HK1158171A1 - Crystalline form of the optical enantiomers of modafinil - Google Patents

Description

The invention relates to crystalline forms of the enantiomers of modafinil.

In particular, the present invention relates to a polymorphic form of the dextrogyre and levogyre enantiomers of modafinil, designated Form I, as described in the claims.

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

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

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

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

The (-) -benzhydrylsulfinylacetatate of (-) -α-methylbenzylamine is then converted by acid hydrolysis to (-) -benzhydrylsulfinylacetic acid, which is esterified in the presence of dimethyl sulfate and then diluted in the presence of ammonia (gas). The enantiomer (-) or I (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.

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 I 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)

A polymorphic form described here is designated as form I, which corresponds to the most thermodynamically stable polymorphic form, under normal temperature and pressure conditions.

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

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

Diffractomètre: Miniflex Rigaku (Elexience)

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

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

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

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

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

The disclosure also aims to propose a new method for the preparation of modafinil optical enantiomers, including the levogyre enantiomer of modafinil.

• PROCESS OF PREPARATION of the polymorphic form I of L-modafinil

Err1:Expecting ',' delimiter: line 1 column 633 (char 632)In other words, it is any solvent A capable of forming, at a given pressure, with at least one of the enantiomers in a first temperature and concentration range, a single-phase system comprising at least one of the enantiomers in solution diluted in solvent A; in a second temperature and concentration range distinct from the previous one, a second two-phase system comprising crystals of the enantiomer in the presence of saturated solution, the two ranges being separated from each other by the solubility curve of the enantiomer T (°C) = f (enantiomer concentration) at the pressure considered.

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

For example, the following solvents may be suitable for the recrystallization process according to the disclosure, but are not limited to: alcoholic solvents, carboxylic acid ester solvents, ether solvents, chlorinated solvents, aromatic solvents, lower aliphatic ketone solvents, other solvents are, 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 process execution according to the disclosure, the crystallization solvents are chosen from acetone, methanol, dioxane 1-4, ethyl acetate, ortho, meta, paraxylene, isopropanol, n-propanol, dimethylcarbonate, tetrahydrofuran, chloroform and methylethyl ketone, water and alcohol/H2O mixtures.

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

The recrystallization solvent, by its interaction with functional groups and electron-attracting or electron-donor substituents, can indeed promote certain molecular arrangements which will give rise to a specific crystalline form under given crystallization conditions. Generally, the recrystallization solvent used in step i is heated, particularly at reflux, until the optical enantiomer of modafinil is completely dissolved in the solvent. If the concentration of the optical enantiomer of modafinil at step i is not a critical modafinil recrystallization factor, it is preferred, however, in the presence of an optical enantiomer concentration of modafinil close to the saturation factor in the recrystallization solvent.

One method of disclosure involves dissolving the modafinil optical enantiomer by heating the reflux solvent and then adding an additional amount of the optical enantiomer in fractions to achieve saturation. Additional solvent may be added to ensure complete dissolution. Another method involves suspending the modafinil optical enantiomer in the reflux heated solvent, and then adding an additional amount of solvent in fractions to achieve a homogeneous solution and saturation.

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

The process of crystallization of the process according to the disclosure can 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 illustrative purposes and not limited to, these two 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 according to the disclosure.

Thus, depending on a particular method of disclosure, crystallization at step (ii) can be performed by precipitation, possibly in the presence of crystal germs of the desired crystal 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.

According to a preferred method of disclosure, 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 of cooling with a cooling range of, for example, -1°C to -5°C/min.

A second method of disclosure is slow cooling, 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 preferably closer to - 0.5 °C/min, to a temperature generally of 15° to 20 °C.

The solvent/anti-solvent combinations of preference according to the disclosure 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.

By way of illustration and not limited to, the disclosure preparation process is most notably used with the levogyre enantiomer of modafinil.

Depending on the particular method of disclosure, the crystalline form obtained by this process is a polymorphic form.

It should be noted that, in general, each of the enantiomers (I) 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 form designated form I thus covers the form CRL40982 form I obtained from the levogyre enantiomer and the form CRL40983 form I 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 disclosure, the process using methanol and a precipitation crystallization step by addition of cold water as an antisolid of methanol leads to the form I.

• Polymorphic forms of (-) - Modafinil

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

SOLVATE DE DIMETHYLCARBONATE
2 Theta (degrés)	d (Å)	I/lo (%)
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.

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

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

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

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

In this context, according to a particular method of disclosure, 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 disclosure also concerns the acetonitrile solvate of (-) -modafinil which can be obtained by the disclosure recrystallization process. - What?

SOLVATE D'ACETONITRILE
2 Theta (degrés)	d (Å)	I/lo (%)
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 the polymorphic form I of (-) - Modafinil, (+) - Modafinil respectively

The invention also relates to pharmaceutical formulations comprising the polymorphic form CRL 40982 form I of (-) -modafinil, CRL 40983 form I respectively, possibly in combination with a pharmaceutically acceptable vehicle.

These compositions may be administered orally, mucously (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 compositions of the invention are administered orally, as immediate-release or controlled-release tablets, pills, oils or granules, as powder, capsules, suspension in a liquid or gel, capsules of haemolysis, lyophilisate, or more likely as a suspension in a liquid or gel, for example, in a polymorphic suspension, which may include several forms of suspension or a polymorphic suspension, which are pharmaceutically acceptable (e.g. in the form of a capsule or gel).

The pharmaceutical compositions of the invention include the polymorphic form of (-) -modafinil and (+) -modafinil I, possibly mixed with the polymorphic forms of (-) -modafinil and (+) -modafinil II, III, IV or V respectively and/or with one or more pharmaceutically acceptable excipients.

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

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

Examples of binders include gelatine, gum gum, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone (PVP), povidone, copovidone, dextran, 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 of the present invention may also contain another crystalline form of (-) -modafinil or (+) -modafinil, respectively, including form I and another active or inactive ingredient mixed with one or more other polymorphic forms of modafinil, such as form III, form II, form IV and form V.

Err1:Expecting ',' delimiter: line 1 column 90 (char 89)

The following examples are given for illustration purposes.

The Commission has also adopted a proposal for a directive on the approximation of the laws of the Member States relating to the labelling of foodstuffs.

Figure 1 shows the X-ray diffraction spectrum on powder corresponding to the dimethylcarbonate solvate of the levogyre enantiomer, dextrogyre of modafinil respectively (diffractometer: Siemens AG).Figure 2 shows the X-ray diffraction spectrum on powder corresponding to the acetonitrile solvate of the levogyre enantiomer, dextrogyre of modafinil respectively (diffractometer: Siemens AG).

Examples Preparation of the crystalline form I of the enantiomer (-) - modafinil and (+) - modafinil respectively The Commission has not yet adopted a decision on the application of this Regulation.

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

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

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

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

(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?

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

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

- Example 3: Recrystallization in methanol

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

- Example 4: Recrystallization in methanol (2e)

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

- Example 5 : recrystallization in dioxane 1-4

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

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

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

- Example 7: Recrystallization in ethyl acetate

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

- Example 8 : from other polymorphic forms

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

- Example 9: from acetonitrile solvate

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

- Example 10: from monodimethyl carbonate solvate

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

The following table shows the results of the analysis of the solvents used in the preparation of the compounds: - Example 11 of reference: Preparation of dimethylcarbonate solvate from (-) -modafinil

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

- Example 12 of reference: 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.

The following is a list of the main types of crystalline structures. - Example 13 : Structure of modafinil acid

The following characteristics are obtained from the acetone: Hexagonal P31 or P32 depending on the enantiomer, so modafinil is a conglomerate; a = 9.55, b = 9.55, c = 13.14 Åα = 90.000, β = 90.000, γ = 120.000°

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

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

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

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

- Example 14 : Structure of (-) and (+) -modafinil form I

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

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

Claims (12)

1. Polymorphic form of the dextrorotatory or levorotatory enantiomer of modafinil, designated form I, characterized in that (i) it produces an X-ray diffraction spectrum comprising intensity peaks at the interplanar spacings: 8.54; 4.27; 4.02; 3.98 (Å); or (ii) it produces an X-ray diffraction spectrum comprising intensity peaks at 2 theta angle values: 15.4; 31.1; 33.1 and 33.4 (degrees), measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation, the error in the 2 theta values being ± 0.2 degrees 2 theta.
2. Polymorphic form according to claim 1 characterized in that it produces an X-ray diffraction spectrum comprising intensity peaks at the interplanar spacings: 8.54; 4.27; 4.02; 3.98 (Å).
3. Polymorphic form according to claim 2 characterized in that it produces an X-ray diffraction spectrum further comprising intensity peaks at the interplanar spacings: 13.40; 6.34; 5.01; 4.68; 4.62 ; 4.44; 4.20; 4.15; 3.90; 3.80; 3.43 (Å).
4. Polymorphic form according to claim 1 characterized in that it produces an X-ray diffraction spectrum comprising intensity peaks at 2 theta angle values: 15.4; 31.1; 33.1 and 33.4 (degrees), measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation, the error in the 2 theta values being ± 0.2 degrees 2 theta.
5. Polymorphic form according to claim 4 characterized in that it produces an X-ray diffraction spectrum further comprising intensity peaks at 2 theta values: 9.8; 20.8; 26.4; 28.3; 28.7; 29.9; 31.6; 32; 34.1; 35.1 and 39 (degrees), measured using a Miniflex Rigaku (Elexience) diffractometer using chromium radiation, the error in the 2 theta values being ± 0.2 degrees 2 theta.
6. Polymorphic form according to any one of claims 1 to 5, wherein the polymorphic form is characterised as follows: CRL 40982 FORM I 2 Theta (degrees) d (A) 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 a Miniflex Rigaku (Elexience) diffractometer using chromium radiation.
7. Pharmaceutical composition comprising the polymorphic form of (-) modafinil or (+) modafinil, designated form I, according to claims 1 to 6 and pharmaceutically acceptable excipients.
8. Pharmaceutical composition consisting of the polymorphic form of dextrorotatory or levorotatory modafinil designated form I, according to any one of claims 1 to 6, and pharmaceutically acceptable excipients.
9. Polymorphic form of modafinil according to any one of claims 1 to 6, wherein the enantiomer is the (-) enantiomer.
10. Polymorphic form of modafinil according to any one of claims 1 to 6, wherein the enantiomer is the (+) enantiomer.
11. Pharmaceutical composition comprising a polymorphic form of (-) modafinil or a polymorphic form of (+) modafinil according to claim 9 or 10 and pharmaceutically acceptable excipients.
12. Pharmaceutical composition consisting of a polymorphic form of (-) modafinil or a polymorphic form of (+) modafinil according to any one of claims 9 and 10 and pharmaceutically acceptable excipients.