HK1078309B - Method for the production of crystalline forms and crystalline forms of optical enantiomers of modafinil - Google Patents

Description

The invention relates to a process for obtaining a crystalline form of modafinil enantiomers.

The application describes a novel process for the preparation of modafinil optical enantiomers from modafinil acid (±).

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 disorders. The process of preparing the two optical enantiomers of modafinil from the (±) 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.

Day et al. (Chem. Commun., 2006, 54-56) study the latent polymorphism of maleic acid, and report the discovery of a second crystalline polymorph of maleic acid.

Dziubek et al. (J. Am. Chem. Soc., 2007, 129, 12620-12621) are interested in quasi-iso-structural polymorphs of ethynylbenzene, more particularly in the resolution of CH ((alcyne) -π ((arena) and cooperative interactions of CH ((alcyne) -π ((alcyne) by pressure freezing.

Sanphui et al. (Chem. Commun., 2011, 47, 5013-5015) disclosed two new crystalline polymorphs and an amorphous phase of curcumin.

The invention relates to a process for the preparation of a polymorphic form of the levogyre or dextrogyre enantiomer of modafinil, characterised 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: (i) dissolve one of the optical enantiomers of modafinil in a solvent selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-methyl-2-pentanol, 1,2-propanediol, t-amyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl formate, n4-methyl ether, isopropanol, butanol, dioxin, 1,2-propanediol, isopropanol, methyl ether, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methacrylate, methyl methalate, methyl methacrylate, methyl methalate, methyl methalate, methyl methacrylate, methyl methalate, methyl methalate, methyl methalate,

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 have shown 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. The declaration by Dr. John Mallamo, filed on 22 March 2012 in the examination procedure of the application on which this patent is based, states that 4 177 290 Io is for a modafinil racemate and that the preparation methods described therein produce a melanochemical intensity of modafinil. It confirms that 4 177 290 US Io is not for the individual enantiomers in the modafinil spectrum. The above-mentioned X-ray and X-ray diffraction ratio (I/I) represents the relative radius of the modafinil. - 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 generally 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 the classical diastereoisomer salt breakdown; the yield is theoretically quantitative due to successive recycling of the mother water; the purification of crystals of raw antienomers 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.

The invention also aims to propose a new method for the preparation of modafinil optical enantiomers, in particular the levogyre enantiomer of modafinil.

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

These and other purposes are achieved by the present invention. The application describes a process for the preparation of crystalline forms of modafinil optical enantiomers, including the following steps: (i) dissolve one of the optical enantiomers of modafinil in a solvent other than ethanol; (ii) crystallize said enantiomer of modafinil; and (iii) recover the crystalline form of said enantiomer of modafinil thus obtained.

Err1:Expecting ',' delimiter: line 1 column 140 (char 139)

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 on demand 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 the process according to the invention, the crystallization solvents are selected from acetone, methanol, dioxane 1-4, ethyl acetate, ortho, meta, paraxylene, isopropanol, n-propanol, dimethylcarbonate, tetrahydrofuran, chloroform and methylethyl ketone, water and alcohol/H mixtures_{2 and}- It's a zero.

Thus, the crystalline forms of modafinil optical enantiomers 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.

Generally, the recrystallization solvent used in step i, including reflux, is heated to complete dissolution of the modafinil optical enantiomer in the solvent. If the concentration of the modafinil optical enantiomer in step i is not a critical factor in the crystallization, it is preferred to operate in the presence of an optical enantiomer 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 shape as expected.

The process of crystallization of the process of the invention 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 of the invention.

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 consists 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 preferred solvent/anti-solvent combinations according to the invention 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 of the invention is particularly applied to the levogyre enantiomer of modafinil.

The crystal 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 powdered 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 invention.

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 invention, the process using methanol and a precipitation crystallization step by addition of cold water as an antisolid of methanol leads to the form I.

Form II

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

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

Form IV

In a variation of the process described in the application, the solvent used in step (i) is chosen from tetrahydrofuran, chloroform and methyl ethyl ketone, and the crystallization step (ii) consists of slow cooling of the solution to 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 in the application, 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 known as V-form.

Dimethylcarbonate 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 application describes the polymorphic form of the levogyre enantiomer of modafinil designated CRL 40982 form II, 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 l/lo 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 application describes 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.

In this context, the application describes in particular the form III of (-) -modafinil producing the following X-diffraction spectrum in which d is the reticular distance and I/Io 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 application describes the polymorphic form of the levogyre enantiomer of modafinil designated CRL 40982 form IV, characterised by producing an X-diffraction spectrum comprising intensity lines at the reticular distances of: 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 is 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 application describes 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). - 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 application describes dimethylcarbonate solvate of (-) -modafinil, characterised by the following diffraction spectrum in which d is the reticular distance and I/Io the relative intensity:

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

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

The application describes a process for converting 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: (i) suspend the crystalline form of the enantiomer of modafinil in a solvent;

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 application mode, 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 application describes the acetonitrile solvate of (-) -modafinil which can be obtained by the recrystallization process of the invention and is characterised by the following diffraction spectrum, where d is the reticular distance and I/I is the relative 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

The application describes 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, where appropriate 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 described in the application are to be administered orally in the form of immediate release or controlled release tablets, tablets, capsules or granules, in the form of powder, capsules, liquid or gel suspension, emulsion or lyophilisate, preferably in the form of tablets, capsules, liquid or gel suspension. The delivery vehicle may contain one or more pharmaceutically acceptable excipients which are likely to ensure the stability of the polymorphic forms (e.g. a polymorphic suspension in an oil).

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

A solid composition for oral administration is prepared by adding to the active substance 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, 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 in the application may also contain another crystalline form of (-) -modafinil or (+) -modafinil, respectively, including, in particular, form I and/or another active or inactive substance 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 88 (char 87)

The application describes the use of 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, for 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, narcolepsy, sleep apnea; obstruction of the nose,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 state due to sun exposure, schizophrenia, low turnover, shift work, 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.

The application describes a process for the preparation of modafinil optical enantiomers from modafinil acid (±) including 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 basal and lower alkyl haloformate is used in step (ii) compared to 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 generally preferable to operate with excess ammonia.

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 shall be carried out by conventional methods known to the professional.

The application describes a process for the preparation of modafinil optical enantiomers including the following steps: (a) to split the two optical enantiomers of modafinil acid (±) or its salts by a preferential crystallization process; (b) to convert the isolated enantiomer into an amide; (c) to recover the enantiomer of the modafinil obtained.

Depending on the preferred method of implementation, step (b) is carried out in two stages: (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, R and S, to form a conglomerate in a solvent A and for a given temperature range D_TThis 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)._Tand for solvent A.

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.

The factors affecting the crystallization kinetics include: The test results are based on the following factors: internal factors in the crystals, in relation to the bonds between the molecules, which cannot be changed by the experimenter; external factors which can be changed by the experimenter; these are the nature of the solvent, the nature and concentration of impurities, the oversaturation obtained over time, the temperature range D_TThe 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 AS3PC preferential crystallization method, the system is placed in such a condition that it generates its own germs for the 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. Hedtmann, 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 T_Da set consisting of the racemic mixture of crystals in the form of a conglomerate, the first enantiomer of modafinil acid and a solvent, with the figurative point E, defined by the concentration and temperature variables T_D(b) rapidly cool the solution prepared in step (a) initially to the temperature T_Dup to temperature T_{F. Other}(c) seed the solution obtained in step (b) during (i.e. between T_Iand T_{F. Other}) or at the end of cooling (i.e. at T)_{F. Other}(d) harvest the crystals of the first enantiomer; (e) add to the mother liqueurs resulting from the harvest at step (d) the racemic mixture of crystals in conglomerate form and homogenise the new set by heating to a temperature T_D, 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 diluted solution;_D, up to temperature T_{F. Other}(g) 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 T_D(j) repeat steps (a), (b), (c), (d), (e), (f), (h) and (j) to obtain successively the first and then the second of the two enantiomers.

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

The following are designated for the purposes of this application: by T_{F. Other}the temperature at which crystallization and filtration end, in the three-phase range; by T_Ithe homogenization temperature of the racemic mixture; by T_Dthe starting temperature at which the starting mixture is a homogeneous solution; per antipodes, 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) to make a set consisting of the racemic mixture of crystals in conglomerate form, the first enantiomer of modafinil acid and solvent, with the figurative point E, defined by the concentration and temperature variables T_{B. Other}(b) apply a programming law of temperature cooling to the biphasic mixture prepared in step (a), such that the mother liqueurs maintain a low oversaturation which favors the growth of the enantiomer present in crystal form, while preventing the spontaneous nucleation of the second enantiomer present in the first solution; (c) adapt during the whole duration of the crystalline growth of the first step (b) bring a rate of agitation increasing with time so that the enantiomer at any time achieves a sufficiently slow growth to achieve a non-cristalline result; (c) avoid the production of large forces and create a rapid and rigidly uniform flow of energy around the first crystal mixture, resulting in a rapid and uniform growth of the enantiomer; (d) generate a high degree of tension and a high degree of tension in the crystal mixture; (e) achieve a rapid and uniform flow of energy at each crystal mixture;_{B. Other}(f) apply the same cooling programming law as in step (b) to the biphasic mixture prepared in step (e) containing the second enantiomer, so that the mother liquors maintain a low oversaturation during crystallization in order to favour the spontaneous growth of the enantiomer in any crystalline form by preventing spontaneous enantiomerisation in the first 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 this application, is referred to as T_HOMOthe homogenization temperature of the assembly consisting of the racemic mixture, the first enantiomer and the solvent.

Thus, at step (a) of the process described in the application, the choice of solvent (s) and the operating temperature range are defined in such a way 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 solvolysis and racemisation; stability of solvates if they are present at equilibrium and if they are dilapidable enantiomers.

In steps (a) and (e) of the process described in the application, the temperature T_{B. Other}is higher than temperature T_IThe test chemical is used to determine the concentration of the substance in the test chemical._HOMOaccording to the enantiomeric excess and for a constant concentration in racemic mixture X_I, said temperature T_{B. Other}is defined so that the mass of the crystal ends of the first enantiomer of steps (a) and (i) and the second enantiomer of step (e), in equilibrium with their saturated solution, is not more than 50% and preferably between approximately 25% and 40% of the expected yield.

In steps (b) and (f) of the application process, the temperature T cooling programming law_{B. Other}to T_{F. Other}, suitable for experimental installation, is defined as follows: The results of the analysis are presented in Table 1 below. The results of the analysis are presented in Table 1 below._{F. Other}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.

Each experimental assembly affects the saturation capacities 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 implemented._{B. Other}, the solubilities of the racemic mixture as a function of temperature, the T-curve_HOMOas a function of the enantiomeric excess for a constant concentration in racemic mixture X_IThe results of the tests are completely independent of the experimental setup.

The programming law of cooling, which is the function relating temperature to time, is determined for its part of T_Ito T_{F. Other}by cooling the concentration solution X_Iof T_I+ 1°C at T_{F. Other}, T_{F. Other}being less than T_I- (T)_HOMO- T is_IThe method of analysis is based on the following equation:_{B. Other}to T_Iby extrapolation of this same law determined from T_I+ 1°C at T_{F. Other}- I 'm not .

The preferential crystallization process of (±) -modafinil acid or its salts has other advantageous characteristics, 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 ends of the racemic mixture in conglomerate form which are added have undergone, before being introduced, a prior treatment which accelerates the dissolution stage, such as grinding and sifting, ultrasonic treatment, partial freezing; these treatments are also intended to provide crystalline ends suitable for generating a growth surface; high crystalline ends at steps (a), (e) and (i), involving dissolution, have 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/enantiomer group.

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._{F. Other}is preferably between 0°C and 40°C for (±) -modafinil acid.

In the case of ethanol, the temperature T_{F. Other}The temperature of the atmosphere is preferably between 0°C and 25°C, and even better it is close to 18°C or 17°C.

In the case of 2-methoxyethanol or methanol, the temperature T_{F. Other}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 temperature T_DThe temperature 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 return._Dto T_{F. Other}is very fast to stay in the single phase range and preferably achieved in less than 20 min, e.g. by tempering.

In a preferred mode of the AS3PC process, the temperature T_{B. Other}is then between the temperatures T_Iand T_HOMOThe temperature T_{B. Other}The temperature of the water may be between 25°C and 50°C.

For example, in the case of ethanol, when the enantiomeric excess is close to 11% by mass, the temperature T_{B. Other}is preferably between 25°C and 40°C, in particular between 30,1°C and 36,2°C and preferably closer to 33,5°C or 31,5°C.

In the case of 2-methoxyethanol, when the enantiomeric excess is close to 8% by mass, the temperature T_{B. Other}is preferably between 35°C and 50°C, in particular between 39.1°C and 47.9°C and preferably closer to 41°C.

In the case of methanol, when the enantiomeric excess is close to 10% by mass, the temperature T_{B. Other}is preferably between 40°C and 55°C, in particular between 45.1°C and 53.9°C and preferably closer to 46.5°C.

The cooling of T is particularly preferred._{B. Other}to T_{F. Other}The time taken for the cooling in step (b) is long enough for the average mass of the enantiomer crystals to be large, but short enough to prevent the enantiomer from crystallizing and thus achieve a high optical purity, especially above 85%.

Similarly, the bearing life at temperature T_{F. Other}for SIPC, AS3PC and S3PC, preferably large enough to allow a high crystal mass of desired enantiomers to be harvested, but not too large to prevent the counter-enantiomer from crystallizing at the same time as the desired enantiomer, and thus to achieve high optical purity.

In a preferred mode, the temperature bearing duration T_{F. Other}The duration of the test is between 15 and 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 the optical enantiomers of modafinil, 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 affected 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 significantly lower than that of the other constituents, in accordance with the conditions mentioned above; the three monovariant curves (φ = 3) or eutectic valleys from the binary eutectic points; the ternary eutectic invariant at Tε (φ = 4), below which the three constituents are crystallized.

Figure 2 shows two isothermal T-cuts superimposed on each other._Dand T_{F. Other}The cutting is made up of four areas at each temperature 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

The isoplet cutting RYT

Figure 3 shows the isoplet cut R-Y-T which is fundamental in understanding the crystallization conducted 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 X_Aand X_Sgiving the mass fractions in solvent and in antipodes S.

Figure 3 shows the following: The monophasic domain of the ternary solution; the liquid of the antipod R, this curve represents the intersection of the R-Y plane of Figure 2 with the crystallization layer of this constituent._I(horizontal segment at T_I) delimit the biphasic domain: saturated solution plus crystals of R; it is extended in the underlying triphasic domain by a metastable solubility curve of the same antipod R (in discontinuous features); the triphasic domain: T and S crystals, plus saturated solution. This domain is bounded at the top by the horizontal trace of the coneid of R, downwards by the trace of the tertiary eutectic invariant plane, at the left by the trace Lm of one of the coneids relative to the antipod S. The trough of the KL crystallization layer of the antipod S which borders the bivariate solution of S in the upper part of the same antipod S. This tertiary solution of S. F is bounded in the lower two traces by the horizontal trace of the coneid of R, and at the left by the trace Lm of one of the coneids relative to the antipod S. The trace of the conelization layer of the antipod S which is bounded in the upper part by the bivariate solution of S. This tertiary solution of S. F is bounded in the lower two traces by the trace of the conectivity of R and the traceable temperature of the coneid and the R1 will be the second most distant from the coneidic field of R, and the traceable location of the coneidic function of the R is about the location of the R and the R is the most distant from the R to the ellipsoid.

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). T_D: temperature at which the starting mixture is a homogeneous solution, andT_{F. Other}: end-crystallization and filtration temperature, located in the three-phase range.

This overall composition E corresponds to a racemic solution slightly enriched by a mass M of antipodes 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 (s) 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 T_DThe solution is homogeneous. the crystallization of antipodes R alone, of T_HOMOup to T_I, the solution point moves simultaneously along the solubility curve of the antipodes R, i.e. from point E to the T-value_HOMO, at point L inside the isoplet R-Y. At point L, the mass M of crystals R in equilibrium with the saturated solution is given by Mt (X_E- X_I1 - X_I) = M and corresponds to the enantiomeric excess present in the initial solution (Figure 3); the abscissa of the L, E and R points correspond to the compositions, and 1 (Figure 3)._I, the solution point moves from L to I_{F. Other}On the monovariate curve containing the solutions of racemic composition, as shown in Figure 2, the R-Y isoplet of Figure 3 is removed, and the R and S crystals are deposited simultaneously and in equal quantities.

The split cannot be achieved under equilibrium conditions for temperatures below T_I- I 'm not .

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

The previous solution E is homogenized at T_D(Figures 4 and 5) To make it supersaturated, it is rapidly cooled to T_{F. Other}The solution is then seeded with very pure antipodal germs of the same chirality as the excess antipodal. The isothermal crystallization of the antipodal R is established and the representative point of the solution moves inside the R-Y-T cup of E at the T-value_{F. Other}The mass of antipodes R recovered is 2M or Mt (X)_E- X_{F. Other}1 - X_{F. Other}) and

Crystallisation of the second antipodes, cyclicity of operations

The previous basic operation thus created a solution F enriched with 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 T_D, we obtain a homogeneous solution E' symmetric of E with respect to the vertical plane A-(RS) -T. The process for obtaining a mass of 2M of antipodes S will also be represented by a path symmetric of the preceding one with respect to this median plane. The solution is homogeneous at T_Dis first cooled to T_{F. Other}, then,seeded in very pure germs of antipodes S; the growth of this antipodes moves the point representative of the solution on the horizontal segment E'F' (at the angle T)_{F. Other});when the solution point is confused with F', the solution is filtered and gives a mass of 2M antipodes S;after a further addition of a mass of 2M racemic mixture and a further heating at T_D, we again obtain a homogeneous solution whose representative point is confused with the initial point E at the T-value_DThe continuation of the process is simply a reproduction of this cycle of operations.

Variants of the SIPC process

The literature (Camelot, G., 1956, Bull. Soc. Chim. 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 homogeneous supersaturated solution. This primary nucleation occurs when the point E representing the composition of the assembly is in the three-phase domain and the solution is not agitated (Collet, A., Brienne, M. J., Jacques, J., 1980, Chemical Reviews 80, 215 3, 30). (b) Sowing during cooling (S3PC) This protocol is most frequently encountered in the literature (Noguchi Institute, 1979; SIP 1 GB, 1968, 80); however, the following common procedures may be found when the following differences in the processes occur: cooling of homogeneous solution of T_Da temperature of less than T_Ibut greater than T_{F. Other};seeding, by germs of the same chirality as the excess antipodes, of the homogeneous supersaturated solution in the three-phase domain;cooling to T_{F. Other}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 the AS3PC programmed drive and self-seeding doubling

In order to better compare the conventional processes and the AS3PC process, the starting 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 larger enantiomeric excess and thus to improve the crystal harvest of each operation.

Crystallisation of the first antipod in excess

At the beginning of the process, and unlike conventional protocols, the whole, crystals plus solution, is no longer homogenized but is brought to the temperature T_{B. Other}The initial solution is then in equilibrium with the excess enantiomer crystals (e.g. R in Figure 7)._EThe two-phase mixture is subjected to a programmed law of temperature decrease without the addition of crystalline germs._EThe first step is to use a solution of the enantiomeric crystals in the solution, which is contained in the R-Y-T plane, and which depends on the kinetics of the cooling (Fig. 7).

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 2M mass of racemic mixture and heating at T_{B. Other}The enantiomeric excess is used to be placed in the biphasic domain containing the saturated solution and the excess antipodal crystals. First, the racemic mixture added during the transition from F to E' (as from F' to E) is ground and sifted to accelerate the dissolution of the two antipodes and in particular the defective antipodes, and thus to allow the formation of a large number of excess antipodal crystals playing the role of seeds introduced during the conventional processes.

The saturated solution S_E, symmetrical of S_EThe crystals present at the beginning of the cooling process grow and then participate in a double growth mechanism + secondary nucleation. As in the case of the first crystallization, no seeding is therefore necessary.

Meanwhile, the representative point of the solution moves along a curve S_{It 's}F'contained in the plane of the isoplet S-Y'-T symmetrical with respect to the bisector plane A-(RS)-T.

When the solution reaches the representative point at F', filtration is carried out to obtain a 2M mass of crushed and sifted racemic mixture followed by a temperature rise to T_{B. Other}returns the two-phase mixture to initial equilibrium.

Continuation of the process then amounts to repeating 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 is achieved in the solvent used and for the temperature interval T_{B. Other}- T is_{F. Other}, a conglomerate (pure antipodes or solvates); however, the existence of a metastable racemate is not a handicap._{B. Other}and T_{F. Other}(c) Determination of the ternary equilibrium temperatures T_Iand T_HOMOThe temperature T is the temperature at which the body is heated._Iis the temperature at which the racemic mixture dissolves in the absence of any enantiomeric excess in the solution._Ithe temperature T is determined_HOMOThe temperature of homogenization of the solution depends on the initial enantiomeric excess and the α ratio of the solubilities of the racemic mixture and the antipodes to T_IKnowledge of the supersaturation capacities of solutions between T_Iand T_{F. Other}The time of appearance of the crystals by primary nucleation in the homogeneous racemic solution L, cooled from a temperature slightly above T, is also necessary._I(d) Knowledge of the kinetics of dissolution of a known mass of racemic mixture (of given particle size) dispersed in solution at T_{B. Other}A few trials 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 is also represented the isotherms at temperatures T_Dand at T_{F. Other}and the ternary euthyxia plan at Tε and containing four phases.Figure 2 is a projection, in terms of concentrations, of equilibriums at T_Dand T_{F. Other}, and a representation of the isoplethal cut RY, where point E represents the composition of the initial mixture slightly enriched in antipodes R and which must deposit the same antipodes.Figure 3 is the isoplethal vertical cut RY of Figure 2 containing the points of composition of the excess antipodes and the initial solution E, where the path, at equilibrium and cooling, of the solution point for a mixture of composition X is shown._E(in bold) For T < T_I, the solution point no longer belongs to this cut.Figure 4 is a projection on the plane of the concentrations of the solution point path (in bold) during the alternating doubling by isothermal drive at T_{F. Other}and seeded, using the SIPC method.Figure 5 is the isoplethal vertical cut containing the RY line of Figure 4 and showing the path of the solution point (in bold) from E to F during the isothermal drive (at T)_{F. Other}) and seeded according to the SIPC method.Figure 6 is a projection on the plane of the concentrations of the solution point path (in bold) during the double-division by the programmed and self-seeded polythermal process (AS3PC).Figure 7 is the isoplethal vertical cut containing the RY line of Figure 6 and illustrating the solution point path (in bold) of S_Eto F during the double-division by the programmed and self-seeded polythermal process (AS3PC).Figure 8 is a projection on the plane of the concentration path of the solution point (in bold) during the double-division by the programmed and self-seeded polythermal process (AS3PC) and verifying the relation s ((±) < 2 - α. All isothermal and isopletal 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 Il 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,Figure 11 represents the X-ray diffraction spectrum on powder corresponding to the form IV of the levogyre enantiomer, dextrogyre of modafinil respectively (diffractometer: Siemens AG).Figure 12 represents the X-ray diffraction spectrum on powder corresponding to the dimethylcarbonate solvate of the leaf enantiomer, dextrogyre of modafinil respectively (Miniflex Rigaku (Elexience)).Figure 13 represents the X-ray diffraction spectrum on powder corresponding to the acetonite enantiomer of the levogyre enantiomer, dextrogyre of modafinil respectively (Figure 14 represents the diffraction spectrum of the X-ray diffraction on powder corresponding to the acetonite enantiomer of the leaf enantiomer, dextrogyre of modafinil AG).Figure 15 shows the X-ray diffraction spectrum on powder corresponding to the acetic acid solvate of the levogyre and dextrogyre enantiomers of modafinil respectively (diffractometer: Bruker GADDS).Figure 16 shows the X-ray diffraction spectrum on powder corresponding to the amorphous form of the levogyre and dextrogyre enantiomers of modafinil respectively (diffractometer: Bruker GADDS).

Examples Preparation of crystalline forms of the enantiomer (-) - modafinil and (+) - modafinil respectively The Commission shall adopt the implementing acts referred to in Article 9 (2).

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 a 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].^{- One .}, the step size being 0.04°; sample preparation with a preferential orientation. using a Miniflex Rigaku (Elexience) system as an X-ray powder diffractometer, with chromium radiation, a 30 KV accelerator speed, a 15 mA tube current and with a rotation of the sample during measurement (angle 3 at 80° [2 theta] at a speed of 0.05° [2 theta].^{- One .}, 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 96-well plate analysis.Analyses are performed at room temperature using a copper CuK radiation_{alpha and alpha}The diffraction spectrum for each well is collected between two ranges of 2 theta angle values (3° ≤ 2 theta ≤ 21° and 19° ≤ 2 theta ≤ 42°) with exposure times between 50 and 250 seconds.

The intensity values can vary depending on the preparation of the sample, the mounting and the measuring instruments. The measurement in 2 theta 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 modafinil enantiomer I 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, under 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 I-form polymorph of the I-enantiomer of modafinil. (b) The modafinil d-enantiomer (555 g), treated under the same experimental conditions as in 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

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 a rate of -0.5°C/min to 10°C under agitation. The reaction mixture is filtered, and the dry solid is dried to obtain the I (-) modafinil form identified by its X-diffraction spectrum. Efficiency 62b) The same experimental conditions applied at different (+) modafinil results in identical X-diffraction spectra.

• Example 3: Recrystallization in methanol

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 (2 ^and (for example)

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 package 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 onto fritted glass and identified as being of the form 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 back to the flow; 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 glass sintered and identified as being of the form I by its X-diffraction spectrum. Efficiency 66%. (b) (+) -modafinil (3 g) was solubilised back to the flow in the ethyl acetate (100 ml) After cooling by immersion in ice water for 30 minutes, the product was then identified as being of the form I by the X-diffraction spectrum. (+) -modafinil was then filtered and produced in the form of a polymorph at 50 °C.

• Example 8 : from other polymorphic forms

(a) CRL40982 form IV (0.5 g) and CRL40982 form Il (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 same results were obtained when (+) -modafinil (CRL 40983) was administered under the same conditions.

• 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.

❖ EXAMPLES 11 to 12: Preparation of the form II (CRL 40982 form II) of (-) - Modafinil. (CRL 40983 form II) of the (+) - Modafinil respectively • Example 11 by rapid cooling

- What? (a) The modafinil enantiomer I was soluble in solvents: ethyl acetate, isopropanol, n-propanol and toluene denatured ethanol (2.5%) at reflux under 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 I-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 fritted glass. The crystallized product has been identified by its X-diffraction spectrum on powder as the polymorph of form II (CRL40982 form II) of the I-antienomenon. The efficiency differs by 42%. The same (+-modafinil) conditions apply to the X-ray spectrum identification.

❖ EXAMPLE 13: Preparation of the form III (CRL 40982 form III) of the (-) - modafinil. • 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 I-enantiomer form III. Efficiency 61%. (b) The same experimental conditions applied to (+) -modafinil lead to an identical X-diffraction spectrum.

❖ EXAMPLES 14 to 16: Preparation of the form IV (CRL 40982 form IV) of (-) - Modafinil, (CRL 40983 form III) of the (+) - Modafinil respectively • 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 onto a fritted glass identified as (-) -modafinil form IV by its X-powder diffraction spectrum. (b) The same experimental conditions applied to (+) -modafinil lead to the 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 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 sintered glass and identified as being of (-) -modafinil form IV 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 backward. 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-ray 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 25 μL of various solvents (concentration = 3.75 mg/25 μL of solvent) are added 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/min. After 30 minutes, the plate is cooled slowly (-0.6°C/min) or rapidly (-300°C/min) to a final temperature of 3°C, and the final product is evaporated for 48 hours or less and then analyzed at a minimum temperature of 1 atmosphere (a) and the solvent is crystallised.

• 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% starting from about 50°C to 110°C. The stoichiometry of the dimethylcarbonate solvate is 1-1. It is therefore a true solvate, being identified as the dimethylmodafinil dimethylcarbonate solvate by X-ray spectroscopy. (+ 88%) The same experimental conditions apply to the diffraction of the dimethylcarbonate powder.

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

(a) Crystals of (-) -modafinil of polymorphic form I 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 reached, 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 solvate was obtained 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 example 20 was transformed into an amorphous form by heating at 120°C for 3 hours.

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

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

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

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

• Conditions related to kinetics

By adjusting T_{B. Other}closer to T_IThis is easy to do when the Z ratio is sufficiently high (greater than or equal to 0.8 per cent of enantiomeric excess).

In the case of modafinil acid, crystallization is correct. Temperature T_B1= 33.5°C and T_B2= 31.5°C. Temperature T_{F. Other}The temperature of the water is approximately 17°C. 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: followed by a plateau at 17°C.

• Reference example 22: Resolution of (±) -modafinil acid by the AS3PC method at 35 cc scale in ethanol • Initial conditions

- What? Enantiomeric excess = 11% - What?

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

- What? Bearing length in T_B1or T_B2That's 30 minutes. 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	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%

• Reference example 23 : Resolution of modafinil acid (±) by the AS3PC method at 400 cc scale in ethanol • Initial conditions

- What? The initial enantiomeric excess = 11 % - What?

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 g Average optical purity = 89,63%

• Reference example 24 : Resolution of modafinil acid (±) by the AS3PC method on 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 g Average optical purity = 90.3%

• Reference example 25 : Resolution of modafinil acid (±) by the AS3PC method on a 10 litre scale in ethanol • Initial conditions

- What? The initial enantiomeric excess = 11.7% - What?

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 a stirring 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 balances

- 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

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

• Reference 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 test shall be carried out at the same temperature as the test._{B. Other}The temperature is: 41 °C The test shall be carried out at the same temperature as the test._{F. Other}The temperature is: 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 balances - 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 - What?

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

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

- What? Enantiomeric excess = 10% The test shall be carried out at the same temperature as the test._{B. Other}The temperature is: Filtration temperature T_{F. Other}The temperature is: 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: • Reference 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

- What? The initial enantiomeric excess = 11.8% Temperature at which the starting mixture is a homogeneous solution T_DThat's like 40 degrees. - What?

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

- What? - Time (scale) to T_{F. Other}before introduction of germs = 0 minutes - Germ mass = 1 % - Crystallization time = cooling as fast as possible by tempering Agitation speed = 200 rpm throughout the process with an agitation motor Impeller^®- I 'm not .

• 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%

• Reference example 29: Resolution of (±) -modafinil acid by the S3PC method at 2 litre scale with seeding during cooling in ethanol

- What? - Initial enantiomeric excess: 11.14% - What?

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

- What? - Seeding temperature is 29°C - Germ mass = 1 % - Crystallization time = cooling as fast as possible by tempering Agitation speed = 200 rpm throughout the process with an agitation motor Impeller^®- I 'm not .

• 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%

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

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

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

In a 10 litre balloon, you load 3.3 litres of acetone, 0.6 litres of water, 349 g of Na_{2 and}CO_{3 and}The test chemical is then heated to reach the reflux, then 330 ml of dimethyl sulphate (3.29 moles) is poured in half an hour, the reflux is extended for one hour and then allowed to return to the ambient in 20 hours.

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 and 436.3 g of methyl ester is obtained (yield = 92.3%).

• Reference 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 (CO emissions)_{2 and}Stir for 2 hours and add crushed ice + water (500 g / 500 ml). The ester crystallizes; after filtration and drying, 94.5 g of ester is obtained.

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

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

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) Melting point = 163 °C.

❖ EXAMPLE 33 and 34: crystal structures • Reference example 33: Structure of modafinil acid

The following characteristics of modafinil crystals have been obtained in acetone: Hexagonal P3_{1 and 2}or P3_{2 and}According to 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 Saintplus, Sadabs, Shelxs software.

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 the (-) 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;P2 space group_{1 and 2}The first two terms of the second sentence of Article 2 (1) of the Directive are:

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

Claims (14)

1. Process for the preparation of a polymorphic form of the levorotatory or dextrorotatory enantiomer of modafinil, 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), said process comprising the following steps:

   i) dissolving one of the optical enantiomers of modafinil in a solvent chosen from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-methyl-2-pentanol, 1,2-propanediol, t-amyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl formate, diethyl ether, tetrahydrofuran, dioxane, dibutyl ether, isopropyl ether, t-butyl methyl ether, tetrahydropyran, chloroform, 1,2-dichloroethane, dichloromethane, chlorobenzene, ortho-, meta- and para-xylene, a mixture of ortho-, meta- and/or para-xylene, methoxybenzene, nitrobenzene, trifluorotoluene, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, butan-2-one, cyclopentanone, isobutyl methyl ketone, 2-pentanone, 3-pentanone, acetic acid, pyridine, acetonitrile, propionitrile, 4-methylmorpholine, N,N-dimethylacetamide, nitromethane, triethylamine, N-methylpyrrolidone, heptane, 2,2,4-trimethylpentane, cyclopentane, cyclohexane, dimethyl carbonate, water and alcohol/water mixtures;

   ii) crystallizing the modafinil enantiomer;

   iii) recovering the crystalline form of the modafinil enantiomer thus obtained.
2. Process according to Claim 1, in which the solvent used in step i) is chosen from acetone, ethanol, 1,4-dioxane, ethyl acetate, ortho-, meta- or para-xylene, mixtures of ortho-, meta- and/or para-xylene, methanol, water, and alcohol/water mixtures.
3. Process according to Claim 1 or 2, in which the modafinil enantiomer is the levorotatory enantiomer.
4. Process according to Claim 1 or 2, in which the modafinil enantiomer is the dextrorotatory enantiomer.
5. Process according to any one of Claims 1 to 4, in which the crystallization is carried out under kinetic or thermodynamic conditions.
6. Preparation process according to any one of Claims 1 to 5, in which the crystallization is carried out by precipitation, optionally in the presence of seeds of crystals in the desired crystalline form.
7. Preparation process according to Claim 6, which uses methanol as solvent in said step i), and which implements a crystallization by precipitation by adding cold water as anti-solvent of the methanol.
8. Preparation process according to any one of Claims 1 to 7, in which the crystallization implements a cooling of the solution obtained in step i).
9. Process according to Claim 8, in which the cooling is slow.
10. Process according to Claim 8, in which the cooling is rapid.
11. Process according to Claim 9, in which the solvent used in step i) is chosen from acetone, ethanol, 1,4-dioxane, ethyl acetate, ortho-, meta- or para-xylene, or a mixture of ortho-, meta- and/or para-xylene.
12. Process according to Claim 10, in which the solvent used in step i) is chosen from methanol, water and alcohol/water mixtures, such as ethanol/water and methanol/water mixtures.
13. Process according to any one of the preceding claims, in which the polymorphic form is characterized in that it produces an X-ray diffraction spectrum comprising intensity lines at the lattice distances: 13.40, 8.54, 6.34, 5.01, 4.68, 4.62, 4.44, 4.27, 4.20, 4.15, 4.02, 3.98, 3.90, 3.80, 3.43 (Å).
14. Process according to Claim 12, in which the polymorphic form is characterized as follows: CRL 40982 FORM I 2 Theta (degrees) d (Å) I/Io (%) 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 an Elexience Miniflex Rigaku diffractometer.