Volume of HCl Test added Final temperature Final pH Mass harvested Test 2 320 μL 25° C. 7.90 0.5546 g

(86) Test 3:

(87) TABLE-US-00016 Volume of HCl Test added Final temperature Final pH Mass harvested Test 3 240 μL 10° C. 9.29 0.5786 g

(88) For each of the tests, x-ray diffraction analyses of the solids obtained and NMR analyses are performed (see FIGS. 8 to 16).

(89) Conclusion:

(90) The x-ray diffraction analyses of the solids obtained demonstrate that all the solids obtained are constituted of enantiomerically pure baclofen in its B polymorphic form (see FIGS. 8, 10 and 12).

(91) The NMR analyses confirm that the samples recovered are mainly constituted of baclofen with a few possible remaining traces of maleic acid (peak at 6 ppm) (see FIGS. 9, 11, 13, 14, 15 and 16).

(92) The masses harvested and the purity indicate a good yield of the process (compared with the initial mass of baclofen dissolved). Tests 2 and 3 indicate that this yield can be optimized without affecting the purity.