HK1192222B - Preparation method and crystalline form of optical enantiomers of modafinil - Google Patents

Abstract

The invention provides a method for the preparation of crystalline forms of optical enantiomers of modafinil comprising the steps of: i) dissolving one of the optical enantiomers of modafinil in a solvent other than ethanol, ii) crystallising the enantiomers of modafinil iii) recovering the crystalline form of the enantiomers of modafinil thus obtained. The invention also relates to a method for the preparation of optical enantiomers of modafinil.

Description

The invention relates to a process for obtaining a crystalline form of the enantiomers of modafinil and a crystalline form which can be obtained by this process.

A novel process for preparing modafinil optical enantiomers from modafinil acid (±) is also described here.

US Patent 4,177,290 describes modafinil in racemic form, also known as (±) 2-benzhydrylsulfinyl) acetamide or (±) 2-[di-phenylmethyl) sulfinyl] acetamide, as a compound with central nervous system stimulating properties.

US Patent 4,927,855 describes the two optical enantiomers of modafinil. It specifically describes the levogyre enantiomer and its use as an antidepressant or stimulant in the treatment of hypersomnia and Alzheimer's disease-related disorders. The process of preparing the two optical enantiomers of modafinil from modafinil acid (±) or (±) benzhydrylsulfinylacetic acid described in this document is shown in the following synthesis diagram: - What?

This method consists in a first step of splitting the optical enantiomers of modafinil acid (±) by forming diastereoisomers with the optically active agent α-methylbenzylamine.

The (-) -benzhydrylsulfinylacetatate of (-) -α-methylbenzylamine is then converted by acid hydrolysis to (-) -benzhydrylsulfinylacetic acid, which is esterified in the presence of dimethyl sulfate and then diluted in the presence of ammonia (gas). The enantiomer (-) or l (levogyre) of modafinil is obtained by this process with an overall yield of 5.7% compared to modafinil acid (±) based on the corresponding yields calculated at each step.

WO 02/10125 A1 describes an improved process for the preparation of modafinil, which can thus be isolated with high purity by a single crystallization. The process produces modafinil free from sulfonated products of suroxidation and other byproducts. Other novel II-VI crystalline forms of modafinil and processes for their preparation are provided.

The statement by John Mallamo, PhD, filed on 22 March 2012 in the context of the examination of the application EP03799631.1 states that WO 02/10125 ( Singer et al. ) describes polymorphic forms of modafinil, but that Singer et al. does not disclose polymorphic forms of (-) -modafinil. It further states that none of the polymorphs described in Singer et al. produces a PXRD spectrum that would correspond to the PXRD spectrum of the claimed polymorph (-) -modafinil I form.

The invention relates to the use of a polymorphic form of the dextrogyre or levogyre enantiomer of modafinil, designated form I, characterized by (i) producing an X diffraction spectrum at reticular distances: 8.54; 4.27; 4.02; 3.98 (A); or (ii) producing an X diffraction spectrum comprising intensity lines at angular values of 2 theta: 15.4; 31.1; 33.1 and 33.4 (degrees), measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation, the error for the 2 theta values being ± 0,2 degrees theta, for the manufacture of a drug for the prevention or treatment of hypertension,sleep apnea, excessive sleepiness associated with illness, obstructive sleep apnea, narcolepsy, sleepiness, excessive sleepiness, excessive sleepiness associated with narcolepsy, disorders of the central nervous system, protection of brain tissue from ischemia, alertness disorders, attention disorders, fatigue, depression, depressive state due to low sunlight, schizophrenia, shift work, shift work, eating disorders, in which modafinil acts as an appetite stimulator, cognitive stimulation at low doses.

The invention also relates to a process for the preparation of a polymorphic form of the dextrogyre or levogyre enantiomer of modafinil, designated form I, characterized by producing an X-diffraction spectrum comprising intensity lines at reticular distances: 8.54 ; 4.27 ; 4.02 ; 3.98 (Å), this process comprising the following steps: (iii) recover the resulting crystalline form of the modafinil enantiomer, in which the solvent used in step (i) is acetone, 1-4 dioxane, ethyl acetate, ortho, meta or paraxylene, a mixture of ortho, meta and/or paraxylene, and in which the crystallization consists of a cooling of the solution obtained in step (i) and the cooling is slow, or in which the solvent used in step (i) is methanol, ethanol, water, or alcohol/water mixtures, and in which crystallization consists of a cooling of the solution obtained in step (i) and the cooling is rapid.

Err1:Expecting ',' delimiter: line 1 column 52 (char 51)

Stereoisomerism can also be denoted by either (D) or (L) or by (R) and (S), which are descriptors of the absolute configuration.

In the following, the levogyr enantiomer of modafinil will be indifferently referred to as enantiomer l or (-), while the dextrogyr enantiomer will be referred to as enantiomer d or (+).

A process has now been discovered to obtain different crystalline forms of the optical enantiomers of modafinil.More specifically, the inventors have shown that the crystalline form obtained depends mainly on the nature of the recrystallization solvent used.

Err1:Expecting ',' delimiter: line 1 column 52 (char 51)

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)

Err1:Expecting ',' delimiter: line 1 column 52 (char 51)

In addition, the inventors showed that l-modafinil and d-modafinil prepared under the conditions described in US Patent 4,177,290 are obtained in the same polymorphic form, form I, which is the most thermodynamically stable polymorphic form, under normal temperature and pressure conditions.

Figure I shows the X diffraction spectrum below in which d is the reticular distance and the ratio (I/Io) the relative intensity. - What?

CRL 40982 FORME I
2 Theta (degrés)	d (Å)	I/Io (%)
9.8	13.40	32
15.4	8.54	87
20.8	6.34	24
26.4	5.01	14
28.3	4.68	19
28.7	4.62	16
29.9	4.44	45
31.1	4.27	100
31.6	4.20	23
32	4.15	14
33.1	4.02	78
33.4	3.98	84
34.1	3.90	16
35.1	3.80	15
39	3.43	22

Diffractomètre: Miniflex Rigaku (Elexience)

The crystalline forms of a given compound usually have very distinct physical, pharmaceutical, physiological and biological properties from each other.

In this respect, the crystalline forms of optically active modafinil, in particular the polymorphic forms, are of interest in that they have advantageous and different characteristics compared to the I form.

A new process for preparing modafinil optical enantiomers from (±) -modafinil acid has now been discovered, which allows each enantiomer to be isolated with yields and optical purity significantly higher than those described in US Patent 4,927,855.

In a particularly advantageous way, a method for the double-division of the two optical enantiomers of (±) -modafinil acid by preferential crystallization has now been developed, which is advantageously applicable at the preparatory scale.

This process of splitting (±) -modafinil acid has many advantages: It avoids the use of an expensive intermediate chiral agent whose subsequent preparation rarely involves losses of less than 10% (De Min., M., Levy, G. and Micheau J.-C., 1988; J. Chem. Phys. 85, 603-19); the two enantiomers are obtained directly, unlike the method using conventional decomposition by formation of diastreoisomer salts; the yield is theoretically quantitative as a result of successive recycling of the mother water; the purification of crystals of raw antiomers is easy.

The purpose of the invention is therefore to provide a method for the preparation of the crystalline forms of the enantiomers of modafinil.

A novel process for the preparation of modafinil optical enantiomers, including the levogyre enantiomer of modafinil, is described here.

• The method of preparation of the polymorphs of I-modafinil

These and other purposes are achieved by this description which is more specifically concerned, firstly, with a process for the preparation of crystalline forms of the optical enantiomers of modafinil, comprising the following steps: (i) dissolving one of the optical enantiomers of modafinil in a solvent other than ethanol; (ii) crystallizing the said enantiomer of modafinil; and (iii) recovering the crystalline form of the said enantiomer of modafinil thus obtained.

Err1:Expecting ',' delimiter: line 1 column 144 (char 143)

In general, crystallization in step (ii) involves switching from a single-phase to a two-phase system by varying the temperature and concentration.

Examples of solvents which may be suitable for the recrystallization process as described include alcoholic solvents, carboxylic acid ester solvents, ether solvents, chlorinated solvents, aromatic solvents, lower aliphatic ketone solvents, other solvents being, for example, carboxylic acid solvents, non-protic polar solvents, alicyclic hydrocarbons, aliphatic hydrocarbons, carbonates, heteroaromatic solvents, water.

Alcoholic solvents include lower alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-methyl-2-pentanol, 1,2-propanediol, t-amyl alcohol, methanol, propanol and isopropanol being particularly preferred.

Solvents such as carboxylic acid esters include alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, alkyl formats such as ethyl formate, with ethyl acetate being particularly preferred.

Are useful as recrystallization ether solvents, with diethyl ether, tetrahydrofuran (THF), dioxane, dibutyl ether, isopropyl ether, t-butyl methyl ether, tetrahydropyrane being particularly preferred.

Chlorinated solvents include chlorinated hydrocarbons, including chloroform, 1,2-dichloroethane, dichloromethane and chlorinated aromatics such as chlorobenzene.

Examples of aromatic solvents include ortho, meta, paraxylene or a mixture of ortho, meta and paraxylene, with methoxybenzene, nitrobenzene, trifluoro-toluene, toluene, ortho, meta and paraxylene being particularly preferred.

Solvents such as acetone, methyl ethyl ketone, methylisobutyl ketone, butan-2-one, cyclopentanone, isobutyl methyl ketone, 2-pentanone, 3-pentanone are useful as ketone solvents.

As an example of a carboxylic acid solvent, acetic acid is particularly noteworthy.

As an example of a heteroaromatic solvent, pyridine is particularly noteworthy.

Examples of non-protic polar solvents include acetonitrile, propionitrile, 4-methylmorpholine, N,N-dimethyl acetamide, nitromethane, triethylamine, N-methyl pyrrolidone (NMP).

Examples of aliphatic hydrocarbons include heptane, 2,2-4-trimethylpentane.

Examples of alicyclic hydrocarbons include cyclopentane, cyclohexane.

Examples of carbonates include alkylcarbonates such as dimethylcarbonate.

According to a preferred method of execution of the process as described, the crystallization solvents are chosen from acetone, methanol, dioxane 1-4, ethyl acetate, ortho, meta, paraxylene, isopropanol, n-propanol, dimethylcarbonate, tetrahydrofuran, chloroform and methylethyl ketone, water and alcohol/H20 mixtures.

Thus, the crystalline forms of the optical enantiomers of modafinil can be obtained by recrystallization of the enantiomers in certain solvents, the nature and possibly the crystallization conditions of which mainly determine the type of crystalline form obtained.

The recrystallization solvent, by its interaction with functional groups and electron-attracting or electron-donating substituents, can favour certain molecular arrangements which will give rise to a given crystalline form under given crystallization conditions.

The recrystallization solvent used in step (i) is generally heated, particularly at reflux, until the optical enantiomer of modafinil is completely dissolved in the solvent. If the concentration of the optical enantiomer of modafinil in step (i) is not a critical factor in the crystallization, it is preferable to operate in the presence of an optical enantiomeric concentration of modafinil close to the saturation concentration in the recrystallization solvent considered.

One embodiment involves dissolving the optical enantiomer of modafinil by heating the reflux solvent and then adding an additional amount of this optical enantiomer in fractions to achieve saturation.

In another embodiment, the optical enantiomer of modafinil is suspended in the reflux-heated solvent, and an additional amount of solvent is then added in fractions to obtain a homogeneous solution and thus saturation.

The process of crystallization of the modafinil optical enantiomer in step ii) can be accelerated by techniques known to the trade, namely cooling the solution, evaporating part of the solvent, adding an anti-solvent, or seeding the solution with optically active modafinil crystals of the same crystalline form as expected.

The process of crystallization of the process described may be carried out under thermodynamic or kinetic conditions.

Err1:Expecting ',' delimiter: line 1 column 93 (char 92)

For example, thermodynamic crystallization can be achieved by slowly cooling the solution obtained in step (i), typically by cooling the solution to room temperature or by applying a cooling rate or ramp of 0,75°C/min or less, preferably 0,6°C and more preferably 0,5°C/min.

Err1:Expecting ',' delimiter: line 1 column 57 (char 56)

For example, so-called kinetic crystallization can be achieved by rapid cooling, for example by applying a cooling ramp of 300°C/min, or by precipitation by adding an anti-solvent to the solution obtained in step i.

For illustration, both types of thermodynamic or kinetic crystallization are performed in this description by slow or rapid cooling.

Of course, any other crystallization technique such as evaporation of the solvent or precipitation, which allows it to be placed under kinetic and/or thermodynamic conditions, also falls within the scope of the process as described.

Thus, according to a particular embodiment, crystallization at step (ii) can be performed by precipitation, possibly in the presence of crystal germs of the desired crystalline form.

The inventors further showed that some solvents can lead to crystalline forms, more specifically polymorphic forms, distinct depending on whether crystallization is carried out under kinetic or thermodynamic conditions.

In a preferred method of manufacture, crystallization consisted of cooling the solution obtained in step (i).

If necessary, the first mode of cooling is rapid and usually consists of soaking the solution obtained in step (i) in a bath of 0°C or less such as an ice bath for a sufficient time to allow complete crystallization of the solution, or cooling with a cooling range of, for example, - 1°C to - 5°C/min.

In the second embodiment, cooling is slow, in which the solution is generally allowed to cool from the solvent backflow temperature to room temperature or the solution is cooled with a cooling range preferably between - 0.1°C/min and - 0.8°C/min, and more preferably close to - 0.5°C/min, to a temperature generally of 15° to 20°C.

The solvent/anti-solvent combinations preferred according to the description include water/acetone, acetonitrile/water, ethanol/water, methanol/water, acetic acid/water.

Finally, the crystalline forms of the optical enantiomers of modafinil can be isolated by conventional methods such as filtration and centrifugation.

For illustration, the preparation process described above is particularly applied to the levogyre enantiomer of modafinil.

Depending on the particular embodiment, the crystalline form obtained by this process is a polymorphic form.

It should be noted that, in general, each of the enantiomers (l) and (d) of a given chemical compound, when recrystallized under the same experimental conditions, leads to crystalline forms, particularly polymorphic, with identical powder X diffraction spectra.

Reference is made in this connection to J. Bernstein's work Polymorphism in molecular crystals 2002, University Press, Oxford, UK, and to the publication by G. Coquerel, Enantiomer, 2000; 5(5): 481-498; Gordon and Breach Science Publishers.

For this reason, the dextrogynous form whose X-diffraction spectra of the crystalline forms are identical to those of the levogynous form described below and reciprocally are part of the description.

In the following, the polymorphic forms referred to as forms I, II, III, IV and V thus cover the forms CRL40982 forms I, II, III, IV, V obtained from the levogyre enantiomer and the forms CRL40983 forms I, II, III, IV, V obtained from the dextrogyre enantiomer.

Form I

In this context, the process using a solvent selected from acetone, ethanol, dioxane 1-4, ethyl acetate and mixtures of ortho, meta, paraxylene, and a slow-cooling crystallization step leads to the formation of form I or CRL40982 form I.

The process using a solvent selected from methanol, water or alcohol/water mixtures, in particular methanol/water and ethanol/water, and a rapid cooling crystallization step leads to Form I or CRL 40982 Form I.

According to another also preferred variant of the description, the process using methanol and a precipitation crystallization step by addition of cold water as an antisolvent of methanol leads to the form I.

Form II

The process is described herein by using a solvent in step (i) chosen from isopropanol, ethyl acetate, n-propanol, or ethanol denatured to toluene, and a rapid cooling crystallization step leading to a polymorphic form designated Form II or CRL 40982 Form II.

In a variant of the process, the form II can also be obtained by slow cooling in isopropanol.

It can be noted that the formation of the form II in isopropanol is not dependent on crystallization conditions (thermodynamic or kinetic).

Form III is amended as follows:

According to another variant of the process described herein, the solvent used in step (i) is acetone, and the crystallization step (ii) consists of rapid cooling, which apparently leads to the formation of a polymorphic form designated form III or CRL 40982 form III.

Form IV

In a variant of the process described herein, the solvent used in step (i) is chosen from tetrahydrofuran, chloroform and methyl ethyl ketone, and the crystallization step (ii) consists of a slow cooling of the solution, resulting in a polymorphic form designated form IV or CRL 40982 form IV.

The recrystallization process of modafinil optical enantiomers may, depending on the nature of the solvent used, lead to solvates.

V-shape

In a variation of the process described herein, the solvent used in step i) is chosen from 2-pentanone and tetrahydrofuran, and the crystallization step ii) consists of a slow cooling of the solution in 2-pentanone and a rapid cooling in THF, resulting in a polymorphic form designated V-form.

Dimethyl carbonate solvate

When the solvent used in step (i) is dimethylcarbonate and the crystallization consists of a slow cooling, a dimethylcarbonate (-) -modafinil solvate is obtained.

Acetic acid solvate

When the solvent used in step (i) is acetic acid and the crystallization consists of a slow or rapid cooling, an acetic acid solvate is obtained.

• Polymorphic forms of (-) - Modafinil

The polymorphic form of the levogyre enantiomer of modafinil, designated CRL 40982 form II, is also described here, characterised by producing an X-diffraction spectrum comprising intensity lines at reticular distances of: 11,33; 8,54; 7,57; 7,44; 4,56; 3,78; 3,71 Å, with intensity lines corresponding to reticular distances of: 8,54; 7,57; 7,44; 4,56; 3,78; 3,71 Å being particularly characteristic.

Specifically, the following X diffraction spectrum, in which d is the reticular distance and I/Io the relative intensity: - What?

CRL 40982 FORME II
2 Theta (degrés)	d (Å)	I/Io (%)
11,6	11,33	54
15,4	8,54	58
17,4	7,57	41
17,7	7,44	34
23,3	5,67	19
24,8	5,33	26
27,4	4,83	19
28,9	4,59	36
29,1	4,56	97
29,8	4,45	23
32,8	4,05	29
34,3	3,88	23
35,3	3,78	100
35,9	3,71	40
40,1	3,34	21
47,7	2,83	20
53,7	2,53	32

Diffractomètre: Miniflex Rigaku (Elexience)

The polymorphic form of the levogyre enantiomer of modafinil designated CRL 40982 form III, characterised by the X-diffraction spectrum comprising intensity lines at the following reticular distances d: 13.40 ; 12.28 ; 8.54; 7.32; 6.17; 5.01; 4.10; 3.97; 3.42; 3.20 Å, and the reticular distances: 12.28; 8.54; 5.01; 4.10; 3.97; 3.42; 3.20 Å corresponding to the most characteristic intensity lines, is described here.

The following X-diffraction spectrum is produced by the (-) -modafinil form III, where d is the reticular distance and I/ Io is the relative intensity. - What?

CRL 40982 FORME III
2 Theta (degrés)	d (Å)	I/Io (%)
9,8	13,40	40
10,7	12,28	39
15,4	8,54	100
18,0	7,32	33
21,4	6,17	23
25,9	5,11	26
26,4	5,01	87
29,6	4,48	26
29,9	4,44	20
31,1	4,27	34
31,7	4,19	20
32,4	4,10	77
33,1	4,02	23
33,5	3,97	64
36,5	3,66	38
39,1	3,42	40
41,9	3,20	32
46,4	2,91	23
52,7	2,58	25

Diffractomètre: Miniflex Rigaku (Elexience)

The polymorphic form of the levogyre enantiomer of modafinil, designated CRL 40982 form IV, is described here, characterised by producing an X-diffraction spectrum comprising intensity lines at the reticular distances: 12,38; 8,58; 7,34; 6,16; 5,00; 4,48; 4,09; 3,66 Å, the most characteristic lines corresponding to the reticular distances of 12,38; 8,58; 7,34; 5,00; 4,09 Å.

Specifically, the IV form of (-) -modafinil is characterised by producing the following X diffraction spectrum, where d is the reticular distance and I/ Io the relative intensity comprising intensity lines at reticular distances: - What?

CRL 40982 FORME IV
2 Theta (degrés)	d (Å)	I/Io (%)
6,37	13,88	26
7,14	12,38	69
8,60	10,27	23
10,30	8,58	100
12,04	7,34	49
14,37	6,16	24
15,65	5,66	11
17,30	5,12	29
17,72	5,00	60
19,12	4,64	15
19,81	4,48	25
20,82	4,26	10
21,24	4,18	12
21,70	4,09	51
23,28	3,82	9
24,30	3,66	30
25,18	3,53	9
26,02	3,42	21
27,13	3,28	9
27,90	3,20	15

Diffractomètre : Siemens AG.

The polymorphic form of the dextrogyl enantiomer of modafinil designated CRL 40983 form V, characterised by producing an X-diffraction spectrum comprising intensity lines at reticular distances: 9.63 ; 5.23; 5.03 ; 4.74 ; 4.66 ; 4.22 ; 4.10 ; 3.77 (Å), is described here. - What?

CRL 40983 FORME V
2 Theta (degrés)	d (Å)	I/Io (%)
6,65	13,27	22
7,24	12,21	5
9,17	9,63	51
10,38	8,51	19
12,28	7,20	15
14,33	6,17	14
15,81	5,60	4
16,95	5,23	68
17,64	5,03	100
18,69	4,74	51
19,03	4,66	58
20,06	4,42	3
21,06	4,22	91
21,67	4,10	64
22,39	3,97	17
23,61	3,77	55
24,64	3,61	8
25,40	3,50	13
26,21	3,40	20
26,95	3,31	18

Diffractomètre : Bruker GADDS

The dimethylcarbonate solvate of (-) -modafinil is described here, characterised by the following diffraction spectrum in which d is the reticular distance and I/I the relative intensity: - What?

SOLVATE DE DIMETHYLCARBONATE
2 Theta (degrés)	d (Å)	I/Io (%)
7,17	12,31	38
9,12	9,69	29
9,72	9,09	16
10,35	8,54	35
12,17	7,27	100
14,25	6,21	16
16,26	5,45	10
17,36	5,10	13
17,72	5,00	21
18,35	4,83	9
19,16	4,63	9
19,88	4,46	14
21,04	4,22	12
21,49	4,13	25
21,73	4,09	24
23,49	3,78	22
24,55	3,62	35
25,24	3,53	8
26,05	3,42	9
26,88	3,32	7
27,48	3,24	13
27,81	3,21	10
28,79	3,10	8

Diffractomètre : Siemens AG.

The acetic acid solvate of the levogyre and dextrogyre enantiomers of modafinil, which can be obtained by the recrystallization process of the invention, is described here, characterised by producing an X-diffraction spectrum comprising intensity lines at reticular distances: 9.45; 7.15; 5.13; 4.15; 3.67 (Å). - What?

SOLVATE D'ACIDE ACETIQUE
2-Theta (degrés)	d (Å)	I/Io %
6,64	13,30	8,5
7,15	12,35	15
9,36	9,45	100
10,43	8,48	6,5
12,38	7,15	25
14,38	6,16	15
16,37	5,41	8
17,29	5,13	28
17,82	4,97	21
18,24	4,86	16
18,96	4,68	7
19,24	4,61	6
20,09	4,42	20
21,40	4,15	75
22,55	3,94	21
23,42	3,80	7
24,25	3,67	40
24,92	3,57	12
25,21	3,53	9,5
26,15	3,40	11
26,78	3,33	8
26,99	3,30	6
28,43	3,14	13
28,79	3,10	14
29,63	3,01	7
30,03	2,97	4
32,33	2,77	9
33,13	2,70	7
34,29	2,61	3
34,86	2,57	7
35,90	2,50	7

Diffractomètre : Bruker GADDS

In addition, the description also concerns a process of conversion of a first crystalline form of one of the enantiomers of modafinil into a second crystalline form distinct from the first, which consists of the steps: (ii) recover the resulting crystalline form.

As solvents that may be suitable for this process, acetonitrile is one example.

The initial crystalline form is generally kept in suspension at a temperature below the homogenization temperature for a sufficient time to allow the total conversion of the initial form. This time may vary depending on the nature of the solvent, the initial crystalline form, the temperature of the medium.

This is illustrated by the use of (-) -modafinil.

In this context, according to a particular embodiment of the description, the process implements the form I in acetonitrile at step i) to obtain an acetonitrile solvate of (-) -modafinil.

For example, the form I is kept in suspension for several days, preferably for 3 days at room temperature and atmospheric pressure.

The acetonitrile solvate of (-) -modafinyl, which can be obtained by the recrystallization process of the invention, is described here and is characterized by the following diffraction spectrum, where d is the reticular distance and I/I is the rotational intensity: - What?

SOLVATE D' ACETONITRILE
2 Theta (degrés)	d (Å)	I/Io (%)
5,46	16,17	46
6,25	14,14	95
7,17	12,32	51
8,28	10,66	81
9,02	9,79	68
9,51	9,29	53
10,34	8,54	53
10,84	8,15	63
11,33	7,80	79
12,47	7,09	53
14,02	6,31	45
15,20	5,83	35
15,76	5,62	34
16,37	5,41	40
17,37	5,10	51
18,10	4,90	46
19,05	4,66	44
19,36	4,58	37
19,89	4,46	39
20,48	4,33	59
21,14	4,20	55
22,10	4,02	100
22,65	3,92	60
23,17	3,835	42
23,89	3,72	33
24,72	3,60	38
24,93	3,57	37
25,81	3,45	37
26,73	3,33	55
27,52	3,24	30
27,97	3,19	30
28,89	3,09	31
29,44	3,03	27

Diffractomètre : Siemens AG.

• Pharmaceutical formulas including polymorphic forms II, III, IV and V of (-) - Modafinil, (+) - Modafinil respectively

Pharmaceutical formulations including the polymorphic forms CRL 40982 form II, CRL 40982 form III, CRL 40982 form IV or CRL 40982 form V of (-) modafinil, CRL 40983 form II, CRL 40983 form III, CRL 40983 form IV and CRL 40983 form V, respectively, are described herein, possibly in combination with a pharmaceutically acceptable vehicle.

These compounds may be administered orally, by the mucous membrane (e.g. ocular, intranasal, pulmonary, gastric, intestinal, rectal, vaginal, or via the urinary tract) or parenterally (e.g. subcutaneously, intradermally, intramuscularly, intravenously, or intraperiotoneally).

The pharmaceutical formulations of the invention are given orally in the form of immediate-release or controlled-release tablets, pills, capsules or granules, in the form of powder, capsules, suspension in a liquid or gel, emulsion or lyophilisate, preferably in the form of tablets, capsules, suspension in a liquid or gel. The delivery vehicle may contain one or more pharmaceutically acceptable excipients that are likely to ensure the stability of polymorphic forms (e.g. a suspension of a polymorph in an oil).

The pharmaceutical formulations described herein include the polymorphic forms of (-) -modafinil and (+) -modafinil, II, III, IV or V, respectively, possibly in combination with each other and/or with one or more pharmaceutically acceptable excipients.

A solid composition for oral administration is prepared by addition to the active substance of one or more excipients, including a filler, and, where appropriate, a binder, a deleting agent, a lubricant, a surfactant and an emulsifier, a solubiliser, a colouring agent, a sugar substitute or a flavour enhancer, and by forming the mixture, for example in the form of tablets or capsules.

Examples of loading include lactose, sucrose, mannitol or sorbitol; cellulose-based preparations, such as, for example, corn starch, rice starch, potato starch.

Examples of binders include gelatine, gum, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone (PVP), povidone, copovidone, dextrane, dextrin, cyclodextrin and its derivatives such as hydroxypropyl-β-cyclodextrin.

Examples of sugar substitutes include aspartame, saccharin, and sodium cyclamate.

Examples of flavor enhancers include cocoa powder, mint in the form of herbs, aromatic powder, mint in the form of oil, borneol and cinnamon powder.

Examples of surfactants and emulsifiers include in particular polysorbate 20, 60, 80, sucrose (7-11-15), poloxamer 188, 407, PEF 300, 400 and sorbitate stearate.

Examples of solubilising agents include miglyole 810, 812, glycerides and their derivatives, propylene glycol.

Examples of deleterious agents include, for example, polyvinyl pyrrolidone, sodium carmelose or alginic acid or a salt thereof such as sodium alginate.

Examples of lubricants include magnesium stearate, sterilized magnesium fumarate, behenic acid, and its derivatives.

The pharmaceutical formulations described herein may also contain another crystalline form of (-) -modafinil or (+) -modafinil, respectively, including form I and/or another active or inactive ingredient mixed with one or more other polymorphic forms of modafinil, such as form III, form II, form IV and form V.

Err1:Expecting ',' delimiter: line 1 column 92 (char 91)

CRL 40982 form II, CRL 40982 form III, CRL 40982 form IV or CRL 40982 form V of (-) -modafinil CRL 40983 form II, CRL 40983 form III, CRL 40983 form IV or CRL 40983 form V of (+) -modafinil, respectively, are described herein for use in the manufacture of a medicinal product for the prevention and/ or treatment of a selected condition of hypersomnia, including idiopathic hypersomnia and hypersomnia in cancer patients treated with morphine analgesics to relieve sleep; sleep apnea, excessive sleepiness associated with illness, sleeping pain, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, narcolepsy, and others are some of these are also known as the most commonly all known as drugs that are not to be used by humans and are not used by humans and are not the same as drugs.excessive sleepiness, excessive sleepiness related to narcolepsy; central nervous system disorders such as Parkinson' s disease; protection of brain tissue from ischemia; alertness disorders, including alertness disorders related to Steinert' s disease, attention deficit hyperactivity disorder (ADHD) for example; fatigue, especially associated with multiple sclerosis and other degenerative diseases; depression, depressed working-related sun exposure, schizophrenia, low turnover, shifting time; eating disorders;In this study, modafinil was used to stimulate appetite, stimulating cognitive function at low doses.

• MODEFINIL OPTICALLY ACTIVE is not intended to be used in the treatment of patients with severe liver disease.

In another respect, the description refers to a process for the preparation of modafinil optical enantiomers from modafinil acid (±) which includes the following steps: (i) to duplicate the two optical enantiomers of modafinil acid (±) and recover at least one of the enantiomers; (ii) to contact one of the two enantiomers obtained with a lower alkyl haloformate and an alcohol in the presence of a base; (iii) to recover the product obtained; (iv) to convert the ester obtained in step (iii) to amide; (v) to recover the product obtained in step (iv).

Preferably, the lower alkyl haloformate is a lower alkyl chloroformate and, better still, it is methyl chloroformate.

The advantage is that the lower alkyl haloformates, including methyl chloroformate, used in this process to esterify modafinil acid, are less toxic than dimethyl sulphate described in the earlier US 4.927.855 process for equivalent or even better yields.

Preferably, an equimolar amount of alkyl halogenate is used, lower and more basic at step (ii) than optically active modafinil acid.

Organic bases, preferably nitrogen bases, are particularly preferred.

The most commonly used base is triethylamine, diisopropylamine, diethylmethylamine, diisopropylethyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Preferably, the solvent used in step (ii) is a lower aliphatic alcohol such as methanol, ethanol, propanol, methanol being particularly preferred.

In a particular manufacturing process, the ester obtained at the end of step (ii) is crystallized by the addition of ice water.

The conversion of the ester to amide in step iv) is preferably by ammonolysis, i.e. treatment with ammonia.

In this context, it is usually preferable to operate with excess ammonia.

According to a preferred variant of the description, the ammonia used is in gaseous form.

The ammonolysis reaction is preferably carried out in a polar solvent, preferably a protic solvent such as lower aliphatic alcohols, e.g. in methanol or ethanol, methanol being particularly preferred.

The recovery of the ester of the (+) or (-) modafinil acid in step iii and of the (+) or (-) modafinil in step iv respectively is carried out by conventional methods known to the professional.

In another respect, the description is concerned with a process for the preparation of modafinil optical enantiomers including the following steps: a. to duplicate the two optical enantiomers of modafinil acid (±) or its salts by a preferential crystallization process;

Depending on the preferred method of implementation, step (b) is carried out in two steps: (b1) convert the enantiomer into a lower alkyl ester; (b2) convert the product obtained in step (b1) into an amide.

In a particularly preferred method, step (b1) is performed in the presence of a lower alkyl haloformate, an alcohol and a base, under the conditions described above.

According to a particularly advantageous method, where b1) is obtained in the presence of methyl chloroformate, a base and an alcohol, and c1) consists of an ammonolysis as described above, this method, in which the (±) modafinil acid is split by preferential crystallization, results in an overall yield generally of the order of 25%. Thus, the yield obtained by this method of the enantiomer (-) modafinil in particular is significantly higher than that obtained in US Patent 4,927,855.

The preferential crystallization technique is a widely used technique in laboratories and industry.

This method is based on the alternate crystallization of two chiral compounds called R and S, producing a conglomerate in a solvent A and for a given temperature range DT. This means that in this temperature range, any mixture, in thermodynamic equilibrium of the two antipodes with the solution, consists of two types of crystals each containing only molecules of the same configuration, incorporating or not solvent molecules (solvates).

Two classes of factors influence the crystallization of optical antipodes, on the one hand, parameters related to ternary heterogeneous equilibriums and, on the other hand, factors affecting the crystallization kinetics.

The parameters related to ternary heterogeneous equilibriums include: the positions of the crystallization layers of solids which are deposited at each temperature and, in particular, the values of the solubilities of the stable and metastable phases, of the racemic mixture s(±) and of the antipodes s(+) = s(- depending on the temperature, and the ratio of the solubilities α = s (±) / s(+);the extent of the stable and metastable domains of solid solutions, racemate, racemic solvate, active solvates and polymorphic varieties of crystallized solids.

Factors affecting the crystallization kinetics include: internal factors in the crystals, in relation to the bonds between the molecules, which cannot be modified by the experimenter; external factors which can be modified by the experimenter; these are the nature of the solvent, the nature and concentration of impurities, the oversaturation acquired over time, the temperature range DT, the speed and mode of agitation, the mass and particle size of the germs, the wall effect, etc.

These two classes of factors directly influence the yield, the purity of the phases obtained and the conduct of the separation operations. The feasibility of filtration will thus depend on the granulometer spectrum and habit of the crystals, the viscosity of the suspension, the vapour pressure of the solvent, the supersaturations acquired by each of the antipodes and the possible presence of a true racemate with a metastable character.

For each set consisting of the antipodal pair (R and S) and the solvent (A), the factors affecting kinetics are a special case.

Err1:Expecting ',' delimiter: line 1 column 177 (char 176)

In the preferential AS3PC self-seeded crystallization method, the system is placed in such a condition that it generates its own germs for the production of the desired enantiomer, while in the SIPC method these germs are introduced by seeding.

For further information on the processes of preferable crystallization by AS3PC, reference may be made to the papers of G. Coquerel, M.-N. Petit and R. Bouaziz, Patent EP 0720595 B1, 1996; E. Ndzié, P. Cardinaël, A.-R. Schoofs and G. Coquerel, Tetrahedron Asymmetry, 1997, 8 (((17), 2913-2920; L. Courvoisier, E. Ndzié, M.-N. Petit, U. Hmann, U. Sprengard and G. Coquerel, Chemistry Letters, 2001, 4, 364-365.

Depending on the particular embodiment, the process of splitting the optical enantiomers of modafinil acid (±) or its salts is a SIPC or S3PC seeded process, which includes the following steps: (a) homogenise at a temperature TD a set consisting of the racemic mixture of crystals in conglomerate form, the first enantiomer of modafinil acid and solvent, the figurative point E of which, defined by the variables concentration and temperature TD, is in the single phase domain of the diluted solution; (b) rapidly cool the solution prepared at step a) initially at the temperature TD to the temperature TF; (c) seed the solution obtained at step b) during (i) the dilution process.(e) add to the mother liquors resulting from the harvest at step (d) the racemic mixture of crystals in the form of conglomerate and homogenise the new set by heating to a temperature TD, so that the figurative point E' is symmetrical to E in relation to the racemic mixture plane of the solvent system, antipode (-), antipode (+), said point E' being in the monophasic domain of the dilute solution;(g) to the temperature TF; (f) to seed the solution obtained in step f) in very pure germs of the second enantiomer; (h) to harvest the crystals of the second enantiomer; (i) to add to the mother liquors resulting from the crystalline harvest in step h) the racemic mixture in the form of a crystal conglomerate and to homogenise the new set by heating to a temperature TD to obtain an identical composition of the entire figurative set at the initial point E; (j) to repeat steps a), b), c), d), e), f), h) and j) to obtain successively the first and then the second enantiomer.

Err1:Expecting ',' delimiter: line 1 column 116 (char 115)

In the following, for the purposes of the present invention, are referred to as: by TF the end temperature of crystallization and filtration, located in the three-phase domain; by TL the homogenization temperature of the racemic mixture; by TD the starting temperature for which the starting mixture is a homogeneous solution; by antipod, an enantiomer.

Preferably, the process of splitting the two optical enantiomers of modafinil acid (±) or their salts by preferential crystallization is an AS3PC self-seeding process, which includes the following steps: (a) make a set consisting of the racemic mixture of crystals in conglomerate form, the first enantiomer of modafinil acid and solvent, the figurative point E of which, defined by the variables concentration and temperature TB, is in the biphasic domain of the excess enantiomer and is in equilibrium with its saturated solution;(c) adjust during the whole period of crystalline growth of the stage (b) a slightly increasing agitation rate with time so that it is at all times sufficiently slow to favour growth of the first enantiomer by avoiding generating too large forces of strictation causing uncontrolled nucleation and sufficiently fast to achieve a homogeneous suspension and rapid renewal of the enantiomer around each crystalline enantiomer; (d) recollect the enantiomer in the first enantiomer; (e) recollect the enantiomer in the first enantiomer, resulting in the addition of the enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomeric enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiomer enantiand bring the new assembly to a temperature level TB for the time necessary to achieve thermodynamic equilibrium, so that the figurative point E' is symmetrical to E in relation to the plane of the racemic mixtures of the solvent system, antipod (-), antipod (+), with said point E' being in the biphasic domain of the second enantiomer in excess and in equilibrium with its saturated solution;during the whole period of crystalline growth of step f), a stirring rate slightly increasing with time so that it is at all times slow enough to promote the growth of the second enantiomer, avoiding the generation of too large a tightening force causing uncontrolled nucleation, and fast enough to achieve a homogeneous suspension and rapid renewal of the parent liquor around each crystallite of the second enantiomer;(b), (c), (d), (e), (f) (g), (h) and (i) to obtain successively the first and then the second of the two enantiomers.

In the following, for the purposes of the present invention, THOMO is the homogenization temperature of the racemic mixture, the first enantiomer and the solvent.

Thus, at step (a) of the invention process, the choice of solvent (s) and the operating temperature range are defined so as to have simultaneously: Antipodes forming a conglomerate and the possible racemate of which is metastable in the working temperature range; liqueurs sufficiently concentrated but of low viscosity and low vapour pressure; absence of solvolution and racemisation; stability of solvates if they are present at equilibrium and if they are di-double enantiomers.

At steps (a) and (e) of the process of the invention, the TB temperature is higher than the TL temperature of homogenization of the amount of racemic mixture contained in the initial suspension, and that, from the THOMO variation curve for enantiomeric excess and for a constant concentration in racemic mixture XL, the TB temperature is defined so that the mass of fine crystals of the first enantiomer of steps (a) and (i) and the second enantiomer of step (e), in equilibrium with their saturated solution, is between 50% and no more and preferably about 25% and 40% of the expected harvest.

At steps (b) and (f) of the invention process, the programming law for cooling from TB to TF, suitable for experimental assembly, is defined as follows: to obtain a low oversaturation during the whole crystallization period of the enantiomer present as crystals at the beginning of each cycle, this low oversaturation causing a mild secondary growth and nucleation; to achieve at TF the maximum oversaturation of the other enantiomer without primary nucleation; to obtain a crystal harvest at steps (d) and (h) which, after addition of racemic mixing and compensation at steps (e) and (i), allows cyclicity of operations.

The experimental assembly affects the saturation capacity of the mixtures used and the efficiency of the agitation, and, consequently, the programming law of cooling is adapted to the circumstances in which the process is carried out.

The cooling programming law, which is the function relating temperature to time, is determined for its part from TL to TF by cooling the solution at concentration XL from TL + 1°C to TF, TF being less than TL - (THOMO - TL), in order to obtain a stable saturated solution without primary nucleation while allowing a double harvest of the initial enantiomeric excess, and the said cooling programming law is determined for its part from TB to TL by extrapolation of this same determined law from TL + 1°C to TF.

The preferential crystallization process of (±) -modafinil acid or its salts has other advantageous characteristics, either alone or in combination, such as: at steps (a) and (i), the mass of crystal ends of the first enantiomer in equilibrium with its saturated solution is approximately 25% to 40% of the expected yield, 50% being a maximum limit; at step (e), the mass of crystal ends of the second enantiomer in equilibrium with its saturated solution is approximately 25% to 40% of the expected yield, 50% being a maximum limit; at steps (b) and (f), the thermicity accompanying the deposition of the first enantiomer and the second enantiomer is integrated into the temperature programming law; at steps (e) and (i),compensation is made by solvent; at steps (a), (e) and (i), the crystalline end of the racemic mixture in conglomerate form which is added has undergone prior treatment which accelerates the dissolution stage, such as grinding and sifting, ultrasonic treatment, partial freezing, before being introduced; these treatments are also intended to provide crystalline end to generate a growth surface; high crystalline end at steps (a), (e) and (i), involving dissolution, has a high agitation rate compared to steps (c) and (g).

In addition to the heterogeneous equilibrium data required to implement the AS3PC process, the operations are also subject to adjustable kinetic constraints, in particular the cooling law, which are a special case for each solvent/enantiomeric set.

Depending on the method of manufacture, the solvent used in step (a) of the SIPC, S3PC or AS3PC processes is absolute or denatured ethanol, possibly mixed with an organic or mineral base or even with one or more solvents, which may improve the solubility of the racemic mixture in ethanol.

Alternatively, the solvent used in step (a) of the SIPC, S3PC or AS3PC processes is 2-methoxyethanol or methanol, possibly mixed with an organic or mineral base, and/or one or more solvents, which may improve the solubility of the racemic mixture in ethanol.

Depending on the preferred method of manufacture, the solvent used in step (a) of the SIPC or AS3PC process is ethanol, 2-methoxyethanol or methanol.

In the case of ethanol, the TF temperature is preferably between 0°C and 25°C, and even better it is close to 18°C or 17°C.

For 2-methoxyethanol or methanol, the TF temperature is preferably between 20°C and 35°C and in particular close to 30°C.

Preferably, the concentration of the racemic mixture at step (a) is then between 2 and 50% by mass, preferably between 2 and 30% by mass, and even better, close to 5,96% by mass in the case of ethanol, 15,99% in the case of 2-methoxyethanol and 25,70% in the case of methanol.

In this context, it is particularly desirable that the enantiomeric excess in step (a) be between 1 and 50% by mass, preferably between 1 and 20% by mass, and even better, close to 11% by mass in the case of ethanol, 8% by mass in the case of 2-methoxyethanol and 10% by mass in the case of methanol.

The TD temperature of the SIPC and S3PC processes, at which the starting mixture is a homogeneous solution, depends on the concentration and is then generally between 35° and 50°C at the solvent's reflux.

In a preferred mode of the AS3PC process, the TB temperature is then between TL and THOMO temperatures.

For example, in the case of ethanol, where the enantiomeric excess is close to 11% by mass, the TB temperature is preferably between 25°C and 40°C, in particular between 30,1°C and 36.2°C and more preferably close to 33.5°C or 31.5°C.

For 2-methoxyethanol, where the enantiomeric excess is close to 8% by mass, the TB temperature is preferably between 35°C and 50°C, in particular between 39.1°C and 47.9°C and more preferably close to 41°C.

In the case of methanol, where the enantiomeric excess is close to 10% by mass, the TB temperature is preferably between 40°C and 55°C, in particular between 45.1°C and 53.9°C and more preferably close to 46.5°C.

It is particularly desirable that TB to TF cooling in step (b) be carried out in a time sufficiently long to ensure that the mean mass of the enantiomer crystals harvested is large, but sufficiently short to prevent the enantiomer counter from crystallizing and thus achieve a high optical purity, especially above 85%.

Similarly, the bearing life at TF for SIPC, AS3PC and S3PC processes is preferably sufficiently long to allow a high crystal mass of desired enantiomers to be harvested, but not too long to prevent the counter-enantiomer from crystallizing at the same time as the desired enantiomer, and thus to achieve high optical purity.

The temperature bearing TF shall be used in a preferred mode for a duration of 15 to 60 minutes, preferably approximately 60 minutes.

The operator can adjust the agitation rate to the type of reactor used in the SIPC, S3PC or AS3PC processes.

Of particular interest is that these preferential crystallization methods allow the isolation of modafinil optical enantiomers, including the levogyre enantiomer, with yields much higher than those obtained by doubling with a chiral agent.

• AS3PC, SIPC and S3PC methods

The AS3PC and SIPC methods mentioned above are described below.

Ternary heterogeneous equilibriums: antipodes R and S, and solvent A

For example, J. E. Ricci (Ed. Dover Publication Inc. New York, 1966, The Phase Rule and Heterogeneous Equilibrium) deals with the general case of heterogeneous equilibriums in ternary systems.

To highlight the particular role of the solvent, this ternary system will be represented from a right triangle-section prism with an isosceles rectangle, on which the temperature is plotted on an axis perpendicular to the concentration plane.

The identity of the thermodynamic variables of the two enantiomers: Tf, ΔHf, solubility in an achiral solvent, etc., makes the representation of the domains symmetrical with respect to the vertical plane A-TS-T, bringing together the optically inactive mixtures, of Figure 1. The only phases that crystallize are the pure constituents in a given arrangement (no racemate, solvate and polymorphism for the antipodes); the miscibility between the independent constituents is zero at the solid state; the solvent has a melting point significantly lower than that of the antipodes; in the temperature range exploited, the solubility of one antipod is not influenced by the presence of the second in the solution (Meyerhoffer's law respected), which results in a value of the ratio α = 2).

Representation of ternary equilibriums by temperature

Figure 1 shows the following phases: the single phase domain of the diluted solution (Φ = 1);the three crystallization layers of the constituents delimiting the two phase domains (Φ = 2). The deposition surface of the solvent is confined to the vicinity of A, because the melting point of this constituent is much lower than that of the other constituents, in accordance with the conditions mentioned above; the three monovariant curves (Φ = 3) or eutectic valleys arising from the binactic eutectic points; the ternary eutectic invariant at Tε (Φ = 4), below which the three constituents are crystallized.

Figure 2 shows two isothermal TD and TF cuts of the ternary shown in Figure 1 superimposed on each other. At each temperature the cut is composed of four areas as detailed in the table below. - What?

Température	Limite du domaine	Nature des phases à l'équilibre	Nombre de phases à l'équilibre
		solution diluée	1
		solution + cristaux de R	2
		solutions + cristaux de S	2
		solution + cristaux de R et S	3
		solution diluée	1
		solution + cristaux de R	2
		solution + cristaux de S	2
		solution + cristaux de R et S	3

RYT isoplet cutting

Figure 3 shows the isoplet cut R-Y-T which is fundamental in understanding the crystallization driven by cooling of ternary solutions, in near thermodynamic equilibrium. This same cut is also necessary for monitoring out-of-equilibrium processes, SIPC, variants and AS3PC. This plan is the geometric location of the points checking the relationship: with XA and XS giving the mass fractions in solvent and in antipodes S.

Figure 3 shows the following: This stable equilibrium curve is formed by the fusion of the antipodes R (not shown) and is bounded towards low temperatures by the point L, belonging to the tertiary eutectic valley of racemic mixtures. This last curve and the coneid line at TL (horizontal segment at TL) delimit the biphasic domain: saturated solution with more crystals of R; it extends into the underlying triphasic domain by a solubility curve with the same characteristic of the antipodes R (in the transverse direction); the T- and S-phases of the field,This region is bounded at the top by the horizontal trace of the conoid of R, downwards by the trace of the ternary eutectic invariant plane, at the left by the trace Lm of one of the conoids relative to the antipod S. The KL trace of the antipod S crystallization sheet which limits at the top the biphasic region : saturated solution plus crystals of S. This region is bounded at its bottom by the traces of the two conoids of S : gm and Lm. The location of this second trace Lm of the ternary eutectic plane relative to the curve of R stability of solubility of the protrusion will be discussed further from the relative position of F1 and F1 relative to α; the functional variabilities of T are the three most important constituent solubilities of the ternary trubulus of EL,R and S.

Evolution at cooling and near thermodynamic equilibrium of ternary solutions with low enantiomeric excess

It is considered that the whole point of the system (i.e. the point representative of the overall composition of the mixture) is on the vertical passing through point E in Figures 2 and 3, its precise position being defined by its temperature (or slope). TD: temperature at which the starting mixture is a homogeneous solution, andTF: temperature at the end of crystallization and filtration, located in the three-phase domain.

This overall composition E corresponds to a racemic solution slightly enriched by an antipodal mass M of R and achieving a total mass Mt (the enantiomeric excess R - S / R + S is usually between 4 and 9%. The equilibrium conditions are achieved by very slow cooling and by seeding in solid phase as soon as the figurative whole point E of the mixture reaches a region where this phase (s) is (are) present at equilibrium.

At the starting temperature TD, the solution is homogeneous. At the point L, the mass M of crystals R in equilibrium with the saturated solution is given by Mt (XE - XL / 1 - XL) = M and corresponds to the enantiomeric excess present in the initial solution (Figure 3); the abscissa of points L, E and R correspond to the compositions, and 1 (Figure 3). From TL, the solution moves from point L on the monovariate curve containing the solutions of the isoplate composition, representing the isoplate solution at Figure 2, thus simultaneously leaving RY and SY; and the quantity of clay RY and IF is then equal.

The split cannot be performed under equilibrium conditions for temperatures below TL.

Evolution of the solution point during conventional drive doubling according to the SIPC process Crystallisation of the first antipod in excess

The solution E is homogenized at TD (Figures 4 and 5) and to make it supersaturated, it is rapidly cooled to TF without any crystallization appearing. This solution, out of thermodynamic equilibrium, is then seeded with very pure antipod R germs of the same chirality as the excess antipod. Isothermal crystallization of the antipod R is established and the representative point of the solution moves inside the R-Y-T cup of E at the rate with which it is first confused, to which F where a rapid filtration is carried out.

Crystallisation of the second antipodes, cyclicity of operations

The previous basic operation thus created a solution F enriched in antipodes S. By adding a mass of 2M of racemic mixture (equal to that of the recovered antipodes) and heating this mixture to the temperature TD, a homogeneous solution E' symmetric of E with respect to the vertical plane A-(RS) -T is obtained. The process for obtaining a mass of 2M of antipodes S will also be represented by a path symmetric of the previous one with respect to this median plane. The solution E' homogeneous at TD is first cooled at TF and then seeded into very pure antipodal germs S; the growth of this antipodal moves the solution representative point on the horizontal segment E'F' (at TF level); when the solution point is mixed with F', the solution is filtered and gives a 2M antipodal mass S; after a further addition of a 2M mass of racemic mixture and a further heating at TD, a homogeneous solution is obtained again; the initial representative point is mixed with point E at TD level and the process simply repeats this cycle of operations.

Variants of the SIPC process

The literature (Camelot, G., 1956, Bull. Soc. Chem. Fr. 447; Collet, A., Brienne, M. J., Jacques, J., 1980, Chemical reviews 80, 3, 215-30; Noguchi Institute, 1968, patent GB 1 197 809) is based on the above general scheme; the main changes which have appeared in the literature are classified as follows: (a) Spontaneous primary nucleation of the excess antipodes In the case of the splitting of (±) threonine (Amiard, G., 1956, Bull. Soc. Chim. Fr. 447), the primary nucleation of the excess antipodes occurs spontaneously in the supersaturated homogeneous solution, when the point E, representing the composition of the assembly, is in the three-phase domain and the solution is not agitated (Collet,(b) Sowing during cooling (S3PC) This protocol is most frequently encountered in the literature (Noguchi Institute, 1968, patent GB 1 197 809) when the process differs from SIPC. cooling of the homogeneous TD solution to a temperature below TL but above TF;seeding of the supersaturated homogeneous solution in the three-phase domain by germs of the same chirality as the excess antipodes;cooling to TF.In some cases this last step is controlled by precise temperature programming (Noguchi Institute, 1968, patent GB 1 197 809).

Err1:Expecting ',' delimiter: line 1 column 91 (char 90)

Evolution of the solution point during programmed drive and self-seeding doubling according to the AS3PC process of the invention

In order to better compare the conventional processes and the AS3PC process, the initial point E is chosen arbitrarily from Figures 6 and 7, identical to the previous case; however, as will be shown in the following examples, the AS3PC process allows a point E to be taken further away from the A-(RS)-T plane and thus with a greater enantiomeric excess and thus to improve the crystal harvest of each operation.

Crystallisation of the first antipod in excess

The initial solution is then in equilibrium with the excess enantiomer crystals (e.g. R in Figure 7), so the figurative points of the solution (SE) and the ensemble (E) are not confused from the beginning of the process. This two-phase mixture is subjected to a programmed law of temperature decline without the addition of crystal germs. The representative point of the solution describes a SEF curve, contained in the R-Y-T plane, dependent on the cooling kinetics (Figure 7). With a correct kinetics regime, one obtains a simultaneous growth of the crystals, then a secondary growth rate is obtained to recover the solution from the anti-growth regime.

Crystallisation of the second antipodes, cyclicity of operations

From point F, which corresponds to the previous parent solution, we proceed to point E', symmetrical of E with respect to the vertical plane A-(RS) -T, by adding a mass of 2M of racemic mixture and heating to TB. The enantiomeric excess is used to place itself in the biphasic region containing the saturated solution and the excess antipod crystals.

The saturated solution S'E, symmetrical to SE, with respect to the plane A-(RS)-T, is subject to the same cooling law. The crystals present at the beginning of the cooling process grow and then participate in a double growth mechanism + secondary nucleation.

Meanwhile, the representative point of the solution moves along a curve SE'F' contained in the isoplet plane S-Y'-T symmetrical to the bisector plane A-(RS) -T.

When the solution reaches the representative point at F', filtration is carried out to collect a 2M mass of crushed and sifted racemic mixture followed by a temperature rise to TB returning the biphasic mixture to initial equilibrium.

Continuation of the process is then to repeat this cycle of operations giving alternately the antipodal crystals R and S.

Conditions necessary for the implementation of the AS3PC process

(a) The equimolar mixture of optical antipodes forms a conglomerate (pure or solvated antipodes) in the solvent used and for the TB-TF temperature range; however, the existence of a metastable racemate is not a handicap. (b) The molecules to be split are stable in this solvent and in the temperature range used between TB and TF. (c) Determination of the ground equilibrium temperatures TL and THOMO is necessary.It depends on the enantiomeric excess of the starting enantiomeric and the α ratio of the solubilities of the racemic mixture and the antipodes to TL. Knowledge of the supersaturation capacities of the solutions between TL and TF is also necessary, depending on the cooling kinetics, agitation mode, nature of the container and the granulometry of the crystals of the excess antipodes.This method has been taken into account in the examples. (d) Knowledge of the kinetics of dissolution of a known mass of racemic mixture (of a given particle size) dispersed in solution at TB. A few tests are sufficient to determine this duration.

The following examples and figures are given for the purpose of illustration of the present invention.

The figures

Figure 1 is a perspective representation of the ternary solvent system A - antipodes R - antipodes S, according to temperature and crystallization layers of each constituent and compositions of the doubly saturated solutions (monovariant curves); on this figure are also represented the isotherms at TD and TF temperatures and the ternary euthyxia plane at Tε and containing four phases.Figure 2 is a projection, in terms of concentrations, of equilibriums at TD and TF, as well as a representation of the isopletic cut RY, on which the point E materializes the composition of the initial mixture slightly enriched in antipodes and must deposit this same antipodes R.Figure 3 is the isoplet vertical cut RY of Figure 2 containing the points of composition of the excess antipodes and the initial solution E, on which the path, at equilibrium and cooling, of the solution point for a mixture of composition XE (in the fat strip) is shown. For T < TL, the solution point no longer belongs to this cut.Figure 4 is a projection onto the plane of the concentrations of the path of the solution point (in the fat strip) during the alternating doubling by isothermal drive at TF and seeded, according to the SC method.Figure 5 is the isoplet vertical cut containing the right path of Figure 4 RY and illustrating the isothermal treatment (in the fat strip) of the solution F and TF (in the fat strip) during the isothermal treatment.according to the SIPC method.Figure 6 is a projection on the plane of the concentration of the solution point path (in grease) when divided by the programmed and self-seeded polythermic process (AS3PC).Figure 7 is the isoplet vertical cut containing the RY line of Figure 6 and illustrating the solution point path (in grease) from SE to F when divided by the programmed and self-seeded polythermic process (AS3PC).Figure 8 is a projection on the plane of the concentration of the solution point path (in grease) when divided by the programmed and self-seeded polythermic process (AS3PC) and verifying the s± (α) - 2 < relationship.- What? All isothermal and isoplet cuts shown in these figures have variable compositions expressed in mass fractions.Figure 9 represents the X-ray diffraction spectrum on powder corresponding to the form II of the levogyre enantiomer, dextrogyre of modafinil respectively (diffractometer: Miniflex Rigaku (Elexience).Figure 10 represents the X-ray diffraction spectrum on powder corresponding to the form III of the levogyre enantiomer, dextrogyre of the modafinil (diffractometer: Miniflexaku (Elexience) respectively).Figure 11 represents the X-ray diffraction spectrum on powder corresponding to the form IV of the levogyre enantiomer, dextrogyre of the Siemens enantiomer (AG) respectively.Figure 12 shows the X-ray diffraction spectrum on powder corresponding to the dimethylcarbonate solvate of the levogyre enantiomer, dextrogyre of modafinil respectively (diffractometer: Siemens AG).Figure 13 shows the X-ray diffraction spectrum on powder corresponding to the acetonitrile solvate of the levogyre enantiomer, dextrogyre of modafinil respectively (diffractometer: Siemens AG).Figure 14 shows the X-ray diffraction spectrum on powder corresponding to the V-shape of the levogyre antigen of modafinil (diffractometer: Bruker GADDS).Figure 15 shows the X-ray diffraction spectrum on powder corresponding to the acetic acid solvate,The X-ray diffraction spectrum on powder corresponding to the amorphous form of the levogyre enantiomer is shown in Figure 16 and the dextrogyre enantiomer is shown in Figure 16 (Bruker GADDS).

Examples Preparation of crystalline forms of the enantiomer (-) - modafinil. The Commission has

The new crystalline forms of modafinil enantiomers were characterised respectively by X-ray diffraction spectroscopy on powder, which provides a unique fingerprint characteristic of the crystalline form studied and allows the differentiation of the latter from amorphous modafinil enantiomers and any other crystalline form of modafinil enantiomers.

The X-ray diffraction data were measured either: using a D5005 system as an X-ray powder diffractometer (Siemens AG, Karlsruhe, Germany, Eva 5.0 data analysis method), with nickel-filtered copper radiation of λ = 1.540 Å (with an accelerator speed of 40 KV, tube current of 40 mA) with a rotation of the sample during measurement (angle 3 to 40° [2 theta]; at a speed of 0.04° [2 theta].s-1, step size being 0.04°; sample preparation with preferential orientation).using a Miniflexaku (Elexience) Rig as an X-ray powder diffractometer,with a chromium radiation, a 30 KV accelerator speed, a 15 mA tube current and with a rotation of the sample during measurement (angle: 3 to 80° [2 theta]; at a speed of 0.05° [2 theta]. s-1, the step size being 0.1°; sample preparation with a preferential orientation).using a GADDS system as an X-ray powder diffractometer (Bruker, the Netherlands), equipped with a detector Hi-Star area and equipped for the analysis of 96 well plates.The analyses are carried out at room temperature using Cube Copper Radiation in the region between 2° and 42 theta between angles 3 and 42°.The diffraction spectrum for each well is collected between two 2 theta angle value ranges (3° ≤ 2 theta ≤ 21° and 19° ≤ 2 theta ≤ 42°) with an exposure time of 50 to 250 seconds.

The intensity values can vary depending on the preparation of the sample, the mounting and the measuring instruments. The 2 theta measurement can also be affected by variations related to the measuring instruments, so that the corresponding peaks can vary from ± 0.04° to ± 0.2° depending on the apparatus.

EXAMPLES 1 to 10: Preparation of the form I of (-) - Modafinil and (+) - Modafinil respectively • Example 1

- What? (a) The enantiomer l of modafinil was solubilized at reflux in polar solvents: methanol, absolute ethanol, absolute ethanol containing 3% water, toluene denatured ethanol (2.5%) and containing 3% water and water, according to the experimental conditions detailed in Table 1. - What? Tableau 1

Solvant	Quantité de I-modafinil (g)	Volume de solvant (ml)	Rendement %
Méthanol	8,37	≤ 50	63
Ethanol absolu	7,85	115	56
Ethanol absolu + 3% d'eau	5	70	54
Ethanol dénaturé au toluène+ 3% d'eau	5	70	56
Eau	5	≥ 400	88

- What? After rapid cooling by soaking in a bath of water and ice for 30 minutes, the medium was filtered and then dried in the oven at 35°C. The crystallized product was identified by its X-ray diffraction spectrum on powder as the l-enantiomer polymorph of modafinil. (b) The modafinil d-enantiomer (555 g), treated under the same experimental conditions as example 1a in a mixture of toluene denatured ethanol (2 L) and water (0.1 L), crystallizes to the polymorphic form I as identified by its X-diffraction spectrum on powder with an efficiency of 91%.

• Example 2: Recrystallization in acetone

(a) 2 g of (-) -modafinil is suspended in acetone (20 ml) in a tricolor balloon equipped with a refrigerant, thermometer and agitator. The mixture is heated at reflux. The reaction mixture is agitated for 30 min at approximately 56°C until the (-) -modafinil is completely dissolved. The solution is then cooled slowly at -0.5°C/min to 10°C under agitation. The reaction mixture is filtered, and the solid is dried to the I form of the (-) -modafinil identified by its X-diffraction spectrum. Efficiency 62b) The same experimental conditions applied to the (+) -modafinil lead to an identical X-diffraction spectrum.

• Example 3: Recrystallization in methanol

(a) 1 g of (-) -modafinil is added to 7 ml of methanol heated at reflux until completely dissolved. The reaction mixture is precipitated by adding 6 ml of water at 1°C. The suspension is agitated for 1 min and then filtered on a sintered glass (No. 3). The isolated solid is dried to lead to the form I of (-) -modafinil identified by its X-diffraction spectrum. Efficiency 55%.

• Example 4: Recrystallization in methanol (2e)

The clear solution is added to 200 ml of water at 1°C and left unstirred for 10 min. The reaction mixture is filtered, and the recovered solid is dried to lead to the form I of (-) -modafinil identified by its X-diffraction spectrum. Efficiency 78%. (b) The same experimental conditions applied to (+) -modafinil lead to an identical X-diffraction spectrum.

• Example 5: recrystallization in dioxane 1-4

(a) 20 mL of dioxane 1-4 is introduced into a 50 mL cylinder and carried back. 2 g of (-) -modafinil is added to achieve saturation; agitation is provided by a magnetic bar (300 Tr/min). The assembly is cooled after total solubilisation of (-) -modafinil with a cooling range of -0.5 °C/min to 20 °C. The resulting crystals are filtered on fritted glass and identified as being of shape I by its X-diffraction spectrum. Efficiency 51%. (b) The same experimental conditions applied to (+) -modafinil lead to an identical X-diffraction spectrum.

• Example 6: Recrystallization in a mixture of ortho, meta and paraxylene

(a) In a 250 mL balloon, 180 mL of a mixture of ortho, meta and paraxylene are introduced and brought to reflux. 0.5 g of (-) -modafinil is added to achieve saturation; agitation is provided by a magnetic bar (300 Tr/min). The assembly is cooled after total solubilisation of (-) -modafinil with a cooling range of -0.5 °C/min to 15 °C. The resulting crystals are filtered on to sintered glass and identified as being of shape I by its X-diffraction spectrum. Efficiency 26%. (b) The same experimental conditions applied to (+) -modafinil lead to the identical X-diffraction spectrum.

• Example 7: Recrystallization in ethyl acetate

(a) 100 mL of ethyl acetate is introduced into a 250 mL cylinder and carried backward; 2 g of (-) -modafinil is added to achieve saturation; agitation is provided by a magnetic bar (300 Tr/min). The set is cooled after total solubilisation of (-) -modafinil with a cooling range of -0.5 °C/min to 20 °C. The resulting crystals are filtered on a sintered glass and identified as form I by its X-diffraction spectrum. Efficiency 66%. (b) (+) -modafinil (3 g) was solubilised backward in ethyl acetate (100 ml). After cooling in an ice bath and heating for 30 minutes, the product was identified as form I by its X-diffraction spectrum. The polymer was then filtered and separated from the medium at 50 °C.

• Example 8: from other polymorphic forms

(a) CRL40982 form IV (0.5 g) and CRL40982 form II (0.5 g) give form I by heating at 100 °C. In addition, the pure form I of (-) -modafinil may be prepared by re-impregnating a mixture of (-) -modafinil form I (0.5 g) and form II (0.5 g) and form III (0.5 g) in acetone (20 ml) for a sufficient time to achieve complete transformation (3 days). In both procedures, form I was identified by its X-diffraction spectrum obtained on powder. (b) The implementation of (+) -modafinil (CRL 40983) under the same conditions led to the same results.

• Example 9: from acetonitrile solvate

(a) 1 g of (-) -modafinil acetonitrile solvate heated at 100 °C for 8 hours is transformed into a white solid identified as (-) -modafinil form I by its X-diffraction spectrum on powder. (b) The implementation of (+) -modafinil (CRL 40983) under the same conditions leads to the same results.

• Example 10: from monodimethyl carbonate solvate

(a) 1 g of (-) -modafinil monodimethyl carbonate solvate heated to 110 °C for 16 hours is transformed into a white solid identified as (-) -modafinil form I by its X-diffraction spectrum on powder. (b) The implementation of (+) -modafinil (CRL 40983) under the same conditions leads to the same results.

The following is a list of the active substances that are to be used in the preparation of the active substance: • Example 11 by rapid cooling

- What? (a) The enantiomer l of modafinil was solubilized at reflux in solvents: ethyl acetate, isopropanol, n-propanol and toluene denatured ethanol (2.5%), according to the experimental conditions detailed in Table 2. - What? Tableau 2

Solvant	Quantité de I-modafinil (g)	Volume de solvant (ml)	Rendement %
Acétate d'éthyle	6,33	385	53
Isopropanol	8	110	69
n-propanol	7,85	65	70
Ethanol dénaturé au toluène (2,5 %)	5	80	54

- What? After cooling by soaking in a bath of water and ice for 30 minutes, the medium was filtered and then dried in the oven at 35°C. In each experimental procedure, the crystallized product was identified by its X-ray diffraction spectrum on powder as the form II polymorph (CRL40982 form II) of the l-enantiomer of modafinil. (b) The modafinil d-enantiomer (3.02 g) was solubilised in 100 ml of reflux isopropanol and then cooled by soaking in a water and ice bath for 30 minutes, filtered and vacuum dried in the oven at 50°C. Under these experimental conditions, (+) -modafinil crystallized to the polymorphic form II (CRL40983 form II) identified by its X-ray diffraction spectrum on powder.

• Reference example 12: by cooling in isopropanol

(a) 100 mL of isopropanol is introduced into a 250 mL balloon and carried backward, then 3 g of (-) -modafinil is added to achieve saturation, the mixture is agitated with a magnetic bar (300 Tr/min). After total solubilization of (-) -modafinil, the solution is cooled slowly to 20°C with a cooling range of -0.5°C/min. The resulting crystals are filtered on a sintered glass. The crystallized product has been identified by its X-ray diffraction spectrum on powder as the polymorph of form II (CRL40982 form II) of the l-nomenclature. The efficiency differs by 42%. The same conditions apply to the (+modafinil) to obtain an X-ray diffraction spectrum.

❖ EXAMPLE 13: Preparation of the form III (CRL 40982 form III) of (-) - Modafinil, (CRL 40983 form III) of the (+) - Modafinil respectively • Reference example 13 : by slow cooling in acetone

(a) The modafinil enantiomer I (5 g) is solubilized at reflux in 90 ml of acetone. After rapid cooling by soaking in a bath of water and ice for 30 minutes, the medium is filtered and then dried in the oven at 35°C. The crystallized product has been identified by its X-diffraction spectrum on powder as the polymorph of the modafinil l-enantiomer form III. Efficiency 61%. (b) The same experimental conditions applied to (+) -modafinil lead to an identical X-diffraction spectrum.

The following is a list of the active substances that are to be used in the preparation of the active substance: • Reference example 14: Recrystallization in Chloroform

(a) 20 mL of Chloroform is introduced into a 50 mL balloon and carried back. 1.5 g of (-) -modafinil is added to achieve saturation; agitation is provided by a magnetic bar (300 Tr/min). The assembly is cooled slowly after total solubilisation of (-) -modafinil with a cooling range of -0.5 °C/min to 20 °C. The resulting crystals are filtered on a fritted glass identified as (-) -modafinil form IV by its X-powder diffraction spectrum. (b) The same experimental conditions applied to (+) -modafinil lead to an identical X-powder diffraction spectrum.

• Reference example 15: Recrystallization in methyl ethyl ketone

(a) 100 mL of methylethylketone is introduced into a 250 mL cylinder and carried back. 2 g of (-) -modafinil is added to achieve saturation; agitation is provided by a magnetic bar (300 Tr/min). The package is cooled slowly after total solubilisation of (-) -modafinil with a cooling range of -0.5 °C/min to 20 °C. The resulting crystals are filtered on a fritted glass and identified as being of the form IV modafinil by its X-powder diffraction spectrum. (b) The same experimental conditions applied to (+) -modafinil lead to the identical X-powder diffraction spectrum.

• Reference example 16: Recrystallization in tetrahydrofuran

In a 50 mL balloon, 20 mL of tetrahydrofuran is introduced and carried back. 1 g of (-) -modafinil is added to achieve saturation; agitation is provided by a magnetic bar (300 Tr/min). The package is cooled slowly after total solubilisation of (-) -modafinil with a cooling range of -0.5 °C/min to 10 °C. The resulting crystals are filtered on a fritted glass and identified as (-) -modafinil form IV by its X-diffraction spectrum on powder.

❖ EXAMPLES OF REFERENCE 17 and 17 BIS: Preparation of the form V (CRL 40982 form V) of the (+) -modafinil, of the (CRL 40983 form V) of the (+) -modafinil respectively • Mode of operation for reference examples 17 and 17a

A methanol solution of modafinil enantiomer d (150 mg/ml) is broken into 96-well plates and the methanol is evaporated under a light vacuum before adding 25 μL of various solvents (concentration = 3.75 mg/25 μL of solvent) at room temperature. The multi-well plates are made of stainless steel (316 L) and each sealed well contains a total volume of 50 μL. The plate is heated to an initial temperature of 60°C according to a temperature gradient of 4.8°C/mn. After 30 minutes, the plate is cooled slowly (-0.6°C/mn) or rapidly (-300°C/mn) to a final temperature of 3°C, then the solvent is evaporated for 48 hours and analyzed at a minimum temperature of 1 (a) or more.

• Reference example 17: Recrystallization in 2-propanone

The d-modafinil crystallized into 2-propanone under the above operating conditions, by slow cooling (- 0.6°C/mn) and maintaining the temperature at 3°C for 1 hour. The crystals are identified as (+) -modafinil V-form (CRL40983 V-form) by its X-diffraction spectrum on powder.

• Reference example 17a: recrystallization in tetrahydrofuran (THF)

The crystals are identified as (+) -modafinil V-form (CRL40983 V-form) by its X-diffraction spectrum on powder.

EXAMPLES OF REFERENCE 18 to 19: Preparation of the solvates of (-) - modafinil and (+) - modafinil • Reference example 18 : Preparation of dimethylcarbonate solvate from (-) -modafinil

The reaction mixture is agitated for 10 min until the (-) modafinil is completely dissolved. The solution is cooled slowly (-0.5°C/mn) to 10°C under agitation. The reaction mixture is then filtered on a sintered glass (No. 3). Analysis of the modafinil dimethylcarbonate solvate shows a mass of about 24% from about 50°C to 110°C. The stoichiometry of the dimethylcarbonate solvate is 1-1.

• Reference example 19 : Preparation of acetonitrile solvate from (-) -modafinil

(a) Crystals of (-) -modafinil of polymorphic form l are suspended in acetonitrile for 3 days at 20°C. The recovered solid is identified as an acetonitrile solvate by X-ray diffraction. The solvate corresponds to a true solvate of stoichiometry 1-1.: identified as the acetonitrile solvate of (-) -modafinil by its X-diffraction spectrum on powder. Efficiency 92%. (b) The same experimental conditions applied to (+) -modafinil lead to an identical X-diffraction spectrum.

• Reference example 20: Preparation of acetic acid solvate

(a) 75 mg of d or I-modafinil have been suspended in acetic acid in Minimax reactors to a concentration of 15% (weight/volume). The crystallization medium, under constant agitation, is brought to an initial temperature of 60°C or 80°C according to a temperature gradient of 3°C/min. After 30 minutes the medium is cooled slowly (- 0.6°C/min) or rapidly (- 300°C/min) until a final temperature of 3°C is obtained, and then maintained at this final temperature for a minimum of 1 hour or a maximum of 48 hours. Under these experimental conditions, the acetic acid soil was identified and obtained by differing X-ray spectra.

• Reference example 21 : Preparation of the amorphous form of (-) and (+) -modafinil

The solvate of (-) or (+) modafinil obtained in reference example 20 was transformed into an amorphous form by heating at 120°C for 3 hours.

❖ EXAMPLES 22 to 29: Solution of (±) MODAFINIC ACID by preferential crystallization According to the AS3PC method in ethanol • Conditions related to balance

- What? - Solubility in ethanol of the racemic mixture:

Température (°C)	10,0	20,0	30,0
Solubilité massique (%)	3,0	4,1	5,96

- What? - Solubility of pure antipodes (+) = 1.99% at 20°C; ratio α = 2.06. - Coordinates of the L point = Concentration: 5.96 %; temperature: 30 °C

• Evolution of THOMO with enantiomeric excess = (racemic mixture / (solvent + racemic mixture)) = 5.96 % = constant

Excès énantiomérique	0	3,94	7,66	11,1
	32,4	34,5	36,3

• Conditions related to kinetics

By adjusting TB closer to TL, about 40% of the final crop in the form of fine crystals can thus be obtained at the beginning of the experiment, leaving only 60% of the final mass expected to be produced.

In the case of modafinil acid, crystallization is correct. - What? The temperature of TB1 is 33.5°C and TB2 is 31.5°C. The temperature of the test vessel is 17°C. The temperature of the water is the temperature of the air. - What? Loi de refroidissement de type I

Température (°C)	33,5	17	17
t (min)	0	60

Loi de refroidissement de type II

Température (°C)	31,5	17	17
t (min)	0	60

In both cases, starting from TB1 or TB2, the cooling law is a linear segment: The test shall be carried out on the test vessel. followed by a plateau at 17°C.

•Example 22: Resolution of (±) -modafinil acid by the AS3PC method at 35 cc scale in ethanol • Initial conditions Enantiomeric excess = 11%

Masse de solvant	Masse (±) (g)	Masse (+) (g)	Loi de refroidissement
38,38	2,43	0,3	Type 1

The bearing duration at TB1 or TB2 = 30 minutes.Running speed = 200 rpm

• The results

N°	Masse d'antipode pur (g)	Pureté optique (%)
1	0,61	(+) 90,7
2	0,65	(-) 89,4
3	0,68	(+) 90,5
4	0,64	(-) 90,6
5	0,65	(+) 88,8
6	0,72	(-) 91,5
7	0,71	(+) 92,8

Average mass of pure antipodal crystals = 0.66 gMedian optical purity = 90.6%

• Example 23: Resolution of modafinil acid (±) by the AS3PC method at 400 cc scale in ethanol • Initial conditions The initial enantiomeric excess = 11%

Masse de solvant	Masse (±) (g)	Masse (+) (g)	Loi de refroidissement
511	32,42	3,99	Type I

- What? The test shall be carried out at a speed of not more than 100 km/h.

• The results

N°	Masse d'antipode pur (g)	Pureté optique (%)
1	8,41	(+) 89,4
2	8,69	(-) 90,7
3	8,57	(+) 89,8

Average mass of pure antipodal crystals = 8,55 gMedian optical purity = 89,63%

• Example 24: Resolution of modafinil acid (±) by the AS3PC method at a 2 litre scale in ethanol • Initial conditions The initial enantiomeric excess = 11.1%

Masse de solvant	Masse (±) (g)	Masse (+) (g)	Loi de refroidissement
1874	118,4	14,84	Type I

• The results

N°	Masse d'antipode pur (g)	Pureté optique (%)
1	32,1	(+) 89,1
2	32,3	(-) 90,3
3	32,5	(+) 91,2
4	32,9	(-) 89,7
5	33,1	(+) 90,3
6	32,7	(-) 90,7
7	32,9	(+) 90,6

Average mass of pure antipodal crystals = 32.6 gMedian optical purity = 90.3%

• Example 25: Resolution of modafinil acid (±) by the AS3PC method on a 10 litre scale in ethanol • Initial conditions The initial enantiomeric excess = 11.7%

Masse de solvant	Masse (±) (g)	Masse (+) (g)	Loi de refroidissement
6481	408	51,32	Type I ou II

- What? Agitation speed = 200 rpm during the whole process with Impeller® agitation motor

• The results

N°	Masse d'antipode pur (g)	Pureté optique (%)	Durée d'un cycle	Loi de refroidissement
1	(+) 121,9	90,5	103	I
2	(-) 121,1	92,2	104	I
3	(+) 137,6	91,3	83	II
4	(-) 134,7	90,8	84	II
5	(+) 135,1	90,6	83	II
6	(-) 134,5	91,2	82	II

Average mass of pure antipodal crystals = 130.8 g Average optical purity = 89.9%

According to the AS3PC method in 2-methoxyethanol • Conditions related to balance

- What? - Solubility in 2-methoxyethanol of the racemic mixture: - What?

Température (°C)	10,0	20,0	30,0	40,0
Solubilité massique (%)	7,4	8	13,5	16

- What? - Solubility of pure antipodes (+) = 4% at 20°C; ratio α = 2.53 - Coordinates of the L point = Concentration: 16 %; temperature: 39.4 °C

• Evolution of THOMO with enantiomeric excess = (racemic mixture / (solvent + racemic mixture)) = 16 % = constant

Excès énantiomérique	0	4%	6%	8%
	44	46	48

• Example 26: Solution of (±) -modafinil acid in 2-methoxyethanol by the AS3PC method on a 10 L scale • Initial conditions

- What? Enantiomeric excess = 10% The temperature of the body at the beginning of the test: 41°C The test chemical is used to determine the concentration of the test chemical in the test medium. Linear temperature rise from 41 °C to 30 °C in 1 hour - What?

Masse de solvant	Masse (±) (g)	Masse (+) (g)
8000g	1523	132

- What? The test shall be carried out at a speed of not more than 100 km/h.

• The results

N°	Masse d'antipode pur (g)	Pureté optique (%)
1	269.86	(+) 100
2	300	(-) 97
3	348.68	(+) 100
4	369.2	(-) 99.97
5	413.97	(+) 100
6	453.2	(-) 95.5
7	423.8	(+) 98
8	456	(-) 99.7
9	494.6	(+) 99.3
10	485.4	(-) 100
11	517	(+) 92
12	487.97	(-) 95.9
13	471.24	(+) 99.5

Average mass of pure antipodal crystals = 422.4 g Average optical purity = 98.2%

According to the AS3PC method in methanol • Conditions related to balance

- What? - Solubility in methanol of the racemic mixture: - What?

Température (°C)	10,0	20,0	30,0	40,0
Solubilité massique (%)	7,4	9,7	13,9	25,7

- What? - Solubility of pure antipodes (+) = 4.9% at 20°C; ratio α = 2.53 - Coordinates of the L point = Concentration: 25.6%; temperature: 46.5°C

• Evolution of THOMO with enantiomeric excess = (racemic mixture / (solvent + racemic mixture)) = 25.7% = constant

Excès énantiomérique	0	4%	6%	8%	10%
	50	52	53	54

• Example 27: Resolution of (±) -modafinil acid by the AS3PC method at a 2 L scale in methanol • Experimental conditions

- What? Enantiomeric excess = 10% The temperature of the body at the beginning of the test: The test chemical is used to determine the concentration of the test chemical in the test medium. Temperature ramp: linear from 39.4°C to 18°C for 1 hour.

Masse de solvant	Masse (±) (g)	Masse (+) (g)
1450g	501,5	55,7

- What? The test is performed at a speed of not more than 300 km/h.

• The results

N°	Masse d'antipode pur (g)	Pureté optique (%)
1	107,1	(+)99,7
2	90, 9	(-) 78,2
3	137,1	(+) 72,7
4	125,5	(-) 84,1
5	95,9	(+) 94,0
6	91,6	(-) 88,6
7	87,0	(+) 85,7
8	92,2	(-) 88,1
9	107,0	(+) 104,2
10	130,6	(-) 120,7
11	159,9	(+) 111,0
12	123,3	(-) 113,8
13	133,0	(+) 130,3
14	143,0	(-) 134,7
15	139,2	(+) 128,5
16	159,4	(-) 127,5
17	114,0	(+) 111,5
18	123,4	(-) 120,9
19	180,6	(+) 99, 3
20	114,2	(-) 110,9
21	123,1	(+) 120,6
22	118,4	(-) 115,0
23	140,1	(+) 135,9
24	186,2	(-) 118,6
25	157,1	(+) 106,8
26	121,2	(-) 102,2
27	126,5	(+) 122,5
28	106,6	(-) 99,0

Average mass of pure antipodal crystals = 108 gMedian optical purity = 87.5%

According to the SIPC method in ethanol The following conditions shall be met for the calculation of the equilibria: • Example 28: Resolution of modafinil acid (±) by the SIPC method at a 2 litre scale with seeding at the end of cooling in ethanol • Initial conditions

Initial enantiomeric excess = 11,8% Temperature at which the starting mixture is a homogeneous solution TD = 40°C.

Masse de solvant	Masse (±) (g)	Masse (+) (g)	Loi de refroidissement
1874	118,4	14,84	20 mn de 40°C à 17°C = température d'ensemencement

Time (paleo) to TF before germ introduction = 0 minutesGerm mass = 1 %Crystallization time = cooling as fast as possible by tempering Agitation speed = 200 rpm throughout the process with an Impeller® agitation motor.

• The results

N°	Masse d'antipode pur (g)	Pureté optique (%)
1	30,9	(+) 90,4
2	31,5	(-) 90,7
3	31,3	(+) 91,4
4	31,2	(-) 90,9
5	31,6	(+) 91,5

Average mass of pure antipodal crystals = 31.28 g Average optical purity = 91%

• Example 29: Resolution of (±) -modafinil acid by the S3PC method at 2 litre scale with seeding during cooling in ethanol - Initial enantiomeric excess: 11.14%

Masse de solvant	Masse (±) (g)	Masse (+) (g)	Loi de refroidissement
1874	118,4	14,84	20 mn de 40°C à 17°C

Seeding temperature = 29°C Germ mass = 1%Crystallization time = cooling as fast as possible by tempering Agitation speed = 200 rpm throughout the process with an Impeller® agitation motor.

• The results

N°	Masse	Pureté optique (%) avant purification
1	25,2	(+) 84,5
2	24,9	(-) 85,6
3	25,6	(+) 84,6
4	25,2	(-) 85,3
5	24,9	(+) 85,8

Average mass of pure antipodal crystals = 25.2 g Average optical purity = 85.2%

❖ EXAMPLE 30 to 32: Conversion of optical enantiomers of modafinil acid into alkyl esters

This step is illustrated by the implementation of (-) modafinil acid.

Examples 30 to 31: Esterification of (-) -modafinil acid • Example 30: in the presence of dimethyl sulphate

In a 10-litre balloon, 3.3 litres of acetone, 0.6 litres of water, 349 g of Na2CO3 (3.29 moles), 451 g of (-) -modafinil acid (1.64 moles) are loaded and heated to reach reflux. 330 ml of dimethyl sulphate (3.29 moles) is then poured in half an hour.

The medium is then melted on 6.6 kg of ice, crystallizing immediately and after 3 hours of additional agitation a filtration process produces a white precipitate which is washed in 6 litres of water.

The precipitate is vacuum dried at 35°C to obtain 436.3 g of methyl ester (yield = 92.3%).

• Example 31: in the presence of methyl chloroformate

In 450 ml of methanol, 100 g (-) -modafinil acid (0.36 mole) and 21.6 ml triethylamine (0.36 mole) are added, and 30 ml of methyl chloroformate (0.36 mole) is gradually added to the solution after the salt has been dissolved.

The casting takes 15 minutes, from 28°C to 35°C (CO2 release).

The ester crystallizes; after filtration and drying, 94.5 g of ester is obtained. (Reflux is 90.1%)

• Example 32: Ammonolysis of the alkyl ester of optically active modafinil acid

A 4-litre double envelope reactor is loaded with 1.63 litres of toluene-denatured methanol, 0.1 litres of water and 425.1 g of methyl ester (1,474 moles).

The temperature is brought to 30°C and the ammonia is started by adjusting the temperature to this temperature. This operation takes 1h45 and the mass of ammonia introduced is 200 g. The agitation is maintained for 21h30 and then cooled by setting the container to 0°C.

The medium is then filtered on sintered glass No 3 and a first jet of 57.2 g and a dry evaporated filtrate are obtained.

First crystallization:

The two jets are joined and recrystallized in 1.83 litres of toluene-denatured ethanol. Hot filtration yields a filtrate which, by cooling, gives a product which is filtered and vacuum dried at 30°C. 162.2 g of white product is obtained.

Second crystallization:

These 162.2 g are mixed with 810 ml of denatured toluene ethanol and heated at low temperature to achieve complete dissolution, then allowed to crystallize in freezing, filtered on sintered glass No. 4 and vacuum dried at 30°C. 147.3 g of (-) -modafinil (CRL 40982) is obtained. The yield is 36.6%. Characteristics of the vehicle: Rotational power = - 18,6 (4,9% solution in methanol) The melting point is 163°C.

❖ EXAMPLE 33 to 34: Crystalline structures are formed by the crystalline • Example 33: Structure of modafinil acid

The following characteristics of modafinil crystals have been obtained in acetone: Hexagonal P31 or P32 depending on the enantiomer, modafinil is therefore a conglomerate; a = 9.55, b = 9.55, c = 13.14 Åα = 90.000, β = 90.000, γ = 120.000°

The diffracted intensities were measured using an automatic SMART APEX (Brucker) diffractometer at 20°C.

The structure was solved with the suite of software Saintplus, Sadabs, Shelxs.

The unusual nature of this space group for organic chiral molecules is noteworthy.

In the crystal lattice, the pattern repeats three times, again Z = 1. These molecules are connected to each other by hydrogen bonds, via the acid and sulfoxide functions.

• Example 34: Structure of (-) and (+) -modafinil form I

The crystal structure of (+) modafinil form I, identified as identical to (-) modafinil form I, has been determined and has the following characteristics: The crystal system is monoclinic; the space group is P21a = 5.6938, b = 26.5024, c = 9.3346 Åβ = 105.970°.

The diffracted intensities were measured using an automatic SMART APEX (Brucker) diffractometer at 20°C.

Claims (14)

1. Use of a polymorphic form of the dextrorotatory or laevorotatory enantiomer of modafinil, denoted form I, characterized in that (i) it produces an X-ray diffraction spectrum at the lattice distances: 8.54, 4.27, 4.02, 3.98 (Å); or (ii) it produces an X-ray diffraction spectrum comprising intensity lines at the 2θ angle values: 15.4, 31.1, 33.1 and 33.4 (degrees), measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation, the error for the 2θ values being ± 0.2° 2θ, for the manufacture of a medicament intended for the prevention or treatment of a condition chosen from hypersomnia, sleep apnoea, excessive somnolence associated with a disease, obstructive sleep apnoea, narcolepsy, somnolence, excessive somnolence, excessive somnolence related to narcolepsy, disorders of the central nervous system, protection of cerebral tissue with respect to ischaemia, vigilance disorders, attention disorders, the state of tiredness, depression, the depressive state related to low sunlight, schizophrenia, shift work, time difference, disorders of feeding behaviour, in which modafinil acts as appetite stimulator, or stimulation of the cognitive functions at low doses.
2. Use according to Claim 1, characterized in that it produces an X-ray diffraction spectrum comprising intensity lines at the lattice distances: 8.54, 4.27, 4.02, 3.98 (Å).
3. Use according to Claim 2, characterized in that it produces an X-ray diffraction spectrum additionally comprising intensity lines at the lattice distances: 13.40, 6.34, 5.01, 4.68, 4.62, 4.44, 4.20, 4.15, 3.90, 3.80, 3.43 (Å).
4. Use according to Claim 1, characterized in that it produces an X-ray diffraction spectrum comprising intensity lines at the 2θ angle values: 15.4, 31.1, 33.1 and 33.4 (degrees), measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation, the error for the 2θ values being ± 0.2° 2θ.
5. Use according to Claim 4, characterized in that it produces an X-ray diffraction spectrum additionally comprising intensity lines at the 2θ angle values: 9.8, 20.8, 26.4, 28.3, 28.7, 29.9, 31.6, 32, 34.1, 35.1 and 39 (degrees), measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation, the error for the 2θ values being ± 0.2° 2θ.
6. Use according to any one of Claims 1 to 5, in which the polymorphic form is characterized as follows: CRL 40982 FORM I 2θ (degrees) d (Å) 9.8 ± 0.2 13.40 32 15.4 ± 0.2 8.54 87 20.8 ± 0.2 6.34 24 26.4 ± 0.2 5.01 14 28.3 ± 0.2 4.68 19 28.7 ± 0.2 4.62 16 29.9 ± 0.2 4.44 45 31.1 ± 0.2 4.27 100 31.6 ± 0.2 4.20 23 32 ± 0.2 4.15 14 33.1 ± 0.2 4.02 78 33.4 ± 0.2 3.98 84 34.1 ± 0.2 3.90 16 35.1 ± 0.2 3.80 15 39 ± 0.2 3.43 22 these values being as measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation.
7. Use according to any one of Claims 1 to 6, in which the enantiomer is the (-) enantiomer.
8. Use according to any one of Claims 1 to 6, in which the enantiomer is the (+) enantiomer.
9. Use according to Claim 1, in which the hypersomnia is idiopathic hypersomnia or hypersomnia in patients affected by cancer who are treated with morphine analgesics to relieve the pain.
10. Use according to Claim 1, in which the disorder of the central nervous system is Parkinson's disease.
11. Use according to Claim 1, in which the vigilance disorders are vigilance disorders related to Steinert's disease.
12. Use according to Claim 1, in which the attention disorders are attention deficit hyperactivity disorders (ADHD).
13. Use according to Claim 1, in which the state of tiredness is that related to multiple sclerosis and other degenerative diseases.
14. Process for the preparation of a polymorphic form of the dextrorotatory or laevorotatory enantiomer of modafinil, denoted form I, characterized in that it produces an X-ray diffraction spectrum comprising intensity lines at the lattice distances: 8.54, 4.27, 4.02, 3.98 (Å), the said process comprising the following stages:

    i) dissolving one of the optical enantiomers of modafinil in a solvent;

    ii) crystallizing the enantiomer of modafinil;

    iii) recovering the crystalline form of the enantiomer of modafinil thus obtained,

    in which the solvent employed in stage i) is acetone, 1,4-dioxane, ethyl acetate, ortho-, metaor para-xylene or a mixture of ortho-, metaand/or para-xylene and in which the crystallization consists of a cooling of the solution obtained in stage i) and the cooling is slow, or in which the solvent employed in stage i) is methanol, ethanol, water or alcohol/water mixtures and in which the crystallization consists of a cooling of the solution obtained in stage i) and the cooling is fast.