CN107721902A - Cocrystallization of Apremilast and niacinamide and its preparation method and application - Google Patents

Cocrystallization of Apremilast and niacinamide and its preparation method and application Download PDF

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Publication number
CN107721902A
CN107721902A CN201711093636.5A CN201711093636A CN107721902A CN 107721902 A CN107721902 A CN 107721902A CN 201711093636 A CN201711093636 A CN 201711093636A CN 107721902 A CN107721902 A CN 107721902A
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niacinamide
apremilast
cocrystallization
organic solvent
preparation
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梅雪锋
王逢源
张奇
王建荣
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The present invention relates to cocrystallization of Apremilast and niacinamide and preparation method thereof.Comprehensive sign has been carried out to cocrystallization with means such as X ray powder diffraction analysis, thermogravimetic analysis (TGA), differential scanning calorimetric analysis, it is found that the cocrystallization has more excellent physical chemistry and patent medicine performance compared with Apremilast.The preparation method of the cocrystallization of the Apremilast and niacinamide is simple, is easily controlled, favorable reproducibility, can stablize the cocrystallization for obtaining Apremilast and niacinamide.

Description

Cocrystallization of Apremilast and niacinamide and its preparation method and application
Technical field
The invention belongs to pharmaceutical chemistry and crystallization processes technical field, and in particular to the cocrystallization of Apremilast and niacinamide and Its preparation method and application.
Background technology
Medicine cocrystallization (eutectic) refer to active constituents of medicine (API) molecule and other physiologically acceptable acid, alkali, Salt, non-ionic compound molecule are connected with other non-covalent bonds with hydrogen bond, pi-pi accumulation effect, Van der Waals force and are incorporated in same In lattice.Eutectic application value maximum in medicine is exactly that can introduce new group while medicine covalent structure is not changed Point, substantially improve the physicochemical property of medicine, such as stability, fusing point, solubility, dissolution rate, bioavilability, and due to The species of part (CCF) has a lot, and the property of medicine can also accordingly obtain different degrees of regulation.Active pharmaceutical ingredient it is every A kind of difference for the physical property that new solid forms are showed can influence its storage stability, compressibility and density and Solubility and dissolution rate.
Compared with other solid forms such as salt, solvate, eutectic has bigger advantage in medicament research and development.It is first First, for solvate, because the acceptable solvent limitednumber in pharmacy, and solvate is in preparation mistake Solvent (water) phenomenon often is gone in journey, is changed into the unstable worse crystal formation of amorphous or dissolubility.Secondly, relatively For salt, because requiring the center of at least one ionization of bulk drug into salt, and each component in pharmaceutical co-crystals can be with It is neutral molecule, thus pharmaceutical co-crystals can cover all API, including acid, alkali and non-ionic compound；It is also, potential Also many for forming the molecule of eutectic with API, these materials may include food additives, preservative, pharmaceutic adjuvant, mineral Matter, vitamin, amino acid and other bioactive molecules, it might even be possible to be other API.Generally speaking, eutectic is that one kind has extensively The solid forms of general application prospect, preformulation study and formulation design to medicine have profound influence.
A kind of eutectic may possess unique property due to its specific crystal habit and specific chemical composition Matter.For example compared with API, eutectic has better pharmacology and pharmacological properties, it is easier to processes；Eutectic has more advantage Dissolution rate and solubility, human body can be made more effectively to utilize active constituents of medicine, therefore have more preferable bioavilability；Eutectic Possess more preferable storage stability.In a word, eutectic may possess other favorable properties in addition to therapeutic effect.
Apremilast it is chemical entitled：S- { 2- [1- (3- ethoxy-4-methoxyphenyls) -2- methylsulfonylethyls] -4- Acetylaminoisoindoline -1,3- diketone }, its chemical structural formula is as follows：
Apremilast is a kind of phosphodiesterase-4 (PDE-4) inhibitor.Being clinically used for treatment has activity psoriasis The moderate of arthritic adult patients and phototherapy and systematic treatment to severe psoriasis in plaques adult patient treatment.Due to Slightly solubility of the Apremilast in water, cause its vivo biodistribution availability low.Up to the present, there has been no Apremilast cocrystallization Report.
Niacinamide, also known as niacinamide, English name：Nicotinamide.Chemical formula：C6H6N2O, its chemical structural formula is such as Under：
For one of above shortcomings, the technical problems to be solved by the invention in the prior art be to provide a kind of Ah Pu Site niacinamide cocrystallization.On the basis of the present invention is using unique hydrogen bond synthon design, Apremilast and nicotinoyl are obtained Amine cocrystallization.Research finds that the cocrystallization crystallinity height of Apremilast and niacinamide, hygroscopicity are small, and form regular crystal Kenel, water solubility are remarkably reinforced, thus are advantageous to the PROCESS FOR TREATMENT of medicine and the improvement of physical and chemical performance, improve patent medicine performance.
The content of the invention
It is an object of the present invention to provide a kind of Apremilast and the cocrystallization of niacinamide.
The second object of the present invention is to provide a kind of preparation method of the cocrystallization of Apremilast and niacinamide.
The third object of the present invention is to provide a kind of pharmaceutical composition, and described pharmaceutical composition includes above-mentioned Apremilast With the cocrystallization and pharmaceutically acceptable carrier of niacinamide.
The fourth object of the present invention is that providing a kind of cocrystallization of Apremilast and niacinamide is preparing for treating work Application in dynamic property psoriatic arthritis and the moderate of phototherapy or systematic treatment to the medicine of severe psoriasis in plaques.
According to the first aspect of the invention, there is provided the cocrystallization of Apremilast and niacinamide, in described cocrystallization, Ah The mol ratio of Pu Site and niacinamide is 2:1.
2 θ angles are about in described Apremilast and the X-ray powder diffraction collection of the cocrystallization of niacinamide:7.39° ± 0.2 °, 9.59 ° ± 0.2 °, 11.25 ° ± 0.2 °, 19.25 ° ± 0.2 °, 22.39 ° ± 0.2 °, 26.26 ° ± 0.2 °, 28.93 ° There is characteristic peak at ± 0.2 °.
Preferably, also in 2 θ angles in the X-ray powder diffraction collection of the cocrystallization of described Apremilast and niacinamide About 15.20 ° ± 0.2 °, 16.35 ° ± 0.2 °, 17.67 ° ± 0.2 °, 20.19 ° ± 0.2 °, 20.72 ° ± 0.2 °, 21.33 ° ± 0.2 °, 22.74 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.75 ° ± 0.2 °, 25.36 ° ± 0.2 °, 25.88 ° ± 0.2 °, 27.46 ° There is characteristic peak at ± 0.2 °, 27.92 ° ± 0.2 °, 29.66 ° ± 0.2 °, 34.37 ° ± 0.2 °.
Especially, the X-ray powder collection of illustrative plates of the eutectic of the Apremilast and niacinamide, have substantially such as the institute of accompanying drawing 1 The XRPD collection of illustrative plates shown.
Due to the difference of measuring condition, each θ angles of peak 2 and relative intensity can change on XRPD diffraction patterns, general 2 θ angles Change also can slightly overflow the scope within ± 0.2 °, it will be understood by those skilled in the art that the relative intensity of diffraction can depend on In for example, sample formulation or device therefor.
The cocrystallization of the Apremilast and niacinamide is tetragonal crystal system, space group P41212, cell parameter is： α=90 °, β=90 °, γ=90 °, unit cell volume are
The thermogravimetic analysis (TGA) of the cocrystallization of the Apremilast and niacinamide about starts weightlessness at 147 ± 1 DEG C, and is decomposing It is preceding not have weightlessness；Especially, the cocrystallization of the Apremilast and niacinamide is with thermal weight loss substantially as shown in Figure 2 point Analyse (TG) collection of illustrative plates.
The differential scanning calorimetric analysis of the cocrystallization of the Apremilast and niacinamide about have feature at 144.9 ± 0.2 DEG C Endothermic peak；Described Apremilast and the cocrystallization of niacinamide have differential scanning calorimetric analysis (DSC) substantially as shown in Figure 3 Collection of illustrative plates.
Described Apremilast and the infrared spectrum of the cocrystallization of niacinamide are at least in about 3367cm-1, 3008cm-1, 2983cm-1, 2947cm-1, 2841cm-1, 1763cm-1, 1699cm-1, 1618cm-1, 1525cm-1, 1479cm-1, 1396cm-1, 1365cm-1, 1300cm-1, 1173cm-1, 1138cm-1, 1101cm-1, 1026cm-1, 872cm-1, 754cm-1, 656cm-1, 592cm-1, 486cm-1, 455cm-1Place has characteristic peak.
The dynamic water absorption test of described Apremilast and the cocrystallization of niacinamide is in 0~95% in relative humidity Hygroscopicity be less than 0.6%.
Described Apremilast and the cocrystallization of niacinamide improves than Apremilast equilbrium solubility itself, has more preferable Dissolution rate, more than more than 5 times of Apremilast.
Described Apremilast and the cocrystallization of niacinamide, stability is preferable, and solubility lifts larger, dissolution rate in water Lifting is beneficial to absorption and utilization of the human body to medicine.
According to the second aspect of the invention, there is provided the preparation method of the cocrystallization of the Apremilast and niacinamide, institute Method is stated as one of following methods：
Method one：
Apremilast and niacinamide are added in organic solvent, after being completely dissolved, slowly volatilization, obtain Apremilast with The cocrystallization of niacinamide；
Method two：
Excessive niacinamide is dissolved in organic solvent, takes supernatant to add slightly excessive Apremilast, stirring is a large amount of to having White solid separates out；Take solid portion to dry, obtain the cocrystallization of Apremilast and niacinamide.
Wherein,
Described organic solvent has certain solubility to raw material and rotten organic solvent is not caused to raw material including all, Can be：The combination of one or several of the organic solvents such as alcohols, ketone, esters, alkane, aromatic hydrocarbon or halogenated alkane, it is preferable that Described organic solvent is one or more mixtures in methanol, ethanol, ethyl acetate, acetone, dichloromethane；
The temperature of the cocrystallization for preparing Apremilast and niacinamide is room temperature~50 DEG C, preferably room temperature.
Preferably,
In method one, the mol ratio of described Apremilast and niacinamide is about 4:1~1:4；Preferably, described A Pu The mol ratio of Si Te and niacinamide is about 2:1；
Described Apremilast and the w/v of organic solvent are about (2~50) mg:1mL；Further preferably about (4~30) mg:1mL；
In method two, the w/v of described niacinamide and organic solvent is about (10~40) mg:1mL；Further Preferably about (20~30) mg:1mL；
Described Apremilast and the w/v of organic solvent are about (10~100) mg:1mL；Further preferably about For (40~70) mg:1mL；
The time of described stirring is more than 24 hours；
Described drying is to be dried in vacuum drying chamber.
Preparation method of the present invention is simple to operate, and crystallization process is easily controlled, and crystallinity is high, and favorable reproducibility, can The stable cocrystallization for obtaining Apremilast and niacinamide.
The third aspect of the present invention is related to a kind of pharmaceutical composition, and it includes the common knot of described Apremilast and niacinamide Brilliant and pharmaceutically acceptable carrier.
The fourth aspect of the present invention is related to the cocrystallization of Apremilast and niacinamide and/or pharmaceutical composition as described above Preparing for treating the moderate of activity psoriatic arthritis and phototherapy or systematic treatment to the medicine of severe psoriasis in plaques Application in thing.
Brief description of the drawings
Fig. 1 is X-ray powder diffraction (XRPD) figure of the cocrystallization of the Apremilast of embodiment 1 and niacinamide；
Fig. 2 is thermogravimetic analysis (TGA) (TG) figure of the cocrystallization of the Apremilast of embodiment 1 and niacinamide；
Fig. 3 is differential scanning calorimetric analysis (DSC) figure of the cocrystallization of the Apremilast of embodiment 1 and niacinamide；
Fig. 4 is infrared spectrum (IR) figure of the cocrystallization of the Apremilast of embodiment 1 and niacinamide；
Fig. 5 is Raman spectrum (Raman) figure of the cocrystallization of the Apremilast of embodiment 1 and niacinamide；
Fig. 6 is dynamic water absorption (DVS) figure of the cocrystallization of the Apremilast of embodiment 1 and niacinamide；
Fig. 7 is equilbrium solubility figure under the Apremilast of embodiment 1 pH different from the cocrystallization of niacinamide；
Fig. 8 is the Apremilast of embodiment 1 polymeric media equilbrium solubility figure different from the cocrystallization of niacinamide；
Fig. 9 is the dissolution rate curve map of the cocrystallization of the Apremilast of embodiment 1 and niacinamide；
Figure 10 is the X-ray single crystal diffraction of the cocrystallization of the Apremilast of embodiment 1 and niacinamide.
Embodiment
With reference to specific embodiment, the present invention is further elaborated, but does not limit the present invention.
Detecting instrument and method：
Instrument used in X-ray single crystal diffraction (SCXRD) is Brooker Instrument Ltd. Bruker SmartApex II type X ray single crystal diffractometers.Condition determination is graphite monochromator, Mo-K alpha raysCarry out at room temperature Test, test voltage 50kV, electric current 30mA.All single crystals structure data convert and structure elucidation work respectively by SAINT -5.0 and SHELXTL -2014 programs are completed, and absorption correction is completed by SADABS programs.Non-hydrogen atom coordinate is by difference letter Number method and least square method are obtained, and hydrogen atom is added in place by theoretical calculation.
X-ray powder diffraction method, INSTRUMENT MODEL：Bruker D8advance, target：Cu K α (40kV, 40mA), instrument Peak position is being corrected using the preceding standard sample carried with instrument.Acquisition software is Diffrac Plus XRD Commander, point It is MDI Jade 6.0 to analyse software.Sample is tested at ambient temperature, and the sample that needs are detected is placed on organic slide.Sample To detector distance：30cm, scanning range：3 °~40 ° (2 θ values), scanning step footpath：0.02 °, step-length：0.1 second/step.
Thermogravimetic analysis (TGA) method, INSTRUMENT MODEL：Netzsch TG 209F3, instrument control software are NETZSCH- Proteus-6, analysis software are Proteus Analysis.With 10 DEG C/min programming rate in 50mL/min drying nitrogens Under protection, temperature range：30~400 DEG C, sweep speed：10K/min, purge gass：25mL/min, protect gas：15mL/min.
Differential scanning calorimetric analysis method, INSTRUMENT MODEL：TADSC Q2000, temperature range：50~200 DEG C, scanning speed Rate：10 DEG C/min, nitrogen flow rate：50mL/min.
Method of infrared spectrophotometry, the infrared spectrometric analyzers of Nicolet FTIR 6700 detect in room temperature, infrared displacement：4000- 400cm-1。
Raman optical spectrum method, INSTRUMENT MODEL：Thermo DXR micro-Raman spectroscopies, Raman shift：3200-300cm-1。
Dynamic water is adsorbed, INSTRUMENT MODEL：SMS DVS Intrinsic, 0~95%RH, temperature：25℃.
Liquid-phase condition：Instrument：Agilent 1260, mobile phase：Water:Acetonitrile=60:40 (0~2min), 40:60 (2~ 9min)、20:80 (9~12min), 60:40 (12~15min), column temperature：30 DEG C, flow velocity：1.0mL/min.
The reagents such as methanol are that analysis is pure, are provided by Chemical Reagent Co., Ltd., Sinopharm Group, agents useful for same and solvent remove Special instruction is outer, without special processing.Apremilast bulk drug is bought from Shanghai De Mo Pharmaceutical Technology Co., Ltd, nicotinoyl The purchase of amine bulk drug is more than 99% from company of lark prestige Science and Technology Ltd., purity.All temperature represent with DEG C (degree Celsius), room Temperature refers to 20~25 DEG C.
Embodiment 1
In room temperature, by Apremilast (0.02mmol) and niacinamide (0.01mmol) stoichiometrically 2:1 is added to first In alcohol (2mL), after sonic oscillation is completely dissolved, room temperature is slowly volatilized, and obtains the cocrystallization of Apremilast and niacinamide.It will prepare Obtained eutectic is characterized using X-ray single crystal diffraction, and the X-ray monocrystalline of the cocrystallization of Apremilast and niacinamide spreads out Penetrate structure chart and see Figure 10, the result of X-ray single crystal diffraction shows that the mol ratio of Apremilast and niacinamide is 2:1.Apremilast Cocrystallization with niacinamide is tetragonal crystal system, space group P41212, cell parameter is： α=90 °, β=90 °, γ=90 °, unit cell volume are
To the cocrystallization of obtained Apremilast and niacinamide using X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetric analysis (DSC), Raman spectrum (Raman), hygroscopicity analysis (DVS) and infrared (IR) spectrum etc. Solid-state approach is analyzed.
X-ray powder diffraction analysis result is shown in accompanying drawing 1, and thermal gravimetric analysis results are shown in accompanying drawing 2, differential scanning calorimetric analysis knot Fruit sees accompanying drawing 3, and infrared analysis result is shown in accompanying drawing 4, and Raman analysis result is shown in accompanying drawing 5, and dynamic water absorption (DVS) analysis result is shown in Accompanying drawing 6.
Embodiment 2
In room temperature, by Apremilast (0.1mmol) and niacinamide (0.05mmol) stoichiometrically 2:1 is added to acetic acid In ethyl ester (2mL), after sonic oscillation is completely dissolved, room temperature is slowly volatilized, and obtains the cocrystallization of Apremilast and niacinamide.
Embodiment 3
In room temperature, by Apremilast (0.1mmol) and niacinamide (0.05mmol) stoichiometrically 2:1 is added to methanol With ethyl acetate (1:1, each 1mL) in the mixed solvent, after sonic oscillation is completely dissolved, room temperature is slowly volatilized, and obtains A Pusi The special cocrystallization with niacinamide.
Embodiment 4
In room temperature, by Apremilast (0.1mmol) and niacinamide (0.05mmol) stoichiometrically 2:1 is added to acetone In (2mL), after sonic oscillation is completely dissolved, room temperature is slowly volatilized, and obtains the cocrystallization of Apremilast and niacinamide.
Embodiment 5
In room temperature, by Apremilast (0.1mmol) and niacinamide (0.05mmol) stoichiometrically 2:1 is added to dichloro In methane (2mL), after sonic oscillation is completely dissolved, room temperature is slowly volatilized, and obtains the cocrystallization of Apremilast and niacinamide.
Embodiment 6
In room temperature, excessive niacinamide (40mg) is dissolved in methanol (2mL), stirs the satiety that part is kept in equilibrium process And state；Suspension is filtered, takes supernatant to add slightly excessive Apremilast (80mg), is stirred at room temperature 24 hours up to have A large amount of white solids separate out；Filtering, take solid portion to be dried in vacuum drying chamber, obtain the cocrystallization of Apremilast and niacinamide Powder.
The Apremilast of preparation in embodiment 2~6 and the cocrystallization of niacinamide, pass through X-ray powder diffraction (XRPD), the Solid-state Chemistry method such as thermogravimetric analysis (TG), differential scanning calorimetric analysis (DSC) and infrared (IR) spectrum characterizes Afterwards, the Apremilast and the cocrystallization of niacinamide that its result is prepared with embodiment 1 are basically identical.
Test case 1
Equilibrium solubility experiments under Apremilast pH different from the cocrystallization of niacinamide, receive test agent source：A Pusi The cocrystallization of special niacinamide is prepared by the above method.Experimental method：Take the cocrystallization powder point of excessive Apremilast and niacinamide Jia Ru not the glycine-HCI cushioning liquid (1mL) of pH 2.0,4.6 disodium hydrogen phosphates of pH-citric acid solution (1mL), pH In 6.8 disodium hydrogen phosphates-citric acid solution (1mL), room temperature is suspended more than 24 hours to filter to get filtrate and surveyed with efficient liquid phase Determine concentration.Its analysis result is shown in Fig. 7.
Test case 2
Apremilast polymeric media Equilibrium solubility experiments different from the cocrystallization of niacinamide, receive test agent source： The cocrystallization of Apremilast and niacinamide is prepared by the above method.Experimental method：Take the common knot of excessive Apremilast and niacinamide Crystalline flour end is separately added into the respectively solubilizer of difference containing 1wt.% (polyethylene glycol PEG2000, hydroxypropyl cellulose HPC, polyvinyl pyrrole Alkanone PVP, TWEEN80 80Tween80, TBAB TBAB) the glycine-HCI cushioning liquid (1mL) of pH 2.0 in, room Temperature is suspended more than 24 hours to filter to get filtrate determines concentration with efficient liquid phase.Its analysis result is shown in Fig. 8.
Test case 3
The intrinsic dissolution rate experiment of the cocrystallization of Apremilast and niacinamide, receives test agent source：Apremilast and cigarette The cocrystallization of acid amides is prepared by above-described embodiment 1.Experimental method：The cocrystallization pressed powder of Apremilast and niacinamide is taken in 10 In milliliter dissolution medium, 0.2 milliliter of solution is taken at regular intervals, and the solution concentration of Each point in time is monitored with efficient liquid phase, Finally give the dissolution rate curve of the cocrystallization of Apremilast and niacinamide.
Leaching condition：Instrument：Micro digestion instrument, dissolution medium：1wt.% hydroxypropyl celluloses HPC 2.0 sweet ammonia of pH Acid-hydrochloric acid buffer solution, mixing speed：75rpm, leaching temperature：37 DEG C, sample time：10,20,30,45,60 minutes.Its point Analysis result is shown in Fig. 9.
The foregoing is only a specific embodiment of the invention, but protection scope of the present invention is not limited thereto, any Those skilled in the art in disclosed technical scope, can without the change that creative work is expected or Replace, should all be included within the scope of the present invention.

Claims (10)

1. the cocrystallization of a kind of Apremilast and niacinamide, it is characterised in that described Apremilast and the cocrystallization of niacinamide The mol ratio of middle Apremilast and niacinamide is 2:1.
2. the cocrystallization of a kind of Apremilast and niacinamide, it is characterised in that described Apremilast and the cocrystallization of niacinamide X-ray powder diffraction collection in 2 θ angles be about 7.39 ° ± 0.2 °, 9.59 ° ± 0.2 °, 11.25 ° ± 0.2 °, 19.25 ° ± There is characteristic peak at 0.2 °, 22.39 ° ± 0.2 °, 26.26 ° ± 0.2 °, 28.93 ° ± 0.2 °.
3. the cocrystallization of Apremilast according to claim 1 or 2 and niacinamide, it is characterised in that described A Pusi Special is about 7.39 ° ± 0.2 ° with 2 θ angles in the X-ray powder diffraction collection of the cocrystallization of niacinamide, 9.59 ° ± 0.2 °, 11.25 ° ± 0.2 °, 15.20 ° ± 0.2 °, 16.35 ° ± 0.2 °, 17.67 ° ± 0.2 °, 19.25 ° ± 0.2 °, 20.19 ° ± 0.2 °, 20.72 ° ± 0.2 °, 21.33 ° ± 0.2 °, 22.39 ° ± 0.2 °, 22.74 ° ± 0.2 °, 23.38 ° ± 0.2 °, 24.75 ° ± 0.2 °, 25.36 ° ± 0.2 °, 25.88 ° ± 0.2 °, 26.26 ° ± 0.2 °, 27.46 ° ± 0.2 °, 27.92 ° ± 0.2 °, There is characteristic peak at 28.93 ° ± 0.2 °, 29.66 ° ± 0.2 °, 34.37 ° ± 0.2 °.
4. the cocrystallization of Apremilast according to claim 1 or 2 and niacinamide, it is characterised in that described A Pusi The X-ray diffracting spectrum of the special cocrystallization with niacinamide, has X-ray powder diffraction collection substantially as shown in Figure 1.
5. the cocrystallization of Apremilast according to claim 1 or 2 and niacinamide, it is characterised in that described A Pusi The differential scanning calorimetric analysis spectrogram of the special cocrystallization with niacinamide about has feature endothermic peak at 144.9 ± 0.2 DEG C.
6. a kind of method of the cocrystallization of Apremilast prepared according to any one of claim 1-5 and niacinamide, its It is characterised by, methods described is one of following methods：
Method one：
Apremilast and niacinamide are added in organic solvent, after being completely dissolved, slowly volatilization, obtains Apremilast and nicotinoyl The cocrystallization of amine；
Method two：
Excessive niacinamide is dissolved in organic solvent, takes supernatant to add slightly excessive Apremilast, stirring is to there are a large amount of whites Solid separates out；Take solid portion to dry, obtain the cocrystallization of Apremilast and niacinamide.
7. the preparation method of the cocrystallization of Apremilast according to claim 6 and niacinamide, it is characterised in that：
Described organic solvent has certain solubility to raw material and rotten organic solvent is not caused to raw material including all, is selected from The combination of one or several of the organic solvents such as alcohols, ketone, esters, alkane, aromatic hydrocarbon or halogenated alkane；Preferably, it is described Organic solvent is one or more mixtures in methanol, ethanol, ethyl acetate, acetone, dichloromethane.
8. the preparation method of the cocrystallization of Apremilast according to claim 6 and niacinamide, it is characterised in that：
In method one, the mol ratio of described Apremilast and niacinamide is about 4:1~1:4；Preferably, described Apremilast Mol ratio with niacinamide is about 2:1；
Described Apremilast and the w/v of organic solvent are about 2~50mg:1mL；Further preferably about 4~ 30mg:1mL；
In method two, the w/v of described niacinamide and organic solvent is about 10~40mg:1mL；Further preferably about For 20~30mg:1mL；
Described Apremilast and the w/v of organic solvent are about 10~100mg:1mL；Further preferably about 40~ 70mg:1mL；
The time of described stirring is more than 24 hours；
Described drying is to be dried in vacuum drying chamber.
9. a kind of pharmaceutical composition, it includes the cocrystallization of the Apremilast and niacinamide any one of claim 1-5 And pharmaceutically acceptable carrier.
10. the cocrystallization of Apremilast and niacinamide according to any one of claim 1-5 or according to claim 9 institute The pharmaceutical composition stated is preparing the moderate that is used to treating activity psoriatic arthritis and phototherapy or systematic treatment to severe spot Application in the medicine of block psoriasis pustulosa.
CN201711093636.5A 2017-11-08 2017-11-08 Cocrystallization of Apremilast and niacinamide and its preparation method and application Pending CN107721902A (en)

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