CN1980888B

CN1980888B - Modafinil compositions

Info

Publication number: CN1980888B
Application number: CN2005800041104A
Authority: CN
Inventors: 马加利·布戈尔·希基; 马修·彼得松; 厄恩·奥尔马松; 马克·奥利韦拉
Original assignee: Cephalon LLC
Current assignee: Cephalon LLC
Priority date: 2004-02-06
Filing date: 2005-02-01
Publication date: 2011-04-13
Anticipated expiration: 2025-02-01
Also published as: CN1980888A

Abstract

Co-crystals and solvates of racemic, enantiomerically pure, and enantiomerically mixed modafinil are formed and several important physical properties are modulated. The solubility, dissolution, bioavailability, dose response, and stability of modafinil can be modulated to improve efficacy in pharmaceutical compositions.

Description

Modafinil compositions

Technical field

The present invention relates to comprise Provigil composition, comprise Provigil pharmaceutical composition, and preparation method thereof.

Background technology

Active pharmaceutical component (API) in the pharmaceutical composition can be prepared as multiple different form.Can prepare this API makes it have multiple different chemical species to comprise chemical derivative, solvate, hydrate, cocrystallization or salt.This API can also be prepared as has different physical form.For example, API can be unbodied, can have different crystalline polymorphs or solvation that can be different or hydration status and exist.By changing the form of API, might change its physical properties.For example, crystalline polymorph typically has the solubleness that differs from one another, and makes that the more stable polymorphic form of thermodynamics is poorer than the solubility of the more unsettled polymorphic form of thermodynamics.Medicinal polymorphic form can also be in many properties differences, as storage life, bioavailability, morphology, vapour pressure, density, color and compressibility.Therefore, the variation of the crystalline state of API is wherein to regulate one of many aspects of its physical properties.

It is favourable that these API have the new form of improving character, particularly as oral preparations.Particularly, the improved form of the API of the character (comprising the water-soluble and stable of increase) that shows remarkable improvement is identified in expectation.In addition, expectation improves the workability or the preparation of medicinal preparations.For example, needle-like crystal form or the crystal habit of API can cause gathering, even also are so in API and other material blended composition therein, obtain uneven mixture.Acicular form can also cause filtration problem (referring to for example, people such as Mirmehrabi, J.Pharm.Sci.Vo1.93, No.7,1692-1700 page or leaf, 2004).Also expectation increases the dissolution rate of pharmaceutical composition in water that contains API, increases the bioavailability and the faster onset that curative effect is provided of liquid preparations for oral administration.Also expect to have a kind of API of form, with it during to the main body administration, its API than the present form known of equivalent reaches peak serum concentration sooner, has the comprehensive engagement of more persistent therapeutics plasma concentration and Geng Gao.

Provigil, as being used for the treatment of the API that suffers from narcoleptic main body, it is water-soluble hardly.Provigil (CAS registration number: 68693-11-8) represent by structural formula (I):

Provigil is owing to the S=O group of chirality becomes chiral molecules.Therefore, Provigil exists as two isomer, and they are R-(-)-Provigil and S-(+)-Provigil.The Provigil of new form with character of improvement is favourable, particularly as oral preparations.Particularly, the improved form of the Provigil show water-soluble and chemical stability with remarkable increase and shape stability is identified in expectation.Also expectation increases the dissolution rate of pharmaceutical composition in water contain API, increases the bioavailability of liquid preparations for oral administration and the faster onset of curative effect is provided.Also expect to have a kind of API of form, with it during to the main body administration, the comprehensive engagement that it reaches peak serum concentration sooner and/or have more persistent therapeutics plasma concentration and Geng Gao than the API of the present form known of equivalent when high dosage.

Summary of the invention

Have been found that the polymorphic form and the solvate that can obtain Provigil now, some of them are compared with the API of free form has different character.

The Provigil that the embodiment of the present invention that include but not limited to polymorphic form and solvate can comprise racemize Provigil, enantiomer-pure (promptly, R-(-)-Provigil or S-(+)-Provigil), or the Provigil of enrichment (55 arriving about 90%ee according to appointment).Similarly, solvent molecule (as, in solvate) form that also can be used as racemic, enantiomer-pure or enrichment is present in embodiment of the present invention.

In another embodiment, the invention provides following Provigil solvate: chloroform, chlorobenzene, ethyl acetate and acetate.

Method of the present invention can comprise that separately the Provigil polymorphic form that wherein will produce thus or solvate are attached to the one or more other step in the pharmaceutical composition.

In other embodiments, the invention provides new R-(-)-Provigil polymorphic form.In specific embodiment, the invention provides R-(-)-Provigil of III, IV and V-arrangement.The present invention also provides the method for producing R-(-)-Provigil polymorphic form.

In other embodiments, the invention provides the method for producing R-(-)-Provigil polymorphic form, this method comprises:

(a) provide R-(-)-m Provigil;

(b) R-(-)-Provigil polymorphic form crystallization from appropriate solvent.

In other embodiments, R-(-)-Provigil polymorphic form is from the organic solvent crystallization.In specific embodiment, organic solvent can be acetonitrile, dimethyl formamide (DMF), methyl alcohol, methyl ethyl ketone, N-Methyl pyrrolidone, ethanol, Virahol, isopropylcarbinol, methane amide, isobutyl acetate, 1,4-dioxane, tetrahydrofuran (THF) (THF), ethyl acetate, o-Xylol, isopropyl acetate, methylene dichloride, propylene glycol, acetate, water, acetone, Nitromethane 99Min., toluene and phenylcarbinol.According to the present invention, neat solvent and mixed solvent all are counted as organic solvent.In specific embodiment, organic solvent is an ethanol.In another embodiment, use the polymorphic form of mixed solvent system crystallization R-(-)-Provigil.Mixed solvent system can be for example ethanol and Virahol or ethyl acetate and ethanol.In other embodiments, the crystallization in the step (b) is finished by thermal crystalline.In other embodiments, the crystallization in the step (b) is finished by evaporating solvent.

In another embodiment, pharmaceutical composition comprises the release profiles of one or more change in racemize Provigil, R-(-)-Provigil and S-(+)-Provigil.The release profiles that changes can comprise for example two or more maximal plasma concentration, as two-fold (dual) release profiles.

The present invention provides the polymorphic form that comprises Provigil or the medicine and the production method thereof of solvate in addition.Typically, medicine comprises one or more pharmaceutically useful carriers, thinner or vehicle in addition.Medicine of the present invention is described in further detail following.

Method of the present invention can comprise that separately the Provigil polymorphic form that wherein will produce thus or solvate are attached to the one or more other step in the medicine.

In another aspect of the present invention; provide treatment to suffer from the method for the main body (preferred human subject) of the excessive daytime sleepiness relevant with hypnolepsy, fatigue, Infertility, eating disorder, attention-deficit hyperactivity disease (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy that multiple sclerosis is relevant, wherein Provigil is effective active medicine to described illness.This method comprises polymorphic form or the solvate to the Provigil of main body drug treatment significant quantity.

In another embodiment, provide treatment to suffer from one or more above-mentioned conditions or illness, include but not limited to the method for somnopathy such as narcoleptic main body, it comprises III shape R-(-)-Provigil of main body drug treatment significant quantity, IV shape R-(-)-Provigil or V-arrangement R-(-)-Provigil.

Description of drawings

Fig. 1-2: R-(-)-Provigil of 1: the PXRD diffractogram of the polymorphic form of S-(+)-Provigil.

R-(-)-Provigil of Fig. 2-2:1: the DSC differential thermogram of the polymorphic form of S-(+)-Provigil.

The PXRD diffractogram of the polymorphic form of Fig. 3-R-(-)-Provigil (III shape).

The DSC differential thermogram of the polymorphic form of Fig. 4-R-(-)-Provigil (III shape).

The PXRD diffractogram of the polymorphic form of Fig. 5-R-(-)-Provigil (III shape).

The PXRD diffractogram of the polymorphic form of Fig. 6-R-(-)-Provigil (IV shape).

The DSC differential thermogram of the polymorphic form of Fig. 7-R-(-)-Provigil (IV shape).

The PXRD diffractogram of the polymorphic form of Fig. 8-R-(-)-Provigil (IV shape).

The PXRD diffractogram of the polymorphic form of Fig. 9-R-(-)-Provigil (V-arrangement).

The PXRD diffractogram of the polymorphic form of Figure 10-R-(-)-Provigil (V-arrangement).

R-(-)-Provigil of Figure 11-2:1: the PXRD diffractogram of S-(+)-Provigil.

R-(-)-Provigil of Figure 12-2:1: the DSC differential thermogram of S-(+)-Provigil.

The PXRD diffractogram of Figure 13-IV shape R-(-)-Provigil.

The PXRD diffractogram of Figure 14-V-arrangement R-(-)-Provigil.

The DSC differential thermogram of Figure 15-V-arrangement R-(-)-Provigil.

The PXRD diffractogram of Figure 16-R-(-)-Provigil chloroform solvent compound.

The TGA differential thermogram of Figure 17-R-(-)-Provigil chloroform solvent compound.

The PXRD diffractogram of Figure 18-R-(-)-Provigil chlorobenzene solvent compound.

The PXRD diffractogram of Figure 19-racemize Provigil ethyl acetate passage (channel) solvate.

The TGA differential thermogram of Figure 20-racemize Provigil ethyl acetate passage solvate.

The PXRD diffractogram of Figure 21-R-(-)-Provigil acetic acid solvent compound.

The TGA differential thermogram of Figure 22-R-(-)-Provigil acetic acid solvent compound.

The DSC differential thermogram of Figure 23-R-(-)-Provigil acetic acid solvent compound.

Detailed description of the invention

The structure of Provigil comprises stereocenter, so its two isomer that can be used as one of racemoid, two pure isomer or any ratio are to existing.The chemical name of racemize Provigil is (±)-2-[(diphenyl-methyl) sulfinyl] ethanamide.The isomer of racemize Provigil is to being R-(-)-2-[(diphenyl-methyl) sulfinyl] ethanamide (or R-(-)-Provigil) and S-(+)-2-[(diphenyl-methyl) sulfinyl] ethanamide (or S-(+)-Provigil).

As used in this article and unless otherwise mentioned, term " enantiomer-pure " comprises the composition that is essentially enantiomer-pure, and it comprises the composition that for example has at least about 90,91,92,93,94,95,96,97,98 or 99% enantiomeric excess.Enantiomeric excess is defined as enantiomorph A%-enantiomorph B%, or is defined by following formula:

Ee%=100* ([R]-[S]/([R]+[S]), wherein R is the mole number of R-(-)-Provigil, S is the mole number of S-(+)-Provigil.

As used in this article, term " Provigil " comprises racemoid, R isomer-and other mixture and the one enantiomorph of S-isomer, but can be illustrated as any mixture of racemoid, R-isomer, S-isomer or R-isomer and S-isomer particularly.

As used in this article and unless otherwise mentioned, term " racemize " is meant and waits molar mixture, solvate or material (as polymorphic form or solvate) that both form by the enantiomorph of Provigil.For example, the solvate that comprises Provigil and non-stereoisomerism solvent molecule have only when exist the Provigil enantiomorph etc. be only " racemic solvate " during molar mixture.Similarly, the solvate that comprises Provigil and stereoisomerism solvent molecule have only when exist the Provigil enantiomorph etc. molar mixture and solvent molecule enantiomorph etc. be only " racemic solvate " during molar mixture.

As used in this article and unless otherwise mentioned, term " enantiomer-pure " is meant that by Provigil and non-essential stereomeric or non-stereomeric molten molecular material wherein the enantiomeric excess of stereoisomerism material is minimum is about 90%ee (enantiomeric excess).

For purpose of the present invention, can with the chemistry of the Provigil of solvate or polymorphic form form and physical properties with compare as the reference compound of multi-form Provigil.Reference compound can be appointed as free form, or more specifically, is the dehydrate or the hydrate of free form, or more specifically is semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, the pentahydrate of for example free form; Or solvate.Also but the designated reference compound is a crystalline or unbodied.Also but the designated reference compound is the most stable known polymorphic form of the true-to-shape of reference compound.

Provigil and solvent molecules more of the present invention have one or more chiral centres, and can have multiple stereoisomerism configuration.Because these chiral centres, Provigil and several solvate of the present invention exist as the mixture of racemoid, enantiomorph with as the mixture of independent enantiomorph and diastereomer and diastereomer.All this racemoid, enantiomorph and diastereomers all fall within the scope of the invention, for example comprise cis and trans-isomer(ide), R-and S-enantiomorph and (D)-and (L)-isomer.Solvate of the present invention can comprise Provigil or solvent molecule or its both isomeric forms.The isomeric forms of Provigil and solvent molecule includes but not limited to steric isomer such as enantiomorph and diastereomer.In one embodiment, solvate comprises racemize Provigil and solvent molecule.In another embodiment, solvate comprises R-or the S-Provigil and the solvent molecule of enantiomer-pure.In another embodiment, solvate of the present invention comprise have about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, greater than 99% or the Provigil and/or the solvent molecule of the enantiomeric excess of any intermediate value.In another embodiment, polymorphic form of the present invention or solvate can comprise have about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, greater than 99% or the Provigil of the enantiomeric excess of any intermediate value.

" enrichment " of the present invention Provigil comprises more than or equal to about 5,6,7,8,9 or 10 weight % and is less than or equal to R-(-)-and S-(+)-isomer of Provigil of the amount of about 90,91,92,93,94 or 95 weight %.For example, the composition that comprises 67 weight %R-(-)-Provigils and 33 weight %S-(+)-Provigils is the modafinil compositions of enrichment.In this example, composition neither racemic neither enantiomer-pure.Term " R-(-)-Provigil of enrichment " can be used for describing and has greater than 50%R-(-)-Provigil with less than the modafinil compositions of 50%S-(+)-Provigil.Similarly, term " S-(+)-Provigil of enrichment " can be used for describing and has greater than 50%S-(+)-Provigil with less than the modafinil compositions of 50%R-(-)-Provigil.

Term " R-(-)-Provigil " and " S-(+)-Provigil " can be used for describing enrichment Provigil, enantiomer-pure Provigil or be the Provigil of enantiomer-pure basically, but also can get rid of particularly enrichment Provigil, enantiomer-pure Provigil and/or be the Provigil of enantiomer-pure basically.

Comprising that the solvate of component enantiomer-pure and/or the enantiomorph enrichment (forming thing as, Provigil or cocrystallization) and polymorphic form can produce with respect to those of the corresponding cocrystallization that comprises racemic component obtains chemistry and/or physical properties through overregulating.

Can also use the Provigil of racemize Provigil, enantiomer-pure or with R-of the present invention (-)-and the polymorphic form and the solvate of any mixture of S-(+)-Provigil (as, the Provigil of enrichment) preparation Provigil.

In another embodiment, comprise the composition of solvate of the present invention and polymorphic form or medicine can with at PROVIGIL (Cephalon, the Provigil of the free form that Inc.) obtains is compared.(referring to US review patent RE37, No. 516).

Pharmaceutically useful cocrystallization can or prolong the method administration that discharges by sustained release.The medicinal products of sustained release has and improves the common objective that pharmacological agent surpasses the pharmacological agent that is realized by its non-sustained release counterpart.Ideally, in medical treatment, use being characterized as in the shortest time of sustained release preparation of optimum design to treat or the control situation with minimum drug substance.The advantage of sustained release preparation comprises: 1) prolong drug activity; 2) reduce the dosage administration frequency; 3) increase patient compliance; 4) total dosage still less; 5) side effect of part or system reduces; 6) Zui Xiao drug accumulation; 7) the blood levels fluctuation reduces; 8) treatment is renderd a service and is improved; 9) enhancing of pharmaceutical activity or loss reduce; With 10) speed improvement of control disease or situation.(Kim，Cherng-ju，Controlled?Release?Dosage?Form?Design，2?TechnomicPublishing，Lancaster，Pa.：2000)。

Conventional formulation provide usually from preparation rapidly or drug release immediately.The pharmacology and the pharmacokinetics that depend on medicine are used conventional formulation can cause at patient's blood and are organized the wide fluctuation of Chinese traditional medicine concentration with other.These fluctuations can influence many parameters, as the maintenance of time length of dosed administration frequency, effect onset, effectiveness, treatment blood levels, toxicity, side effect, or the like.Advantageously, the sustained release preparation can be used for controlling the time length of pharmaceutically-active onset, effect, blood plasma level and the blood peak concentration in the treatment window.Particularly, sustained release or prolongation release dosage form or preparation can be used for guaranteeing to realize the maximum validity of medicine, and potential side effect and safety problem are minimized, it can take place when (that is, below minimum treatment level) takes place for the dosed administration deficiency (under dosing) of medicine and surpass the toxic level of medicine.

Most of sustained release preparations are used for the initial medicine (active ingredient) that produces required therapeutic action rapidly that discharges to be measured, and little by little and continuously discharges other amount of medicine, is used for keeping this treatment or prophylactic effect level in the time that prolongs.In order to keep medicine in the intravital this constant level of body, medicine must discharge from formulation by metabolism with from the speed of the amount of body excretes to replace medicine.The sustained release of active ingredient is subjected to the stimulation of multiple condition, and it includes but not limited to pH, ionic strength, seepage water pressure, temperature, enzyme, water and other physiological condition or compound.

Multiple known sustained release is arranged or prolong release dosage form, preparation and device and can be suitable for using with solvate of the present invention and composition.Its example includes but not limited at United States Patent (USP) 3,845 770,3,916,899,3,536,809,3,598,123,4,008,719,5,674,533,5,059,595,5,591,767,5,120,548,5,073,543,5,639,476,5,354,556,5,733,566 and 6,365, those described in the 185B1, its each all be merged in this paper as a reference.These formulations can be used for providing the slow release or the sustained release of one or more active ingredients, and it for example uses HPMC, other polymer matrix, gelifying agent, permeable membrane, osmosis system (as OROS (Alza Corporation, Mountain View, Calif.USA)), multiple coatings, particulate, liposome or microsphere or its combination are to provide the release profiles of required different ratios.In addition, ion-exchange material can be used for preparing the cocrystallization that fixed is adsorbed, thereby and realizes that controlled delivery of pharmaceutical agents sends.The example of concrete anionite includes but not limited to Duolite

A568 and Duolite

AP143 (Rohm﹠amp; Haas, Spring House, PA.USA).

One embodiment of the invention comprise unit dosage form, it comprises pharmaceutically useful solvate, hydrate, dehydrate, anhydride, amorphous form, with one or more pharmaceutically useful vehicle or thinner, wherein compounding pharmaceutical composition, medicine or formulation are used for sustained release.Concrete formulation adopts the osmosis type drug delivery system.

Concrete is referred to as OROS with known osmosis type drug delivery system

(AlzaCorporation, Mountain View, Calif.USA).This technology can easily be suitable for sending compound of the present invention and composition.The many aspects of this technology are at United States Patent (USP) 6,375,978B1,6,368,626B1,6,342,249B1,6,333,050B2,6,287,295B1,6,283,953B1,6,270,787B1,6,245,357B1 and 6,132, open in 420, its each be merged in this paper as a reference.The concrete OROS that can be used for administration compound of the present invention and composition Remodeling includes but not limited to OROS

Push-Pull ^TM, Delayed Push-Pull ^TM, Multi-Layer Push-Pull ^TMAnd Push-Stick ^TMSystems, it all is well-known.Referring to for example, Http:// www.alza.comThe other OROS that can be used for the in check oral delivery of compound of the present invention and composition

System comprises OROS

-CT and L-OROS

.Id., also referring to Delivery Times, vol.II, issue II (Alza Corporation).

Conventional OROS The production of oral dosage form is tablet coating by with the hard tablet of drug powder boil down to derivatived cellulose, to form semipolar linkage, boring on dressing then (as, use laser).Kim，Cherng-ju，Controlled?Release?Dosage?Form?Design，231-238(Technomic?Publishing，Lancaster，Pa.：2000)。The advantage of this formulation is that the delivery rate of medicine is not subjected to the influence of physiology or experiment condition.Also can send even have the deliquescent medicine of pH dependency with constant speed, and regardless of the pH of delivery media.But, these advantages provide the OROS of routine because being accumulation by the seepage water pressure in formulation administration after

Drug delivery system can not be used for sending effectively the medicine with low water solubility.Id.at?234。

Concrete formulation of the present invention comprises: limit the wall in chamber, wall has the outlet that forms therein, and at least a portion wall is semi-permeable; Be positioned at the chamber away from the expandable layer that exports and be communicated with the semipermeability segment fluid flow of wall; Be positioned at chamber and outlet in abutting connection with and with expandable layer be the dry of direct or indirect contact relation or the medicine layer that is essentially drying regime; And be inserted in the mobile promoting layer between the outside surface at least of the internal surface of wall and the medicine layer in the chamber, wherein medicine layer comprises its polymorphic form or solvate, hydrate, dehydrate, anhydride or amorphous substance.Referring to United States Patent (USP) 6,368,626, it is merged in this paper as a reference in full.

Another concrete formulation of the present invention comprises: limit the wall in chamber, wall has the outlet that forms therein, and at least a portion wall is semi-permeable; Be positioned at the chamber away from the expandable layer that exports and be communicated with the semipermeability segment fluid flow of wall; Be positioned at the chamber with the outlet in abutting connection with and with expandable layer be the medicine layer of direct or indirect contact relation; Medicine layer comprises fluid, is absorbed in the active agent formulation in the porous granule, porous granule is suitable for resisting the force of compression of the medicine layer that enough forms compactness and does not have significantly oozing out of fluid, active agent formulation, dosage form selection ground has placebo layer between outlet and medicine layer, wherein active agent formulation comprises its polymorphic form or solvate, hydrate, dehydrate, anhydride or amorphous substance.Referring to United States Patent (USP) 6,342,249, it is merged in this paper as a reference in full.

In another embodiment, pharmaceutical composition or medicine comprise Provigil of the present invention new form (as, polymorphic form or solvate) and the mixture of racemize Provigil.This embodiment can be used as for example sustained release, lasting release or the prolongation release dosage form.In another embodiment, prolong release dosage form and comprise racemize Provigil and polymorphic form of the present invention or solvate.

In another embodiment, pharmaceutical composition or medicine comprise the release profiles of one or more change in racemize Provigil, R-(-)-Provigil and S-(+)-Provigil.The release profiles that changes can comprise for example two or more maximal plasma concentration, as dual release profile.The release profiles of this change may help to use composition of the present invention or pharmacological agent to experience for example patient of awakening disappearance in afternoon (loss of wakefulness in the afternoon)." break out (burst) " or discharge to have the second time of at least 2,3,4,5 or 6 hours API after administration and help overcome this effect.In another embodiment, can adopt and be included in the little loading dose that discharges immediately after the administration, in 2,3,4,5 or 6 hours, be pharmaceutical composition or medicine subsequently near the zero level release profiles.In this composition, the peak blood plasma level can reached approximately noon.

In another embodiment, the pharmaceutical composition or the medicine of release profiles that comprises the change of Provigil comprises R-(-)-Provigil and S-(+)-Provigil, wherein R-(-)-Provigil provides the initial increase (because Cmax of R-(-)-Provigil) of plasma concentration, and S-(+)-Provigil provides the increase (because Cmax subsequently of S-(+)-Provigil) of the delay of plasma concentration.Because the Cmax of the delay of S-(+)-Provigil increases can be because after the initial Cmax of R-(-)-Provigil 2,3,4,5,6 hours or more of a specified duration.In another embodiment, the Cmax of delay is approximately equal to initial Cmax.In another embodiment, the Cmax of delay is greater than initial Cmax.In another embodiment, the Cmax of delay is less than initial Cmax.In another embodiment, the Cmax of delay is owing to the racemize Provigil, rather than S-(+)-Provigil.In another embodiment, the Cmax of delay is because R-(-)-Provigil rather than S-(+)-Provigil.In another embodiment, initial Cmax is owing to the racemize Provigil, rather than R-(-)-Provigil.In another embodiment, initial Cmax is because S-(+)-Provigil rather than R-(-)-Provigil.In another embodiment, the release profiles of change has 3,4,5 or more a plurality of " outbursts " of plasma concentration.

In another embodiment, pharmaceutical composition or medicine comprise the release profiles of the change of Provigil, and wherein one or more forms with solvate or polymorphic form exist in racemize Provigil, R-(-)-Provigil or S-(+)-Provigil.

In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of R-(-)-Provigil are used for oral preparations.The first pass metabolism that this composition can make Provigil become sulfone minimizes.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of racemize Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of S-(+)-Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of racemize Provigil and R-(-)-Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of racemize Provigil and S-(+)-Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of S-(+)-Provigil and R-(-)-Provigil are used for oral preparations.In another embodiment, comprise that wherein the pharmaceutical composition or the medicine of the release profiles of the change of racemize Provigil, S-(+)-Provigil and R-(-)-Provigil are used for oral preparations.

In another embodiment, the pharmaceutical composition or the medicine of release profiles that comprises the change of Provigil is used for transdermal administration.This transdermal (TD) is sent and can be avoided first pass metabolism.In addition, can adopt " pill-and-patch " strategy, wherein only the part of per daily dose be passed through dermal delivery,, increase oral administration on its basis to guarantee the awakening effect to form the system level on basis.

The vehicle that is used for pharmaceutical composition of the present invention and medicine can be solid, semisolid, fluid or its combination.Preferably, vehicle is a solid.The composition of the present invention and the medicine that comprise vehicle can be by comprising vehicle and API or the known pharmaceutical technology preparation of therapeutical agent blended.Every dosage device of pharmaceutical composition of the present invention or medicine comprises the API of desired amount, if and be used for oral administration, any other form that it can be tablet for example, capsule sheet, pill, hard or soft capsule, lozenge, cachet, assignable powder, particle, suspension, elixir, dispersion, fluid or reasonably is suitable for this administration.If be used for parenterai administration, it can be the form of suspension for example or percutaneous plaster.If be used for rectal administration, it can be for example form of suppository.The present preferably unitary oral dosage form of discrete doses of the API of each self-contained predetermined amount is as tablet or capsule.

The non-limitative example of vehicle that can be used for preparing pharmaceutical composition of the present invention or medicine is as follows.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable carrier or thinner are as vehicle.Carrier that is fit to or thinner illustrative ground includes but not limited to, and is independent or make up, and lactose comprises lactose hydrous and Spherolac 100; Starch comprises that the starch that can directly compress and hydrolyzed starch are (as, Celutab ^TMAnd Emdex ^TM); N.F,USP MANNITOL; Sorbitol Powder; Xylitol; Glucose (as, Cerelose ^TM2000) and Glucose monohydrate; Bibasic calcium phosphate dihydrate; The thinner of sucrose system; The candy manufacturing is with sugared; Monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, particulate calcium lactate trihydrate; Dextrates; Inositol; Hydrolyzed cereal solids; Amylose starch; Mierocrystalline cellulose, comprise Microcrystalline Cellulose, food grade source and α-and amorphous cellulose (as, RexcelJ), cellulose powder, hydroxypropylcellulose (HPC) and HPMC (HPMC); Lime carbonate; Glycine; Wilkinite; Segmented copolymer; Polyvinylpyrrolidone; Or the like.If exist, this carrier or thinner amount to account for composition total weight about 5% to about 99%, preferred about 10% to about 85%, more preferably from about 20% to about 80%.Preferred carrier, variety carrier, thinner or the plurality of diluent of selecting shows suitable flow characteristics, and shows suitable compressibility when tablet needs.

Lactose, N.F,USP MANNITOL, Di-Sodium Phosphate and Microcrystalline Cellulose (particularly Avicel PH Microcrystalline Cellulose such as Avicel PH 101), independent or combination, be preferable absorbent.These thinners and API are that chemistry is compatible.The use of outer (extragranular) Microcrystalline Cellulose of particle (that is, be added in the particulate composition Microcrystalline Cellulose) can be used for improving hardness (for tablet) and/or disintegration time.Preferred especially lactose, particularly Spherolac 100.Lactose typically provides the composition with suitable API rate of release, stability, precompression flowability and/or dry property with low relatively thinner cost.It provides the high-density substrate that helps compacting in granulation process (wherein using wet granulation) and therefore improve mixture flow dynamic characteristic and tablet character.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable disintegrating agents are as vehicle, especially for tablet formulation.The disintegrating agent that is fit to includes but not limited to, and is independent or combination, and starch comprises that Explotab is (as, the Explotab of PenWest ^TM) and pregelatinized W-Gum (as, the National of National Starch and Chemical Company ^TM1551, National ^TM1550 and Colocorn ^TM1500), clay is (as, the Veegum of R.T.Vanderbilt ^TMHV), Mierocrystalline cellulose such as pure Mierocrystalline cellulose, Microcrystalline Cellulose, methylcellulose gum, Cellulose,ether with glycolic acid and Xylo-Mucine, cross-linked carboxymethyl cellulose sodium are (as, Ac-Di-Sol ^TM, derive from FMC), alginates, Crospovidone and natural gum is as agar, guar gum, Viscogum BE, kuteera gum, pectin and tragacanth gum.

Disintegrating agent can add in any suitable step in the preparation composition process, particularly adds before granulation or in the lubricated step process before the compression.If exist, this disintegrating agent amount to account for composition total weight about 0.2% to about 30%, preferred about 0.2% to about 10%, more preferably from about 0.2% to about 5%.

Cross-linked carboxymethyl cellulose sodium is the preferred disintegrating agent that is used for tablet or capsule disintegration, if exist, preferably its account for composition total weight about 0.2% to about 10%, more preferably from about 0.2% to about 7%, more preferably from about 0.2% to about 5%.Cross-linked carboxymethyl cellulose sodium is given through the pharmaceutical composition of the present invention of granulation and the higher interior disintegration ability of particle of medicine.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable binding agents or tackiness agent are as vehicle, particularly for tablet formulation.Preferred this binding agent and tackiness agent are given by the powder of compressing tablet with sufficient cohesion, allowing conventional technological operation such as gluing, lubricated, compression and packing, but allow still that disintegration of tablet and composition are absorbed when picked-up.This binding agent also can prevent or suppress crystallization or the recrystallization of API of the present invention when salt has been dissolved in the solution.The binding agent and the tackiness agent that are fit to include but not limited to, and be independent or combination, gum arabic; Tragacanth gum; Sucrose; Gelatin; Glucose; Starch such as but not limited to pregelatinized Starch (as, National ^TM1511 and National ^TM1500); Mierocrystalline cellulose such as but not limited to methylcellulose gum and carmethose (as, Tylose ^TM); Lalgine and alginates; Magnesium aluminum silicate; PEG; Guar gum; Polysaccharide acid; Wilkinite; Polyvidone, for example 30 POVIDONE K 30 BP/USP-15, K-30 and K-29/32; Polymethacrylate; HPMC; Hydroxypropylcellulose (as, the Klucel of Aqualon ^TM); And ethyl cellulose (as, the Ethocel of the Dow Chemical Company ^TM).If exist, this binding agent and/or tackiness agent amount to the gross weight that constitutes pharmaceutical composition or medicine about 0.5% to about 25%, preferred about 0.75% to about 15%, more preferably from about 1% to about 10%.

Many binding agents are the polymkeric substance that comprises acid amides, ester, ether, alcohol or ketone group, thereby are preferably included in pharmaceutical composition of the present invention and the medicine.Special preferably polyethylene pyrrolidone such as 30 POVIDONE K 30 BP/USP-30.The polymer-type binding agent can have different molecular weight, degree of crosslinking and polymer grade.The polymer-type binding agent can also be multipolymer, as comprises the segmented copolymer of the mixture of oxyethane and propylene oxide units.The variable effect character and the performance of these unitary ratios in known polymer.Example with segmented copolymer of different block unit compositions is poloxamer 188 and poloxamer 237 (BASF Corporation).

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable wetting agents are as vehicle.This wetting agent of preferred selection is to keep combining closely of API and water, and water is considered to improve the condition of composition bioavailability.

The non-limitative example that can be used as the tensio-active agent of wetting agent in pharmaceutical composition of the present invention and medicine comprises quaternary ammonium compound, as benzalkonium chloride, benzethonium chloride and hexadecylpyridinium chloride; Dioctyl sodium sulfosuccinate; Polyoxyethylene alkyl phenyl ether such as nonoxynolum (nonoxynol) 9, nonoxinol 10 and hot menthylphenoxypolyethoxy ethanol 9, poloxamer (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glyceryl ester and oils such as polyoxyethylene (8) caprylic/capric direactive glyceride and two glyceryl ester (as, the Labrasol of Gattefosse ^TM), polyoxyethylene (35) Viscotrol C and polyoxyethylene (40) hydrogenated castor oil; Voranol EP 2001 such as polyoxyethylene (20) hexadecanol stearyl alcohol ether; Polyoxyethylene fatty acid ester such as polyoxyethylene (40) stearate, polyoxyethylene sorbitan such as polysorbas20 and tween 80 (as, the Tween of ICI ^TM80); Propylene glycol fatty acid ester such as propylene glycol lauric acid fat (as, the Lauroglycol of Gattefosse ^TM); Sodium lauryl sulphate; Its lipid acid and salt such as oleic acid, sodium oleate and triethanolamine oleate ester, glycerin fatty acid ester such as glyceryl monostearate; Sorbitan such as sorbitan laurate, dehydrating sorbitol monooleate, sorbitan-monopalmityl ester and anhydrosorbitol monostearate, tyloxapol, and composition thereof.If exist, this wetting agent amount to the gross weight that constitutes pharmaceutical composition or medicine about 0.25% to about 15%, preferred about 0.4% to about 10%, more preferably from about 0.5% to about 5%.

The wetting agent of preferred anionic tensio-active agent.Sodium lauryl sulphate is particularly preferred wetting agent.If exist, sodium lauryl sulphate amount to the gross weight that accounts for pharmaceutical composition or medicine about 0.25% to about 7%, preferred about 0.4% to about 4%, more preferably from about 0.5% to about 2%.

Pharmaceutical composition of the present invention and drug selectivity ground comprise that one or more pharmaceutically acceptable lubricants (comprising release agent and/or glidant) are as vehicle.The lubricant that is fit to includes but not limited to, and is independent or combination, Glyceryl Behenate (as, the Compritol of Gattefosse ^TM888); Stearic acid and salt thereof comprise Magnesium Stearate, calcium and sodium; Hydrogenated vegetable oil (as, the Sterotex of Abitec ^TM); Colloided silica; Talcum; Wax; Boric acid; Sodium Benzoate; Sodium acetate; Sodium fumarate; Sodium-chlor; The DL-leucine; PEG (as, the Carbowax of the Dow Chemical Company ^TM4000 and Carbowax ^TM6000); Sodium oleate; Sodium lauryl sulphate; And Stepanol MG.If exist, this lubricant amount to the gross weight that constitutes pharmaceutical composition or medicine about 0.1% to about 10%, preferred about 0.2% to about 8%, more preferably from about 0.25% to about 5%.

Magnesium Stearate is to be used for for example reducing the preferred lubricant that rubs between tablet formulation compression process equipment and granulation mixture.

The release agent that is fit to includes but not limited to talcum, W-Gum, DL-leucine, sodium lauryl sulphate and metallic stearate.Talcum is to be used for for example reducing to the bonding of equipment surface and minimizing preferred release agent of mixture electrostatic or glidant.If exist, talcum constitute pharmaceutical composition or medicine gross weight about 0.1% to about 10%, preferred about 0.25% to about 5%, more preferably from about 0.5% to about 2%.

Glidant can be used for promoting the flow of powder of solid dosage.The glidant that is fit to includes but not limited to colloidal silica, starch, talcum, tribasic calcium phosphate, Solka-floc and Magnesium Trisilicate.Preferred especially colloidal silica.

Other vehicle such as tinting material, seasonings and sweeting agent are known in the pharmaceutical field, can be used in pharmaceutical composition of the present invention and the medicine.Tablet can or not have dressing with the enteric coating dressing.Composition of the present invention can comprise for example buffer reagent in addition.

Optionally, can use one or more effervescent as disintegrating agent and/or the organoleptic property that improves pharmaceutical composition of the present invention and medicine.In being present in pharmaceutical composition of the present invention and medicine when promoting the formulation disintegration, the total amount of preferred one or more effervescent is that about 30 weight % of pharmaceutical composition or medicine arrive about 75 weight %, preferred about 45 weight % are to about 70 weight %, and the amount of for example about 60 weight % exists.

The particularly preferred embodiment according to the present invention provides the dispersion of API in aqueous medium of improvement to be present in effervescent in the solid dosage less than the amount that effectively promotes the formulation disintegration.Be not bound by theory, think that effervescent effectively quickens API and disperse from formulation in gi tract, absorb and the rapid onset of therapeutic action thereby further improve.In being present in pharmaceutical composition of the present invention or medicine but when not improving disintegration to promote gi tract to disperse, preferred effervescent arrives about 20 weight % with about 1 weight % of pharmaceutical composition or medicine, more preferably from about 2.5 weight % are to about 15 weight %, and more preferably from about 5 weight % exist to the amount of about 10 weight %.

" effervescent " in this article refers to and is included in the reagent of emitting one or more compounds of gas when contacting with water, and compound works together or works respectively.The gas of emitting is oxygen or be generally carbonic acid gas most normally.Preferred effervescent is included in the existence of water and reacts down to form the bronsted lowry acids and bases bronsted lowry of carbon dioxide gas.Preferably, alkali comprises basic metal or alkaline earth metal carbonate or supercarbonate, and acid comprises aliphatic carboxylic acid.

As the non-limitative example of the alkali that is fit to that can be used for the effervescent component among the present invention comprise carbonate (as, lime carbonate), supercarbonate (as, sodium bicarbonate), sesquicarbonate, and composition thereof.Lime carbonate is preferred alkali.

As the non-limitative example of the acid that is fit to that can be used for effervescent component of the present invention and/or solid acid comprise citric acid, tartrate (as D-, L-or D/L-tartrate), oxysuccinic acid, toxilic acid, fumaric acid, hexanodioic acid, succsinic acid, these sour acid anhydrides, these sour acid-salts, and composition thereof.Citric acid is preferred acid.

Effervescent comprises in the preferred embodiments of the invention of bronsted lowry acids and bases bronsted lowry therein, and acid is about 1: 100 to about 100: 1 with the weight ratio of alkali, more preferably about 1: 50 to about 50: 1, and more preferably about 1: 10 to about 10: 1.Effervescent comprises in the further preferred embodiment of the present invention of bronsted lowry acids and bases bronsted lowry therein, and acid is stoichiometric approximately with the ratio of alkali.

The vehicle of the metal-salt of dissolving API typically has hydrophilic and hydrophobic zone simultaneously, or is preferably amphipathic or has the amphipathic zone.A type of amphipathic or part amphipathic vehicle comprises amphiphilic polymer or is amphiphilic polymer.Concrete amphiphilic polymer is a polyalkylene glycol, and it is made up of ethylene glycol and/or propylene glycol subunit usually.This polyglycol can be at its end by carboxylic acid, ester, acid anhydrides or other group esterification that is fit to.The example of this vehicle comprises that the polyalkylene glycol acid esters of poloxamer (the symmetric segmented copolymer of ethylene glycol and propylene glycol as, poloxamer 237), vitamin-E (comprises by two or the ester that forms of polyfunctional carboxylic acid; As, d-alpha-tocopherol polyoxyethylene glycol-1000 succinate) and polyethylene glycol glycerol ester (macrogolglyceride) (form by the alcoholysis of oil and the esterification of polyglycol, to produce list, two and the mixture of Witepsol W-S 55 and list and di-esters; As, stearyl polyoxyethylene glycol-32 glyceryl ester).This pharmaceutical composition and medicine be oral administration advantageously.

Pharmaceutical composition of the present invention and medicine can comprise that about 10 weight % arrive about 45 weight % or the about 30 weight % API to about 35 weight % to about 50 weight %, about 25 weight % to about 50 weight %, about 30 weight %; The about 50 weight % of about 10 weight %, about 25 weight % arrive about 50 weight %, about 30 weight % arrive about 35 weight % to about 45 weight % or about 30 weight % inhibition crystalline vehicle; Arrive about 35 weight % or about 30 weight % binding agent to about 50 weight %, about 10 weight % to about 40 weight %, about 15 weight % with about 5 weight % to about 35 weight %.In an example, API and inhibition crystalline vehicle are about 1: 1: 1 to the weight ratio of binding agent.

Solid dosage of the present invention can be not limited to described method herein by any suitable method preparation.

Illustrative method comprise (a) with salt of the present invention and one or more mixed with excipients with the step that forms mixture with (b) with mixture compressing tablet or incapsulate respectively to form tablet or capsular step.

In a preferred method, prepare solid dosage by the method that may further comprise the steps: (a) with API salt of the present invention and one or more mixed with excipients to form the step of mixture, (b) with mixture pelleting with the step that forms granule with (c) with mixture compressing tablet or incapsulate respectively to form tablet or capsular step.Step (b) can be finished by any dry method as known in the art or wet granulation technology, but preferred dry granulation step.Salt of the present invention advantageously arrives about 25 micron particle to form about 1 micron to about 100 microns, about 5 microns to about 50 microns or about 10 microns through granulation.Preferably add one or more thinners, one or more disintegrating agents and one or more binding agents at for example mixing step, optionally increase and add wetting agent and preferably after granulation, still add one or more disintegrating agents at compressing tablet or before incapsulating in for example granulation step.Preferably before compressing tablet, add lubricant.Mixing and granulation can be carried out under low or high-shear independently.The particulate API content that method for preferential selection forms evenly, disintegration easily, fully easily flow make can in filled capsules or compressing tablet process, control reliably weight differential and in bulk enough dense make can be in the equipment of selecting processing batch of material and concrete dosage is filled in appointment capsule or the tablet mould.

In embodiment optionally, prepare solid dosage by the method that comprises the spraying drying step, wherein API and one or more vehicle are suspended in one or more sprayable fluids, preferred non-proton (as, non-water or non-alcohol) can spray fluid, spraying drying promptly on hot blast then.

The particle spraying dry powder that is produced by above-mentioned illustrative method can compress or is molded with the preparation tablet or incapsulate with the preparation capsule.Can use conventional compressing tablet as known in the art and encapsulation technology.During the need of coating sheet, conventional packaging technique is fit to therein.

The preferred vehicle of selecting to be used for tablet composition of the present invention, be provided at the standard disintegration analyze in less than about 30 minutes, preferred the longest be about 25 minutes, more preferably the longest be about 20 minutes, more preferably the longest be about 15 disintegration time.

In another embodiment of the invention, can prepare and comprise Provigil and other pharmaceutical composition or medicine.Mixture or combination that Provigil and other API can be used as active medicine component are included in wherein.For example, composition can comprise Provigil and the caffeine as combination.The composition useful as therapeutics that comprises Provigil and caffeine is with the treatment situation identical with Provigil.In comprising this composition of Provigil and caffeine, caffeine can produce the characteristics (with respect to the little Tmax of Provigil) of snap-out release for solubility curve, and Provigil causes that there is therapeutic action in a few hours after administration.For example, the Tmax of caffeine can be 0.001,0.01,0.05,0.1,0.2,0.3,0.4,0.5,0.6,0.7 or 0.8 times of Provigil.Combination therapy is included in two or more API of administration in the same preparation, or in the preparation of two or more co-administereds two or more API of administration.API administration together simultaneously, or with appointed interval administration respectively.

In other embodiments, the invention provides the polymorphic form of new R-(-)-Provigil.In specific embodiment, the invention provides III, IV and V-arrangement R-(-)-Provigil.The present invention also provides the method for producing R-(-)-Provigil polymorphic form.

In other embodiments, the invention provides the method for producing R-Provigil polymorphic form, this method comprises:

(a) provide R-(-)-m Provigil; With

(b) crystallization goes out the polymorphic form of R-Provigil from appropriate solvent.

In other embodiments, R-(-)-Provigil polymorphic form is from the organic solvent crystallization.In specific embodiment, organic solvent is an ethanol.In another embodiment, use the polymorphic form of mixed solvent system crystallization R-(-)-Provigil.Mixed solvent system can be for example ethanol and Virahol and ethyl acetate and ethanol.In other embodiments, the crystallization in the step (b) is finished by thermodynamic recrystallization.In other embodiments, the crystallization in the step (b) is finished by evaporating solvent.

Being applied as of Provigil is well-known, and it comprises that hypnolepsy, fatigue, Infertility, eating disorder, attention that multiple sclerosis is relevant lack the treatment of hyperkinetic syndrome (ADHD), Parkinson's disease, incontinence, sleep apnea or myopathy.In another embodiment, any one or more in the modafinil compositions of the present invention can be used for treating one or more above-mentioned conditions.The dosage of modafinil compositions of the present invention and administration can use the ordinary method in this area to measure, but are generally about 50 to about 700mg/ days.

In another embodiment, provide treatment to stand one or more above-mentioned conditions or illness, include but not limited to the method for the main body that somnopathy such as hypnolepsy are tormented, it comprises III shape R-(-)-Provigil of main body drug treatment significant quantity, IV shape R-(-)-Provigil or V-arrangement R-(-)-Provigil.

In another embodiment, composition of the present invention can be by injection to the Mammals administration.Injection includes but not limited to intravenous injection, subcutaneous injection and intramuscular injection.In another embodiment, composition of the present invention is formulated as and is used for being expelled to the Mammals that needs result of treatment.

Embodiment

Analytical procedure

The differential scanning calorimetric (DSC) of sample is analyzed and is used Q1000 Differential ScanningCalorimeter (TA Instruments, New Castle, DE, U.S.A.) carry out, it uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release2.0 (2001 TA Instruments-Water LLC).In addition, the analysis software of use is the Universal Analysis 2000 that is used for Windows 95/98/2000/NT, version 3 .1E; Uild3.1.0.40 (2001 TA Instruments-Water LLC).

For dsc analysis, the purgative gas that uses is drying nitrogen, the empty aluminium dish of reference material for curling, and sample cleaned to 50mL/ minute.

The dsc analysis of sample is undertaken by the Provigil sample being placed the aluminium dish with curling disk cover.Starting temperature typically is 20 ℃, and heating rate is 10 ℃/minute, and end temp is 200 ℃.Unless otherwise indicated, the DSC indicator of all reports is shown in their temperature of changing of the neither endothermic nor exothermic at peak separately, and error is+/-2 ℃.

The thermogravimetric analysis of sample (TGA) is analyzed and is used Q500 Differential ScanningCalorimeter (TA Instruments, New Castle, DE, U.S.A.) carry out, it uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release2.0 (2001 TA Instruments-Water LLC).In addition, the analysis software of use is the Universal Analysis 2000 that is used for Windows 95/98/2000/NT, version 3 .1E; Uild3.1.0.40 (2001 TA Instruments-Water LLC).

For the TGA experiment, the purgative gas that uses is drying nitrogen, and balance is cleaned the N for 40mL/ minute ₂, and sample cleans the N for 60mL/ minute ₂

By placing the platinum dish that sample is carried out TGA in the Provigil sample.Starting temperature typically is 20 ℃, and heating rate is 10 ℃/minute, and end temp is 300 ℃.

The powder x-ray diffraction of sample (PXRD) figure uses D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, TX, U.S.A.) obtain, it uses RINTRapid Control Software, Rigaku Rapid/XRD, and version 1.0.0 (1999 Rigaku Co.) is as its control software.In addition, the analysis software that uses is RINT Rapid display software, version 1.18 (Rigaku/MSC); With JADE XRD Pattern Processing, version 5.0 and 6.0 ((1995-2002, Materials Data, Inc.).

Analyze for PXRD, acquisition parameter is as follows: gamma ray source is that the K line is 1.5406

Cu; The x-y Stage microscope is manual; Collimator tube is of a size of 0.3mm; (MA U.S.A.) is 0.3mm ID to kapillary for Charles SupperCompany, Natick; Use reflective-mode; Power to X-ray tube is 46kV; Electric current to X-ray tube is 40mA; The ω axle with 1 degree/minute speed in the scope internal vibration of 0-5 degree; The Φ axle rotates with the angle of 360 degree with the speed of 2 degree/seconds; 0.3mm collimator tube; Acquisition time is 60 minutes; Temperature is a room temperature; And do not use well heater.Sample is presented to x-ray source in being rich in the glass capillary of boron.

In addition, analytical parameters is as follows: integration 2 θ scopes are the 2-60 degree; Integration χ scope is the 0-360 degree; The number of χ part is 1; The step-length of using is 0.02; Integration utility is cylint; Use normalization method; Dark counts is 8; The Ω skew is 180; Skew is 0 with χ and Φ.

Also obtain the PXRD diffractogram by Bruker AXS D8 Discover X-ray Diffractometer.This instrument and equipment have GADDS ^TM(General Area Diffraction DetectionSystem), according to system calibration at the Bruker of 15.05cm distance AXS HI-STAR AreaDetector, Tong Yuan (Cu/K _α1.54056 dust), the x-y-z Stage microscope of automatization and 0.5mm collimator tube.With sample boil down to granule form and be installed on the x-y-z Stage microscope.Under reflective-mode, keep sample to be fixed under the envrionment conditions (25 ℃) simultaneously and obtain diffractogram with the power setting of 40kV and 40mA.For each sample exposure asynchronism(-nization) and to each sample is the fixed time.The diffractogram that obtains is the step-length integration of 2.1-37 degree with 0.02 degree along χ from-118.8 to-61.8 degree and 2 θ through how much pincushion distortions of the heavy conversion process in space with explanation area wave-detector then, and normalization method is set to scale-of-two normalization method.

In the diffractogram relative intensity at peak unnecessary be the restriction of PXRD figure because different sample peak intensities may be different, for example since crystalline impurities cause.In addition, the angle at each peak can be made an appointment with+/-0.1 degree difference, and is preferred+/-0.05 degree.Owing to change at other of calibration, setting and different instrument and different operator, most of peaks of whole figure or figure also can have an appointment+/-0.1 spend the displacement of degree approximately+/-0.2.At the PXRD peak of all reports in accompanying drawing, embodiment and other places herein all with the Discrepancy Report of 2 θ of ± 0.1 degree approximately.

For PXRD data herein, comprise table and figure, each composition of the present invention can by any, any two, wantonly three, wantonly four, wantonly five, wantonly six, wantonly seven or wantonly eight or more a plurality of 2 θ horns sign.Can also use any, two, three, four, five or six DSC change and characterize compositions of the present invention.The various combination characterize combinations that can also use PXRD peak and DSC to change.

On Zeiss Axioplan 2 microscopes that are equipped with Mettler Toledo FP90 controller, carry out heat (hot platform (hotstage)) microscopy.The hot platform that uses is Mettler ToledoFP82HT.All fusing point tests are all undertaken by sample being placed on the slide glass and covering with cover glass.Starting temperature be set to 30 ℃ and temperature with 10 ℃/speed increase.Observe fusion by the 5x micro objective.

HPLC method: (adapt people such as order Donovan, Therapeutic Drug Monitoring25:197-202.

Post: Astec Cyclobond I 2000 RSP 250x4.6mm (Part No.411121)

Mobile phase A: 20 mM sodium phosphates, pH 3.0

B: 70: 30 mobile phase A: acetonitrile

Flow velocity: 1.0mL/min (～1500 PSI)

Flow program: gradient

Working time: 35 minutes

Detect: UV@225nm

Injection volume: 10 microlitres

Column temperature: 30+/-1 ℃

Standard thinner: 90: 10 (v/v) mobile phase A: acetonitrile

Pin washing: acetonitrile

Qing Xirongji ﹠amp; Sealing washing: 90: 10 (v/v) water: acetonitrile

The moving phase preparation:

1. preparation 1M SODIUM PHOSPHATE, MONOBASIC: the 120g SODIUM PHOSPHATE, MONOBASIC is dissolved in the water and makes it to be 1000mL; Filter.

The preparation mobile phase A (the 20mM sodium phosphate, pH3.0): for one liter, dilute with water 20mL 1 M sodium phosphate is to 1000mL; Regulate pH to 3.0 with phosphoric acid.

3. prepare Mobile phase B (70: 30 (v/v) 20 mM sodium phosphates, pH3.0: acetonitrile):, the 700mL mobile phase A is mixed with the 300mL acetonitrile for one liter.

Specimen preparation:

With sample dissolution at 90: 10 (v/v) 20mM sodium phosphates, pH3.0: in the acetonitrile near the concentration of 20 micrograms/mL.

Raman is gathered

Sample stayed therein in the vial that sample is handled or with the aliquot of sample transfer on the slide glass.Vial or slide glass are placed the combustion chamber.The Almega of 785nm laser source is equipped with in use ^TMDispersive Raman (Almega ^TMDispersiveRaman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495) system measures.The microscope with 10x object lens (unless otherwise mentioned) of using appts is partially manually with focal in the sample sets, thus with laser orientation to sample surfaces.Use the parameter of describing in the Table A to obtain spectrum.(duration of contact may be different with frequency of exposure; Indicate the variation of parameter for each collection)

Table A. the Raman spectrum acquisition parameter

Parameter	The setting of using
		Duration of contact (s)	2.0
Frequency of exposure	10
		Laser source wavelength (nm)	785
Laser power (%)	100
		Iris shape	Pin hole
Aperture scale (um)	100
		Spectral range	104-3428
Stop position	Single
		Temperature during collection (℃)	24.0

IR gathers

Use NexusTM 470 FT-IR, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495 obtain IR spectrum and use Control and Analysissoftware:OMNIC, Version 6.0a, (C) Thermo-Nicolet, 1995-2004 analyzes.

Embodiment 1

R-(-)-Provigil of 2: 1: S-(+)-Provigil

(about 80: 20 R-isomer: the S-isomer, methyl alcohol by weight) (125mL) solution was kept 10 minutes for 8.62g, 0.0299mol by comprising R-diphenyl-methyl sulfinyl methyl esters with the anhydrous ammonia gas bubbling.Self-reacting pressure gathers and causes that sodium bicarbonate is back to the reaction mixture from trap.With reaction terminating and collecting precipitation thing.Filtrate decompression is concentrated, obtain xanchromatic solid residue (2.8g).Yellow solid is crossed post (silica gel, grade 9385,230-400 order, 60 dusts), and with 3: the ethyl acetate of 1v/v: hexane is as elutriant.Then filtrate is merged and concentrating under reduced pressure, obtain slightly yellowy solid (most yellow is retained on the post).Then with solid from ethyl alcohol recrystallization, up to its cool to room temperature then that seethes with excitement, obtain R-(-)-Provigil of 2: 1 by heated mixt: S-(+)-Provigil is colorless solid (580mg).The solid that obtains is carried out PXRD and dsc analysis, and measuring solid is R-(-)-Provigil and S-(+)-Provigil with weight ratio existence in about 2: 1 of pure form.

R-(-)-Provigil of above-mentioned 2: 1 of obtaining: S-(+)-Provigil solid by among Fig. 1 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 8.97,10.15,12.87,14.15,15.13,15.77,18.19 and 20.39 2 θ that spend (being the data that directly collect).

The above-mentioned solid DSC that obtains shows at about 167 ℃ endothermic transition (referring to Fig. 2).

Embodiment 2

The polymorphic form of R-(-)-Provigil

Observed several polymorphic forms of R-(-)-Provigil, every kind all characterizes by PXRD.These PXRD diffractograms (for directly collecting the data that obtain) of the polymorphic form of Fig. 3,6 and 9 expression III shapes, IV shape and V-arrangement.

Proved that recrystallization is the otherwise effective technique that is used to form and obtains R-(-)-Provigil polymorphic form.The suitable solvent of crystalline that is used for one or more polymorphic forms of R-(-)-Provigil includes but not limited to acetonitrile, dimethyl formamide (DMF), methyl alcohol, methyl ethyl ketone, N-Methyl pyrrolidone, ethanol, Virahol, isopropylcarbinol, methane amide, isobutyl acetate, 1,4-dioxane, tetrahydrofuran (THF) (THF), ethyl acetate, o-Xylol, isopropyl acetate, methylene dichloride, propylene glycol, acetate, water, acetone, Nitromethane 99Min., toluene and phenylcarbinol.Can use the mixture of neat solvent and solvent to be used for one or more polymorphic forms that crystallization goes out R-(-)-Provigil.

III shape R-(-)-Provigil

(8.3g, methyl alcohol 0.0288mol) (75mL) solution was kept 10 minutes by R-diphenyl-methyl sulfinyl methyl esters with the anhydrous ammonia gas bubbling.To be reflected at then stirred 1 hour in 5 ℃ the ice bath and again with the ammonia bubbling by other 10 minutes.Continue to stir other 2 hours and once more the ammonia bubbling was passed through 10 minutes.After stirring one hour again, form throw out (575mg) and with its collection.Use dense HCl that filtrate is neutralized then, form another throw out, with its collection.Then with solid residue from 1: the ethanol of 1v/v and isopropanol mixture recrystallization, by with mixture heating up up to boiling, then with its cool to room temperature, obtain III shape R-(-)-Provigil, be colorless solid (1.01g).

III shape R-(-)-Provigil can by among Fig. 3 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Rigaku PXRD is for directly collecting the data that obtain) of 7.21,10.37,17.73,19.23,21.17,21.77 and 23.21 degree.

The DSC of III shape R-(-)-Provigil that characterizes in Fig. 4 shows at about 161 ℃ endothermic transition.

Preparation second crowd of III shape R-(-)-Provigil is used for further analyzing by heatable stage microscope inspection and PXRD.Also obtained dissolubility data.These data are in following discussion.

The solubleness of III shape R-(-)-Provigil equals 6.1-7.0mg/mL.Solubleness is from recording the isopropyl acetate slurry of 25 ℃ of stirrings.Carrying out solubleness by HPLC measures.The solid that derives from the solubleness sample is dry and characterize by PXRD and heatable stage microscope inspection under nitrogen.The form of not observing in operating process transforms.

Heat (hot platform) microscopy is carried out with 10 ℃/minute heating rate, to measure the fusing point of III shape R-(-)-Provigil, measures it for about 156-158 ℃.

III shape R-(-)-Provigil can by among Fig. 5 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Rigaku PXRD is for removing the data of background) of 7.19,10.37,12.11,14.41,17.73,19.17,21.71,23.17,24.39,25.17,26.07 and 27.91 degree.

IV shape R-(-)-Provigil

(8.3g, methyl alcohol 0.0288mol) (75mL) solution was kept 10 minutes by R-diphenyl-methyl sulfinyl methyl esters with the anhydrous ammonia gas bubbling.To be reflected at then stirred 1 hour in 5 ℃ the ice bath and again with the ammonia bubbling by other 10 minutes.Stir and continued other 4 hours.After stirring one hour again, form throw out (422mg) and with its collection.Use dense HCl that filtrate is neutralized then, form another throw out, with its collection.Solid material (3g) is crossed post (silica gel, grade 9385,230-400 order, 60 dusts), and with 3: the ethyl acetate of 1v/v and hexane are as elutriant.Then post is washed with ethyl acetate (250mL).Filtrate is merged and concentrating under reduced pressure, obtain IV shape R-(-)-Provigil, be colorless solid (590mg).

IV shape R-(-)-Provigil can by among Fig. 6 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Rigaku PXRD is for directly collecting the data that obtain) of 7.79,10.31,11.77,16.49,17.33,19.47 and 23.51 degree.

The DSC of IV shape R-(-)-Provigil that characterizes in Fig. 7 shows at about 147 ℃ endothermic transition.

Preparation second crowd of IV shape R-(-)-Provigil is used for further analyzing by heatable stage microscope inspection and PXRD.Also obtained dissolubility data.These data are in following discussion.

The solubleness of IV shape R-(-)-Provigil equals 3.5-4.0mg/mL.Solubleness records from the isopropyl acetate slurry 25 ℃ of stirrings.Carrying out solubleness by HPLC measures.The solid that derives from the solubleness sample is dry and characterize by PXRD and heatable stage microscope inspection under nitrogen.The form of not observing in operating process transforms.

Heat (hot platform) microscopy is carried out with 10 ℃/minute heating rate, to measure the fusing point of IV shape R-(-)-Provigil, measures it for about 147-158 ℃.

IV shape R-(-)-Provigil can by among Fig. 8 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (RigakuPXRD is for removing the data of background) of 7.77,10.33,11.75,16.53,19.43,19.89,21.87,23.49 and 26.69 degree.

V-arrangement R-(-)-Provigil

IV shape R-(-)-Provigil (preparing in aforesaid operations) heats in ethanolic soln up to the mixture boiling, then with its cool to room temperature.Collect solid material then and characterize as V-arrangement R-(-)-Provigil.

V-arrangement R-(-)-Provigil can by among Fig. 9 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Rigaku PXRD is for directly collecting the data that obtain) of 6.61,10.39,13.99,16.49,17.73,19.03,20.87,22.31 and 25.99 degree.

Preparation second crowd of V-arrangement R-(-)-Provigil is used for further analyzing by heatable stage microscope inspection and PXRD.Also obtained dissolubility data.These data are in following discussion.

The solubleness of V-arrangement R-(-)-Provigil equals 2.1-2.6mg/mL.Solubleness is recorded by the isopropyl acetate slurry 25 ℃ of stirrings.Carrying out solubleness by HPLC measures.The solid that derives from the solubleness sample is dry and characterize by PXRD and heatable stage microscope inspection under nitrogen.The form of not observing in operating process transforms.

Heat (hot platform) microscopy is carried out with 10 ℃/minute heating rate, to measure the fusing point of V-arrangement R-(-)-Provigil, measures it for about 159 ℃.

V-arrangement R-(-)-Provigil can by among Figure 10 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD is for directly collecting the data that obtain) of 6.53,10.19,13.90,16.56,17.35,17.62,18.99,20.93,22.08,23.36 and 25.91 degree.

Similarity called after III, IV and V-arrangement in those PXRD diffractograms of finding in the diffractogram of the polymorphic form of R-(-)-Provigil according to the racemize Provigil of corresponding III, IV in laid-open U.S. Patents application 20020043207 on April 18 in 2002 and V-arrangement.

Embodiment 3

R-(-)-Provigil of 2: 1: S-(+)-Provigil

Preparation comprises R-(-)-Provigil, and (80.16mg is 0.293mmol) with racemize Provigil (20.04mg, 0.0366mmol) solution in ethanol (2mL).Mixture heating up is arrived boiling, so that all solids dissolving, cool to room temperature (25 ℃) then.After room temperature kept 15 minutes, with solution in 5 ℃ of standing over night.Decant falls solution and remaining crystal is dry and use HPLC, PXRD, DSC and heatable stage microscope inspection to characterize under nitrogen gas stream then.

The crystal that obtains comprises R-(-)-Provigil of about 63 to about 67%, and the crystalline rest part is S-(+)-Provigil.HPLC analyzes demonstration, and crystal is for comprising 2: 1 phases of two R-(-)-Provigil molecule with respect to each S-(+)-Provigil molecule.

R-(-)-Provigil at 2: 1: carry out PXRD on the single crystal samples of S-(+)-Provigil.R-(-)-Provigil of 2: 1: S-(+)-Provigil can by among Figure 11 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Rigaku PXRD is for directly collecting the data that obtain) of 8.95,10.17,11.87,14.17,15.11,17.39,18.31,20.39,21.09,24.41 and 26.45 degree.

2: 1 R-(-)-Provigil that characterizes in Figure 12: the DSC of S-(+)-Provigil shows at about 168 ℃ endothermic transition.

Heat (hot platform) microscopy is carried out with 5 ℃/minute heating rate, and to measure R-(-)-Provigil of 2: 1: the fusing point of S-(+)-Provigil is determined as about 160-166 ℃.

Embodiment 4

IV shape R-(-)-Provigil

R-(-)-Provigil of 105.9mg was pulled an oar 2 days in 1.5mL ethanol.Filter liquid and drying under nitrogen gas stream.Analyze the solid that obtains by PXRD, be determined as IV shape R-(-)-Provigil (Figure 13).

IV shape R-(-)-Provigil can by among Figure 13 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD is for directly collecting the data that obtain) of 7.64,10.17,11.61,16.41,19.34,21.71,22.77 and 23.36 degree.

By from the alcoholic acid thermodynamic recrystallization with by reclaiming IV shape R-(-)-Provigil from the slow evaporating solvent of ethanol.

Embodiment 5

V-arrangement R-(-)-Provigil

R-(-)-Provigil of 107.7mg is dispersed in the ethyl acetate of 3mL.Suspension is gone up heating so that the solid dissolving at hot-plate (60 ℃).With nitrogen gas stream evaporate be subjected to hot solvent about 1/3rd to half.Then with mixture cool to room temperature (25 ℃).Use centrifugal filter to go out solid from liquid separation.By the solid that PXRD and dsc analysis obtain, be determined as V-arrangement R-(-)-Provigil (Figure 14 and 15).

V-arrangement R-(-)-Provigil can by among Figure 14 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD is for directly collecting the data that obtain) of 6.52,10.23,13.93,16.37,17.61,18.97,20.74,22.21,23.36 and 25.90 degree.

V-arrangement R-(-)-Provigil has been carried out DSC.Figure 15 is presented at about 161-162 (161.57) ℃ endothermic transition.

Embodiment 6

R-(-)-Provigil chloroform solvent compound

The chloroform of 200 microlitres is joined in R-(-)-Provigil of 30.5mg.Mixture 75 ℃ of heating 30 minutes, is added 200 other microlitre chloroforms then.After other 30 minutes, solid dissolves fully.Sample was heated other 2 hours.The heating after, with sample with about 1 the degree/minute speed be cooled to 5 ℃.When reaching 5 ℃, sample still is uniform liquor.Then sample is placed nitrogen gas stream next minute, cause crystal and begin to form.Sample is cultivated at 5 ℃ again, more solid precipitation is arranged.Then that sample is dry and characterize by PXRD and TGA under nitrogen gas stream.

R-(-)-Provigil chloroform solvent compound is carried out PXRD.R-(-)-Provigil chloroform solvent compound can by among Figure 16 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD is for directly collecting the data that obtain) of 8.97,12.07,14.20,16.91,17.49,18.56,20.87,21.45,23.11 and 25.24 degree.

R-(-)-Provigil chloroform solvent compound is carried out TGA.Figure 17 is presented between about 25 ℃ and about 150 ℃ 15% weight loss.

Embodiment 7

R-(-)-Provigil chlorobenzene solvent compound

(102.6mg 0.375mmol) is suspended in the chlorobenzene (5mL) and on 60 ℃ hot-plate and heats with R-(-)-Provigil.Mixture is cooled to about 25 ℃.Then with the slurry reheat and add THF, up to all solid dissolvings.With the solution cooling, at room temperature in the bottle of sealing, store 4 days then.After storing, collect the solid that obtains and characterize by PXRD by vacuum filtration.

R-(-)-Provigil chlorobenzene solvent compound is carried out PXRD.R-(-)-Provigil chlorobenzene solvent compound can by among Figure 18 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (RigakuPXRD is for directly collecting the data that obtain) of 4.51,6.25,7.77,10.37,11.43,11.97,16.61,17.95,20.19,20.89,23.41 and 30.43 degree.

Embodiment 8

The ethyl acetate passage solvate of racemize Provigil

(53.7mg, 0.196mmol) (75.5mg, 0.401mmol) solution in the ethyl acetate of 2.4mL makes the ethyl acetate passage solvate of racemize Provigil with 1-hydroxyl-2-naphthoic acid by dissolved racemize Provigil on 60 ℃ of hot-plates.Once cooling, with solution with R-(-)-Provigil: the grinding eutectic of 1-hydroxyl-2-naphthoic acid (referring to the embodiment 17 of PCT/US2004/29013) carries out crystallization as kind of crystalline substance.

Ethyl acetate passage solvate to the racemize Provigil has carried out PXRD.The ethyl acetate passage solvate of racemize Provigil can by among Figure 19 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD is for directly collecting the data that obtain) of 8.88,14.09,19.83,21.59,23.04 and 25.94 degree.

Ethyl acetate passage solvate to the racemize Provigil has carried out TGA.Figure 20 be presented at about 25 and about 150 ℃ between 3.6% weight loss is arranged.

Embodiment 9

R-(-)-Provigil acetic acid solvent compound

Form R-(-)-Provigil acetic acid solvent compound by R-(-)-Provigil (105.5mg) that in the stainless steel cylinder, grinds in 0.066mL acetate with Wig-L-Bug mill/mixing tank.Then powder is analyzed by DSC, TGA and PXRD.

R-(-)-Provigil acetic acid solvent compound is carried out PXRD.R-(-)-Provigil acetic acid solvent compound can by among Figure 21 any, any two, wantonly three, wantonly four, wantonly five or wantonly six or more a plurality of peak sign, it includes but not limited to 2 θ (Bruker PXRD is for directly collecting the data that obtain) of 9.17,10.20,16.61,17.59,18.90,21.11 and 24.11 degree.

R-(-)-Provigil acetic acid solvent compound is carried out TGA.Figure 22 be presented at about 25 and about 125 ℃ between 11% weight loss is arranged.

R-(-)-Provigil acetic acid solvent compound is carried out DSC.Figure 23 is presented at about 56 ℃ endothermic transition.

Claims

1. the composition that comprises V-arrangement R-(-)-Provigil, wherein V-arrangement R-(-)-Provigil is characterised in that under Rigaku PXRD test condition, and the peak of deriving comprises 2 θ of 6.61,10.39,13.99,16.49,17.73,19.03,20.87,22.31,25.99 ± 0.1 degree.

2. the composition of claim 1, wherein composition is a pharmaceutical composition.

3. the method for V-arrangement R-(-)-Provigil of production claim 1, this method comprises:

(a) provide R-(-)-Provigil; With

(b) make V-arrangement R-(-)-Provigil from the ethyl acetate crystallization.

V-arrangement R-(-)-Provigil of claim 1 be used for the treatment of in preparation suffer from the excessive daytime sleepiness relevant with hypnolepsy, the application in the medicine of the main body of fatigue, Infertility, eating disorder, attention-deficit hyperactivity disease, Parkinson's disease, incontinence, sleep apnea or myopathy that multiple sclerosis is relevant.

5. the application of claim 4, wherein main body is the human subject.

6. the application of claim 4 is used for the treatment of excessive daytime sleepiness or the sleep apnea relevant with hypnolepsy.

7. the application of claim 4 is used for the treatment of attention-deficit hyperactivity disease.