CN101102994A - Polymorphs of memantine hydrochloride - Google Patents
Polymorphs of memantine hydrochloride Download PDFInfo
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- CN101102994A CN101102994A CNA2006800020422A CN200680002042A CN101102994A CN 101102994 A CN101102994 A CN 101102994A CN A2006800020422 A CNA2006800020422 A CN A2006800020422A CN 200680002042 A CN200680002042 A CN 200680002042A CN 101102994 A CN101102994 A CN 101102994A
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Abstract
A crystalline Form II of memantine hydrochloride, pharmaceutical compositions containing crystalline Form II, and methods of preparing crystalline Forms I and II of memantine hydrochloride are provided.
Description
Related application
The application requires the rights and interests of U.S. Provisional Patent Application of submitting on January 11st, 2,005 60/642,957 and the United States Patent (USP) provisional application of submitting on May 3rd, 2,005 60/677,599, and its content is incorporated into herein as a reference.
Invention field
The present invention relates to 1-amino-3, the Form II of 5-dimethyladamantane hydrochloride (" memantine "), the preparation method of described crystalline form, contain the pharmaceutical composition of memantine Form II, and the method for preparing the memantine crystalline form I.
Background of invention
Memantine, 1-amino-3,5-dimethyladamantane hydrochloride are a kind of in three rings antiviral (TAV).Memantine also provides nervus centralis N-methyl-D-aspartate (NMDA) acceptor good and persistent activation, can be used for treating Parkinson's disease and Alzheimer thus.Evidence suggests constantly in memory loss in the Alzheimer and dull-witted and the brain that the dysfunction of the signal of transmission information is relevant between the neurocyte.The overactivity that chemically is called L-glutamic acid causes the Alzheimer symptom especially, and the progress of these diseases.L-glutamic acid acts on nmda receptor, and it is found in the neurocyte in the brain.Transmission is information-related in these acceptors and neurocyte and the brain, and this is extremely important in learning and memory.It is reported that L-glutamic acid is by overstimulation nmda receptor injured nerve cell.Memantine is by the nmda receptor in the blocking-up brain, the overactivity effect of blocked glutamic acid, but the normal activation of permission nmda receptor when brain produces memory.Memantine can improve brain function thus in Alzheimer, and can block the L-glutamic acid activation that may produce damage in addition to brain cell.Memantine is licensed for the serious or serious Alzheimer of treatment moderate.Research has shown that memantine produces slight the improvement or stabilization in Alzheimer patient's cognition effect and daily function, and cognitive effect i.e. thinking, learning and memory.
The chemical structure of memantine is as follows:
The polymorphism of memantine is not disclosed in the prior art.Yet being reported that, memantine crystalline example do not have to disclose in the patent any polymorph form in some patents.For example, U.S. Pat 3,391 discloses in 142 and precipitated memantine from anhydrous aether solution, and raw product crystallization in alcohol-ether mixture.U.S. Pat 4,122,193 disclose by bubbling hydrochloric acid precipitation memantine in the ethereal solution of memantine free alkali, and CZ282398 discloses and adds hydrochloric acid so that hydrochloride to be provided in the memantine toluene solution.The art methods of the preparation memantine that is useful on causes forming the single crystalline form of crystalline form I herein, be characterised in that at about 6.3,12.5 and 18.8 ± 0.2 degree, 2 θ to have the X-ray diffraction (XRD) of peak value, and be further characterized in that peak value at about 11.0,14.2,16.6,21.8,22.7,24.4 and 27.4 ± 0.2 degree, 2 θ.
The present invention relates to the solid state physical properties of memantine.These performances can obtain the condition changing of memantine by control with solid-state form.Solid state physical properties is drawn together for example flowability of abrasive solid.The mobile complexity of handling material that during being processed into medicine, influences.When the particle of powder compound can not easily flow each other, formulator must be considered this fact when development tablet or capsule preparations, may use glidant, for example colloid silica, talcum, starch or tricalcium orthophosphate like this.
Another important solid character of medical compounds is its dissolution rate in aqueous fluid.Because it gives the upper limit that the oral administration active ingredient arrives the speed of blood samples of patients, the dissolution rate of active ingredient in patient's gastric juice has the therapeutics influence.Dissolution rate also is a consideration in preparation syrup, elixir and other liquid preparation.The solid-state form of compound also can influence its performance aspect compacting and stability in storage.
These practical physical characteristics are by molecular structure in the structure cell and orientation influence, and this has defined the specific polymorph form of material.The polymorph form may produce the thermal characteristics that is different from amorphous substance or other polymorphic forms.Thermal characteristics can be measured by the method for for example capillary melting point method, thermogravimetric analysis (TGA) and dsc (DSC) in the laboratory, and can be used for some polymorph form and the difference of other form are come.Specific polymorph form also can cause special spectrum character, and this can pass through powder X-ray ray crystalline diffraction method, solid-state
13C nuclear magnetic resonance spectrum and infrared spectroscopy detect.
Therefore, the discovery of the useful new polymorph form of compound of pharmacy provides the new chance of improving the medicine performance characteristic.Enlarged the effectively material list of design of preparation technique personnel like this, the pharmaceutical dosage form that for example has target release profiles or other required feature.This area needs other crystalline form of memantine.
Summary of the invention
The present invention relates to be appointed as the crystallization of the memantine of Form II herein, it is characterized in that having the X-ray powder diffraction figure of peak value and at about 50 ℃, 90 ℃ and 341 ℃ DSC thermograms with three endotherm(ic)peaks at about 6.7,13.3 and 20.2 ± 0.2 degree, 2 θ.
The memantine Form II is characterised in that corresponding to Karl Fisher volumetry in addition at about 117 ℃ of TGA thermograms that show the weight loss of the about 8.5 weight % of about 7.5-.
The invention still further relates to the method that produces the memantine Form II, comprise the solution of acetone with memantine and water is mixed; Remove anhydrate and acetone to obtain the memantine Form II; And reclaim the memantine Form II.
The present invention relates to the pharmaceutical preparation that contains memantine Form II and pharmaceutically acceptable vehicle in addition.
The invention still further relates to treatment and suffer from the patient's of Parkinson's disease, Alzheimer method, described method comprises the said medicine preparation of drug treatment significant quantity.
The invention provides the method that is used to prepare the memantine crystalline form I, comprise providing memantine at C
1-4Solution in the alcohol; Solution is exposed to is selected from C
1-5Ketone or C
1-5The anti-solvent of alkyl ester is to obtain precipitation; And recovery memantine crystalline form I.
The invention provides the other method of preparation memantine crystalline form I, comprise providing memantine being selected from water, C
1-5Solution in the solvent of alcohol, DMF and DMSO, and be selected from C
6-10Aromatic hydrocarbon, open chain or closed C
1-5Alkyl oxide, C
1-5Ketone, C
1-5The anti-solvent of acid amides, carbonic ether, ester and acid amides is to produce precipitation; And recovery memantine crystalline form I.
The invention provides the another method of preparation memantine crystalline form I, comprise that memantine is being selected from water, C
1-4Alcohol, C
6-10Aromatic hydrocarbon, C
1-4Halohydrocarbon, ester and C
1-5Solution in the solvent of alkyl oxide; Cooling solution is to cause precipitation; And recovery memantine crystalline form I.
The invention provides the another method of preparation memantine crystalline form I, comprise the concentrating hydrochloric acid memantine and be selected from C
1-4The solution of the solvent of pure and mild its halides; And recovery memantine crystalline form I.
The accompanying drawing summary
Fig. 1 represents the characteristic X-ray powder diagram of memantine Form II;
Fig. 2 represents the feature FT-IR spectrum of memantine Form II;
Fig. 3 represents the feature DSC curve of memantine Form II;
Fig. 4 represents the feature TGA curve of memantine Form II; And
Fig. 5 represents the characteristic X-ray powder diagram of memantine crystalline form I.
Detailed Description Of The Invention
Term used herein " memantine crystalline form I " refers to the crystalline form that obtains by crystallisation described in the prior art, and it also is the anhydrous form of commercially available memantine.
The present invention relates to be appointed as the manufacture method, the pharmaceutical composition of memantine Form II of crystalline form, memantine crystalline form I and II of the memantine of Form II herein, and the methods for the treatment of of using the memantine Form II.
The invention provides the crystalline form of the memantine of being appointed as Form II herein, it is characterized in that having at about 6.7,13.3 and 20.2 ± 0.2 degree, 2 θ at least a X-ray powder diffraction figure of peak value; About 3446,3396,1621 and 1532cm-1Infrared spectrum with peak value, and at about 50 ℃, 90 ℃ and the 341 ℃ DSC thermograms with endothermic peak.
The memantine Form II is characterised in that basically as shown in Figure 1 the X-ray powder diffraction figure that has peak value at about 14.5,17.2,18.6,22.9,23.9 and 29.0 ± 0.2 degree, 2 θ in addition.
The further feature of memantine Form II also is about 2056,1650,1521,1384,1190,1162,1061,1030,965,934 and 721cm-1Basically as shown in Figure 2 infrared spectrum with peak value.
Three endothermic peaks 50 ℃, 90 ℃ and 341 ℃ in the DSC of Form II thermogram represent respectively desolventizing, except anhydrating and the sample fusing. During decomposing so that burn, the material fusing do not obtain clear and definite fusing point. The DSC thermogram of memantine Form II as shown in Figure 3.
Corresponding to Karl Fisher titration, the TGA thermogram of memantine Form II is in about 117 ℃ of losses in weight that show about 8.5 % by weight of about 7.5-. Because Form II is the monohydrate of memantine, this loss in weight is equivalent to the theoretical value of memantine monohydrate moisture content. The TGA curve of Form II also demonstrates the loss in weight at about 200 ℃, shows the at a slow speed decomposition of material. The feature TGA thermogram of memantine Form II as shown in Figure 4.
The memantine crystal has irregular contour, and the maximum about 200 μ m of size, preferred at most about 150 μ m, more preferably maximum about 100 μ m, and maximum about 75 μ m most preferably.
The present invention also provides the method for producing the memantine Form II, comprising: the solution of acetone with memantine and water is mixed; Except anhydrating with acetone to obtain the memantine Form II; And reclaim the memantine Form II.
Memantine solution can make by memantine is suspended in the water, the about 0.6 mole hydrochloride memantine/premium on currency of preferably about 0.4-.According to the water yield of using, be heated to about 50 ℃ and help dissolving to about 100 ℃ temperature.Preferably be heated to about 80 ℃ to about 90 ℃ temperature, more preferably be heated to about 85 ℃ to about 90 ℃ temperature.
Before mixing acetone preferably with the solution cooling, most preferably be cooled to about 50 ℃ to about 55 ℃ temperature.Preferably, acetone is generally about 0.05 to about 2 mole hydrochloride memantines/the rise amount of acetone, the most preferably from about concentration of 0.6 mol.Solution preferably is cooled to about room temperature then, and remains on this temperature with the precipitation memantine, and evaporating solvent about 3 days to about 3 months, most preferably from about 1 month.
Removing acetone and water can be undertaken by any-mode known in the art, however preferred spontaneous evaporation.
Reclaiming the memantine Form II can be undertaken by any-mode known in the art.Preferably undertaken by filtration and debris.
The memantine that is used as raw material can derive from and be purchased, or obtain by any-mode known in the art, the co-pending U. S. application US11/XXX that submitted on January 11st, 2006 for example is described in the XXX, it requires the rights and interests of the U.S. Provisional Application 60/642,957 of submission on January 11st, 2005.
The present invention further provides the pharmaceutical preparation that contains memantine Form II and pharmaceutically acceptable vehicle.
The present invention also provides treatment to suffer from the patient's of Parkinson's disease or Alzheimer method, and described method comprises the said medicine preparation of drug treatment significant quantity.
The invention provides the method that is used to prepare the memantine crystalline form I, comprise providing memantine at C
1-4Solution in the alcohol; Described solution is exposed to is selected from C
1-5Ketone or C
1-5The anti-solvent of alkyl ester; And recovery memantine crystalline form I.
C in the memantine solution
1-4Alcohol is preferably methyl alcohol.C
1-5Ketone is preferably acetone.C
1-5Alkyl ester is preferably methyl acetate.Preferably make solution be exposed to anti-solvent by the saturated atmosphere that anti-solvent is provided.The memantine crystalline form I can reclaim by any-mode known in the art, for example filters with dry to obtain product.
The invention provides the other method of preparation memantine crystalline form I, comprising: provide memantine being selected from water, C
1-5Solution in the solvent of alcohol, DMF and DMSO, and be selected from C
6-10Aromatic hydrocarbon, open chain or closed C
1-5Alkyl oxide, C
1-5Ketone, C
1-5The anti-solvent of acid amides, carbonic ether, ester and acid amides forms to cause precipitation; And recovery memantine crystalline form I.
Solvent is preferably selected from methyl alcohol, IPA, propyl carbinol, water, ethanol, DMSO and DMF.Anti-solvent is preferably selected from toluene, isopropyl ether, n-butyl acetate (n-BuOAc), ethyl acetate (AcoEt), acetone, acetonitrile, DMC, THF, MTBE and MEK.Precipitation is sometimes by precipitation or evaporation are carried out at a slow speed.
Recovery can be undertaken by any means known in the art.In addition, the memantine crystalline form I of recovery is wettable or dry.When water was used as solvent, toluene or MEK were as anti-solvent, and wet salt acid memantine comprises the mixture of crystalline form I and II.Obtain the memantine crystalline form I after the drying.
The invention provides the another method of preparation memantine crystalline form I, comprising: provide memantine being selected from water, C
1-4Alcohol, C
6-10Aromatic hydrocarbon, C
1-4Halohydrocarbon, ester and C
1-5Solution in the solvent of alkyl oxide; Cooling solution is to cause precipitation; And recovery memantine crystalline form I.
Solvent is preferably selected from water, DMF, propyl carbinol, 2-butanols, Pentyl alcohol, chloroform, ethyl acetate, acetone, ester, water, MTBE, DMC and IPA.Choose wantonly and obtain solution by heating.When using ethyl acetate, the saturated atmosphere of hydrogen chloride gas can be used for causing precipitation.
Recovery can be undertaken by any means known in the art.In addition, the memantine crystalline form I of recovery is wettable or dry.
The invention provides the another method of preparation memantine crystalline form I, comprise the concentrating hydrochloric acid memantine and be selected from C
1-4The solution of the solvent of pure and mild its halides; And recovery memantine crystalline form I.
Concentrating of solution can be undertaken by any means known in the art, for example concentrates or evaporation.Evaporative process can be evaporative process at a slow speed.The memantine crystalline form I can reclaim by any means known in the art.When reclaiming wet salt acid memantine, during as solvent, wet salt acid memantine comprises the mixture of crystalline form I and II at ethanol or ethanol-dichloromethane solution.
The example and the condition that can be used for forming the different solvents of memantine crystalline form I are listed in table 1-4.
Pharmaceutical composition can be prepared into medicine, with oral, parenteral, rectum, transdermal, through cheek (bucally) or through the nose administration.Be used for the form that solid dosage forms for oral administration comprises tablet, compression or coated pill, drageeing, wafer (sachet), hard or soft gelatin capsule, sublingual tablet, syrup or suspension.The dosage forms of administered parenterally comprises water or non-aqueous solution or emulsion, yet comprises the suppository with hydrophilic or hydrophobic vehicle for the suitable formulation of rectal administration.For topical, the invention provides suitable transdermal delivery system well known in the prior art, and for suitable aerosol delivery systems well known in the prior art is provided through the nose administration.
Pharmaceutical preparation of the present invention comprises memantine Form II disclosed herein.Pharmaceutical composition can only contain the memantine of single form, and the mixture of perhaps multi-form memantine has or do not have amorphous form.Except active ingredient, pharmaceutical composition of the present invention can contain one or more vehicle or auxiliary agent.Based on experience and consider standard program and this area bibliography, formulation specialist can easily be selected vehicle and determine its usage quantity.
Thinner increases the volume of solid composite medicament, and makes pharmaceutical dosage form contain to make the component that patient and medical personnel are easier to handle.The thinner that is used for solid-state composition for example comprises Microcrystalline Cellulose (Avicel for example
), microfine cellulose, lactose, starch, pregelatinized starch, lime carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dicalcium phosphate dihydrate, tricalcium orthophosphate, kaolin, sal epsom, magnesium oxide, Star Dri 5, N.F,USP MANNITOL, polymethacrylate (Eudragit for example
), Repone K, Solka-floc, sodium-chlor, Sorbitol Powder and talcum.
Be compressed in the solid composite medicament of the formulation of tablet for example and can contain vehicle, it helps after compacting active ingredient is attached to other vehicle.The tackiness agent of solid pharmaceutical composition comprises gum arabic, alginic acid, carbomer (carbomer) (for example carbopol (carbopol)), Xylo-Mucine, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, Natvosol, hydroxypropylcellulose (Klucel for example
), Vltra tears (Methocel for example
), liquid glucose, neusilin, Star Dri 5, methylcellulose, polymethacrylate, polyvidone (Kollidon for example
, Plasdone
), pregelatinized starch, sodiun alginate and starch.
The dissolution rate of compacting solid pharmaceutical composition in patient's stomach can increase by add disintegrating agent in composition.Disintegrating agent comprises alginic acid, calcium carboxymethylcellulose, Xylo-Mucine (Ac-Di-Sol for example
, Primellose
), colloidal silica, cross-linked carboxymethyl cellulose sodium (croscarmellose sodium), Crospovidone (Kollidon for example
, Polyplasdone
), guar gum, neusilin, methylcellulose gum, Microcrystalline Cellulose, Polacrilin potassium, Solka-floc, pregelatinized starch, sodiun alginate, sodium starch glycolate (Explotab for example
) and starch.
Can add glidant improving the flowability of non-compacting solid-state composition, and improve dose accuracy.The vehicle that can be used as glidant comprises colloidal silica, Magnesium Trisilicate, Solka-floc, starch, talcum and tricalcium orthophosphate.
When the compacting by powder composition of the formulation of for example tablet prepared, composition was accepted the pressure from punching and punch die.Some vehicle and active ingredient tend to be adhered to punching and punch die surface, and this can cause product to have indenture or other surface imperfection.Lubricant can join in the composition to reduce bonding and to make product be easy to discharge from punch die.Lubricant comprises Magnesium Stearate, calcium stearate, glyceryl monostearate, palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyoxyethylene glycol, Sodium Benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talcum and Zinic stearas.
Seasonings and sweetener make formulation better to eat to the patient.The seasonings commonly used and the sweetener that use in the medicine in the pharmaceutical composition of the present invention be can be included in and voitol, vanillin food grade,1000.000000ine mesh, vanirone, menthol, citric acid, fumaric acid, veltol plus and tartrate comprised.
Solid and liquid composition also can use pharmaceutically acceptable tinting material dyeing to improve its outward appearance and/or to help patient identification product and unit dosage level.
In composition of liquid medicine of the present invention, memantine and any other solid excipient are dissolved or suspended in the liquid vehicle, and liquid vehicle is water, vegetables oil, alcohol, polyoxyethylene glycol, propylene glycol or glycerine for example.
Can contain emulsifying agent in the composition of liquid medicine, be dispersed in the composition with active ingredient or other vehicle that will be insoluble in the liquid vehicle.The emulsifying agent that can be used in the composition of liquid medicine of the present invention comprises for example gelatin, yolk, casein, cholesterol, gum arabic, tragacanth, Chondrus, pectin, methylcellulose gum, carbomer, 18 hexadecanols and hexadecanol.
Also can contain the mouthfeel of viscosity intensifier in the composition of liquid medicine of the present invention, and/or be coated on GI surface with the raising product.This viscosity intensifier can comprise gum arabic, alginic acid bentonite, carbomer, calcium carboxymethylcellulose or sodium, 18 hexadecanols, methylcellulose gum, ethyl cellulose, gelatin guar gum, Natvosol, hydroxypropylcellulose, Vltra tears, Star Dri 5, polyvinyl alcohol, polyvidone, propylene carbonate, Protanal Ester SD-LB, sodiun alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
The sweeting agent that can add for example Sorbitol Powder, asccharin, soluble saccharin, sucrose, aspartame, fructose, N.F,USP MANNITOL and Nulomoline is to improve taste.
Safe level be can absorb and the sanitas of for example alcohol, Sodium Benzoate, Yoshinox BHT, butylated hydroxyanisol and ethylenediamine tetraacetic acid (EDTA) and sequestrant added with the raising stability in storage.
According to the present invention, also can contain buffer reagent in the liquid composition, for example glyconic acid, lactic acid, citric acid or acetate, gluconic acid sodium salt, Sodium.alpha.-hydroxypropionate, Trisodium Citrate or sodium acetate.
Based on experience and consider standard program and this area bibliography, formulation specialist can easily be selected vehicle and determine its usage quantity.
Solid-state composition of the present invention comprises powder, granula, agglutinator and compacted compositions.Dosage comprise be suitable for oral, oral cavity, rectum, parenteral (comprising subcutaneous, intramuscular and intravenously), suck and eye with the dosage of administration.Though only administering mode depends on sanatory character and severity under given arbitrarily situation, the most preferred route of administration of the present invention is oral.Dosage can be chosen wantonly with unit dosage and exist, and can be by the known any means preparation of pharmaceutical field.
Formulation comprises solid dosage, for example tablet, pulvis, capsule, suppository, wafer, lozenge and dragee (losenges), and liquid sugar sirup, suspension and elixir.
Formulation of the present invention can be duricrust or the interior capsule of soft shell that contains the composition that is preferably powder of the present invention or particulate composition.Shell can be made by gelatin, and optional contains for example softening agent of glycerine and Sorbitol Powder, and opalizer or tinting material.
Active ingredient and vehicle can be formulated in composition and the formulation by methods known in the art.
The composition that is used for the filling of tablet or capsule can prepare by wet granulation.In wet granulation, the partly or entirely active ingredient and the vehicle blend of powder type further mixes in the presence of the liquid that is generally water then, is particle with powder lumping.With particle screen selecting and/or grinding, drying, screen and/or grind to form desired particle size then.With the particle compressing tablet, perhaps added other vehicle before compressing tablet then, other vehicle is glidant and/or lubricant for example.
Tablet composition prepares by dry blending usually.For example, but the blend composition briquetting or the sheet of active ingredient and vehicle are ground into fine and close particle then.Fine and close particle is pressed into tablet subsequently.
As the replacement scheme of non-slurry pelletizing, blend compositions can use direct compact technique directly to be pressed into the formulation of compacting.Directly compacting produces does not have particulate tablet more uniformly.The vehicle that is particularly suitable for direct compression comprises Microcrystalline Cellulose, spray-dried lactose, dicalcium phosphate dihydrate and colloidal silica.In direct compression the suitable use of these and other vehicle for those skilled in the art particularly direct compression field those of skill in the art be known.
Capsule of the present invention fill can comprise above-mentioned arbitrarily described in the tablet and do not carry out the blend or the particle of last compressing tablet step.
Physical test method
XRD analysis uses the ARL x-ray powder diffraction instrument X ' TRA-030 with Peltier detector to carry out, and uses the circular standard aluminum sampling receptacle with circular zero background quartz plate.Sweep parameter is as follows: range is the continuous sweep of 2 ° of-40 ° of 2 θ of 3 °/minute.Since the test difference of instrumentation, specimen preparation etc. for example, peak position tolerance range is defined as ± 0.2 °.
Obtain on the sample of Fourier transform (FT-IR) spectral measurement in the Nujol null of Perkin-Elmer Spectrum 1000Spectrometer, measure and use 4000-400cm
-116 scanning 4cm in the range
-1Resolving power, use blank cell as a setting.
It is that the about 5 milligrams sample of about 3-is at Mettler Toledo DSC 822 that dsc (DSC) is measured operating weight
cCarry out on/700.In the crucible in the hole with about 40 ml/min of nitrogen jet speed, heating rate is 10 ℃/minute, and sweep limit is about 30 ℃ to about 370 ℃.
Thermogravimetric analysis uses the about 15 milligrams sample of about 7-at Mettler Toledo TGA/SDTA851
c, in the nitrogen gas stream of about 50 ml/min of flow velocity, to carry out, heating rate is 10 ℃/minute, sweep limit is about 25 ℃ to about 250 ℃.
The form of monocrystalline and granularity are used Zeiss Axiolab Pol type polarized light microscope observing.
Below unrestricted embodiment only be used to illustrate the preferred embodiments of the invention, and should not be considered as restriction of the present invention, its scope is limited in the claims.
Embodiment
Used some preferred embodiment that the present invention has been described, considered the description of specification sheets, other embodiment will it will be apparent to those skilled in the art.The present invention further specifies useful composition of the present invention and method according to the embodiment of following detailed description.It will be apparent for a person skilled in the art that and under the prerequisite of not leaving the scope of the invention, to have done multiple change material and method.
Embodiment 1: the preparation of memantine Form II
Carried out the existence that test of many times is determined memantine and the different polymorphic forms of precursor thereof.Only found a different polymorphic form.The experimental technique that produces polymorphic form is as described below.
31 gram memantines join four neck round-bottomed flasks to form suspension with 250 ml waters.Suspension is heated to about 85 ℃ extremely about 90 ℃ to dissolve memantine fully.Solution is cooled to about 50 ℃ to about 55 ℃, and add temperature about 40 ℃ to 1400 milliliters of about 50 ℃ acetone.Crystallization does not appear when cool to room temperature.Solution is placed the opening flask, make the spontaneous evaporation of solution, and after about 1 month, little crystallization occurs at drag.Crystal is filtered and washing, the XRD analysis that half wets, second half carried out XRD analysis after under room temperature and the barometric point 2 days.Wet product is the memantine Form II, and the dry labor thing is the memantine crystalline form I.
Use different solvents and/or solvent mixture to carry out a plurality of crystallization trials.Dried and wet product carries out XRD analysis.Though in drying at room temperature, part is in vacuum-drying under barometric point for most of products.Test and experimental result are listed in table 1-4.Whole samples of listing in the table 1 carry out XRD analysis with the dry labor thing.
Embodiment 2: use solvent and anti-solvent to depress preparation memantine crystalline form I in saturated atmosphere
Table 1
*
| Test | Condition | Resistates | The crystalline form that XRD determines |
| Q489-p28-1 | Solvent: methanol anti-solvent: the acetone of saturated solution liquid atmosphere | Wet | I |
| Q489-p28-2 | Solvent: methanol anti-solvent: the acetone of saturated solution liquid atmosphere | Do | I |
| Q489-p38-1 | Solvent: methanol anti-solvent: the methyl acetate of saturated solution liquid atmosphere | Wet | I |
| Q489-p38-2 | Solvent: methanol anti-solvent: the methyl acetate of saturated solution liquid atmosphere | Do | I |
*Sample drying in the table 1, dry under room temperature and barometric point.
Embodiment 2: use solvent and anti-solvent to prepare the memantine crystalline form I
Table 2
*
| Test | Condition | Resistates | The crystalline form that XRD determines |
| Q481-p23 | From solvent: methyl alcohol, anti-solvent: crystallization methyl alcohol in the toluene: toluene=5: 1 | Do, 50 ℃ of u.v. dryings | I |
| Q481-p26 | From solvent: IPA, anti-solvent: crystallization IPA in the isopropyl ether: isopropyl ether=12: 5 | Do | I |
| Q481-p112 | From solvent: propyl carbinol, anti-solvent: crystallization in the n-butyl acetate | Do | I |
| Q481-p118 | From solvent: propyl carbinol, anti-solvent: crystallization in the ethyl acetate | Do | I |
| Q481-p121-2 | From solvent: water, anti-solvent: crystallization in the acetone | Do | I |
| Q481-p122-1 | From solvent: water, anti-solvent: CH 3Slowly crystallization among the CN | Wet | I+II |
| Q481-p122-2 | From solvent: water, anti-solvent: CH 3Slowly crystallization among the CN | Do | I |
| Q481-p124-1 | From solvent: ethanol, anti-solvent: evaporating solvent in the toluene | Wet | II＞I |
| Q481-p124-2 | From solvent: ethanol, anti-solvent: evaporating solvent in the toluene | Do | I |
| Q481-p125-1 | From solvent: ethanol, anti-solvent: crystallization in the acetone | Wet | I |
| Q481-p125-2 | From solvent: ethanol, anti-solvent: crystallization in the acetone | Do | I |
| Q481-p126-1 | From solvent: ethanol, anti-solvent: crystallization among the DMC | Wet | I |
| Q481-p126-2 | From solvent: ethanol, anti-solvent: crystallization among the DMC | Do | I |
| Q481-p127-1 | From solvent: ethanol, anti-solvent: crystallization among the THF | Wet | I |
| Q481-p127-2 | From solvent: ethanol, anti-solvent: crystallization among the THF | Do | I |
| Q481-p129-1 | From solvent: ethanol, anti-solvent: precipitate among the MTBE | Wet | I |
| Q481-p129-2 | From solvent: ethanol, anti-solvent: precipitate among the MTBE | Do | I |
| Q481-p132-1 | From solvent: DMSO, anti-solvent: precipitate among the MTBE | Wet | I |
| Q481-p132-2 | From solvent: DMSO, anti-solvent: precipitate among the MTBE | Do | I |
| Q481-p133-1 | From solvent: DMF, anti-solvent: crystallization among the MEK | Wet | I |
| Q481-p133-2 | From solvent: DMF, anti-solvent: crystallization among the MEK | Do | I |
| Q481-p134-3 | From solvent: 2-butanols, anti-solvent: precipitate among the MTBE | Wet | I |
| Q481-p134-4 | From solvent: 2-butanols, anti-solvent: precipitate among the MTBE | Do | I |
| Q481-p131-1 | From solvent: water, anti-solvent: slowly crystallization among the MEK | Wet | II＞I |
| Q481-p131-2 | From solvent: water, anti-solvent: slowly crystallization among the MEK | Do | I |
*If the sample in the table 2 is not pointed out in addition, and is dry under room temperature and barometric point.
Embodiment 3: prepare the memantine crystalline form I by crystallization
Table 3
*
| Test | Condition | Resistates | The crystalline form that XRD determines |
| Q481-p9 | Crystallization from water | Do, 40 ℃ of u.v. dryings | I |
| Q481-p10 | Crystallization from DMF | Do, 60 ℃ of u.v. dryings | I |
| Q481-p20 | Crystallization from propyl carbinol | Do, 50 ℃ of u.v. dryings | I |
| Q481-p21 | Crystallization from chloroform | Do, 50 ℃ of u.v. dryings | I |
| Q481-p65-7 | Crystallization from ethyl acetate | Do | I |
| Q481-p68-4 | Crystallization from Pentyl alcohol | Do | I |
| Q481-p72-8 | Use hydrogen chloride gas crystallization from ethyl acetate | Do, 55 ℃ of u.v. dryings | I |
| Q481-p72-9 | Use hydrogen chloride gas crystallization from ethyl acetate | Do, 55 ℃ of u.v. dryings | I |
| Q481-p83-9 | Crystallization from butylacetate | Do | I |
| Q481-p90-11 | Crystallization from acetone | Do | I |
| Q481-p90-13 | Crystallization from water | Do | I |
| Q481-p99-12 | Crystallization from MTBE | Do | I |
| Q481-p107-5 | Crystallization from methylcarbonate | Do, 50 ℃ of u.v. dryings | I |
| Q481-p113 | Crystallization from n-butyl acetate | Do | I |
| Q481-p114-5 | Crystallization from IPA | Wet | I |
| Q481-p114-6 | Crystallization from IPA | Do, 50 ℃ of u.v. dryings | I |
| Q481-p134-1 | Crystallization from the 2-butanols | Wet | I |
| Q481-p134-2 | Crystallization from the 2-butanols | Do | I |
*Sample in the table 2, if it is do not point out in addition, dry under room temperature and barometric point.
Embodiment 4: by removing the preparation memantine crystalline form I that desolvates
Table 4
*
| Test | Condition | Resistates | The crystalline form that XRD determines |
| Q489-p19-3 | Concentrate propyl carbinol | Wet | I |
| Q489-p19-4 | Concentrate propyl carbinol | Do | I |
| Q489-p31-2 | Concentrate propyl carbinol | Wet | I |
| Q489-p32-3 | Concentrate propyl carbinol | Do | I |
| Q481-p128-2 | Evaporating solvent ethanol-methylene dichloride | Do | I |
| Q481-p123-2 | Evaporating solvent ethanol | Do | I |
| Q481-p123-1 | Evaporating solvent ethanol | Wet | I+II |
| Q481-p128-1 | Evaporating solvent ethanol-methylene dichloride | Wet | I＞II |
*If it is dry that the sample in the table 2 is not pointed out in addition under room temperature and barometric point.
Though it is apparent that, the present invention disclosed herein is very suitable for realizing above-mentioned target, should be understood that those skilled in the art can make multiple change and embodiment.Therefore, the claims intention covers all these changes and the embodiment that falls into practicalness of the present invention and scope.
Claims (32)
1. the memantine Form II is characterised in that at least a X-ray powder diffraction figure that has peak value at about 6.7,13.3 and 20.2 ± 0.2 degree, 2 θ; About 3446,3396,2056,1650,1621,1532,1521,1384,1190,1162,1061,1030,965,934 and 721cm
-1Has the infrared spectra of peak value and at about 50 ℃, 90 ℃ and 341 ℃ DSC thermograms with endotherm(ic)peak.
2. the described memantine Form II of claim 1 is characterised in that the X-ray powder diffraction figure that has peak value at about 6.7,13.3 and 20.2 ± 0.2 degree, 2 θ.
3. the described memantine Form II of claim 2 is further characterized in that the X-ray powder diffraction figure that has peak value at about 14.5,17.2,18.6,22.9,23.9 and 29.0 ± 0.2 degree, 2 θ.
4. the described memantine Form II of claim 3 is further characterized in that basically X-ray powder diffraction figure as shown in Figure 1.
5. the described memantine Form II of claim 1 is characterised in that about 3446,3396,1621 and 1532cm
-1Infrared spectra with peak value.
6. the described memantine Form II of claim 5 is characterised in that about 2056,1650,1521,1384,1190,1162,1061,1030,965,934 and 721cm
-1Infrared peak.
7. the described memantine Form II of claim 5 is characterised in that basically infrared spectra as shown in Figure 2.
8. the described memantine Form II of claim 1 is characterised in that the DSC thermogram that has endotherm(ic)peak at about 50 ℃, 90 ℃ and 341 ℃.
9. the described memantine Form II of claim 1 is characterised in that basically DSC thermogram as shown in Figure 3.
10. prepare the method for the described memantine Form II of claim 1, comprising: the solution of acetone with memantine and water is mixed; Remove anhydrate and acetone to obtain the memantine Form II; And recovery memantine Form II.
11. the described method of claim 10, wherein the ratio of memantine and water is the about 0.6 mole hydrochloride memantine/premium on currency of about 0.4-.
12. the described method of claim 10 is wherein anhydrated and acetone by keeping mixture to remove in about 3 days to about 3 months.
13. the described method of claim 10 wherein kept mixture about 1 month.
14. the described method of claim 10, wherein the solution of memantine and water is heated to about 50-100 ℃ temperature.
15. the described method of claim 14 wherein was heated to about 80 ℃-Yue 90 ℃ temperature with the solution of memantine and water before mixing acetone.
16. the described method of claim 15 wherein was heated to about 85 ℃-Yue 90 ℃ temperature with the solution of memantine and water before mixing acetone.
17. the described method of claim 10 wherein was cooled to about 50 ℃-Yue 55 ℃ temperature with solution before mixing acetone.
18. contain the pharmaceutical preparation of described memantine Form II of claim 1 and pharmaceutically acceptable vehicle.
19. treatment suffers from the patient's of Parkinson's disease and Alzheimer method, comprises the pharmaceutical preparation of the claim 18 of drug treatment significant quantity.
20. preparation is characterised in that in the method for the memantine crystalline form of the X-ray powder diffraction peak value of about 6.3,12.5 and 18.8 ± 0.2 degree, 2 θ, comprises: provide memantine at C
1-4Solution in the alcohol; Solution is exposed to is selected from C
1-5Ketone or C
1-5In the anti-solvent of alkyl ester with obtain the precipitation; And recovery memantine crystalline form I.
21. the described method of claim 20, wherein C
1-4Alcohol is methyl alcohol.
22. the described method of claim 20, wherein C
1-5Ketone is acetone.
23. the described method of claim 20, wherein C
1-5Alkyl ester is a methyl acetate.
24. the described method of claim 20 is wherein by providing with the saturated atmosphere exposure solution of anti-solvent.
25. preparation is characterised in that in the method for the memantine crystalline form of the X-ray powder diffraction peak value at about 6.7,13.3 and 20.2 ± 0.2 degree 2 θ places, comprises: provide memantine being selected from water, C
1-5Solution in the solvent of alcohol, DMF and DMSO, and be selected from C
6-10Aromatic hydrocarbon, open chain or closed C
1-5Alkyl oxide, C
1-5Ketone, C
1-5The anti-solvent of acid amides, carbonic ether, ester and acid amides forms to cause precipitation; And recovery memantine crystalline form I.
26. the described method of claim 25, wherein solvent is selected from methyl alcohol, water, IPA, propyl carbinol, water, ethanol, DMSO and DMF.
27. the described method of claim 25, wherein anti-solvent is selected from toluene, isopropyl ether, n-butyl acetate, ethyl acetate, acetone, acetonitrile, DMC, THF, MTBE and MEK.
28. preparation is characterised in that this method comprises: provide memantine being selected from water, C in the method for the memantine crystalline form of the X-ray powder diffraction peak value at about 6.7,13.3 and 20.2 ± 0.2 degree, 2 θ ± 0.2 degree, 2 θ places
1-4Alcohol, C
6-10Aromatic hydrocarbon, C
1-4Halohydrocarbon, ester and C
1-5Solution in the solvent of alkyl oxide; Cooling solution is to cause precipitation; And recovery memantine crystalline form I.
29. the described method of claim 28, wherein solvent is selected from water, DMF, propyl carbinol, 2-butanols, Pentyl alcohol, chloroform, ethyl acetate, acetone, ester, water, MTBE, DMC and IPA.
30. the described method of claim 28, wherein solvent is removed by concentrating or evaporating.
31. preparation is characterised in that in the method for memantine crystalline form of the X-ray powder diffraction peak value at about 6.7,13.3 and 20.2 ± 0.2 degree 2 θ places, comprises: with memantine be selected from C
1-4Solution concentration in the solvent of alcohol and halohydrin thereof; And recovery memantine crystalline form I.
32. the described method of claim 31 wherein concentrates and is undertaken by slow evaporation.
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| CNA2006800020422A Pending CN101102994A (en) | 2005-01-11 | 2006-01-11 | Polymorphs of memantine hydrochloride |
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| CN106966909A (en) * | 2016-09-06 | 2017-07-21 | 南京优科制药有限公司 | A kind of purification process of memantine |
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| CN102942490A (en) * | 2012-12-02 | 2013-02-27 | 陕西方舟制药有限公司 | Synthesis of memantine hydrochloride |
| CN104557567B (en) * | 2013-10-15 | 2018-02-23 | 重庆医药工业研究院有限责任公司 | A kind of preparation method of memantine |
| CN107573375B (en) * | 2016-10-20 | 2019-07-26 | 成都苑东生物制药股份有限公司 | A kind of Memantine derivative and preparation method thereof |
| CN112730652A (en) * | 2020-12-17 | 2021-04-30 | 植恩生物技术股份有限公司 | Memantine hydrochloride and detection method of impurities thereof |
| CN115073304A (en) * | 2022-06-28 | 2022-09-20 | 北京云鹏鹏程医药科技有限公司 | Post-treatment preparation method of memantine hydrochloride |
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| CN106966909A (en) * | 2016-09-06 | 2017-07-21 | 南京优科制药有限公司 | A kind of purification process of memantine |
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