CN109641869A - Crystal form of lenalidomide and its preparation method and application - Google Patents
Crystal form of lenalidomide and its preparation method and application Download PDFInfo
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- CN109641869A CN109641869A CN201780052376.9A CN201780052376A CN109641869A CN 109641869 A CN109641869 A CN 109641869A CN 201780052376 A CN201780052376 A CN 201780052376A CN 109641869 A CN109641869 A CN 109641869A
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to novel crystal forms J of a kind of lenalidomide and preparation method thereof, and composition and medical usage containing crystal form J.
Description
The invention belongs to chemical pharmacy fields.Specifically, the present invention relates to novel crystal forms J of lenalidomide and preparation method thereof, pharmaceutical composition and its medical usage containing crystal form J.
Lenalidomide is a kind of TNF-α inhibitor researched and developed by celgene company, and in December, 2005, FDA had approved the lenalidomide capsule preparations revlimid of celgene company, for treating myelodysplastic syndrome.In June, 2006, FDA had approved lenalidomide and dexamethasone combination treatment Huppert's disease.The product is in China in June, 2013 granted listing, the auspicious multiple beauty of trade name.The chemical name of lenalidomide are as follows: 3- (4- amino -1- oxo -1,3- dihydro-isoindole -2- base)-piperidines -2,6- diketone, structural formula are as follows:
CN101838261B discloses crystal form A, B, C, D, E, F, G, H of lenalidomide, the preparation method of this eight kinds of crystal forms is (such as: hexane, toluene, acetone, acetonitrile, methanol, ethyl acetate) to dissolve by heating lenalidomide in water or organic solvent, and then cooling precipitates crystal or long agitation turns brilliant and obtains in the pulp system of solid-liquid two-phase.
CN101696205A discloses three kinds of lenalidomide new crystal form I, II, III.WO2011111053A discloses another new crystal form I.WO2010129636A discloses the new crystal form Form 1 of lenalidomide.WO2012127493A discloses the new crystal form H1 of lenalidomide.
For polymorph medicine, different crystal forms has different physics and chemical property, including fusing point, chemical stability, apparent solubility, rate of dissolution, optically and mechanically property etc., and these physical and chemical performances directly determine whether certain specific crystal form can be used for preparing pharmaceutical preparation, and influence the quality of bulk pharmaceutical chemicals and preparation.Therefore, although the prior art has disclosed some crystal forms of lenalidomide, it is still necessary to explorative can stablize, and there are the novel crystal forms of elegant formulations application prospect to meet the industrial production demand of drug.
Summary of the invention
On the one hand, the present invention relates to a kind of lenalidomide crystal form J, radiated using Cu-K α, X-ray powder diffraction (XRPD) map, 2 θ being expressed in degrees 12.0 ± 0.2 °, 13.6 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °,
There is characteristic peak at 26.7 ± 0.2 °, 27.5 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
In a specific embodiment, lenalidomide crystal form J of the present invention, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees have characteristic peak at 12.0 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 18.6 ± 0.2 °, 20.0 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
In a more specific embodiment, lenalidomide crystal form J of the invention, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees are at 12.0 ± 0.2 °, 12.6 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 17.5 ± 0.2 °, 18.6 ± 0.2 °, 20.0 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, 28.7 ± 0.2 °, 29.9 ± 0.2 °, 30.5 ± 0.2 °, 3 There is characteristic peak at 2.0 ± 0.2 °, 34.7 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
In one embodiment, lenalidomide crystal form J is characterized in that, X-ray powder diffraction collection is substantially as shown in.In another embodiment, lenalidomide crystal form J is characterized in that, DSC map has the first endothermic peak at 110-117 DEG C, there is the second endothermic peak at 266-271 DEG C.In yet another embodiment, lenalidomide crystal form J is characterized in that, DSC map is substantially as shown in Figure 3.
In one embodiment, lenalidomide crystal form J is dihydrate crystal form.
On the other hand, the present invention relates to a kind of methods for preparing lenalidomide crystal form J, which is characterized in that the method includes crystallizing lenalidomide from phosphate aqueous solution, to obtain the crystal form J of the lenalidomide.
It yet still another aspect, described method includes following steps the present invention relates to a kind of method for preparing lenalidomide crystal form J:
(1) lenalidomide is added in phosphate aqueous solution, heating stirring makes it dissolve, and obtains the phosphate aqueous solution of lenalidomide；
(2) optionally, filtration step (1) acquired solution；
(3) step (1) or (2) acquired solution are cooled to -5 to 5 DEG C, crystallization；
(4) isolated lenalidomide crystal form J.
On the other hand, the present invention provides the pharmaceutical composition of lenalidomide crystal form J containing the therapeutically effective amount as active constituent a kind of.Preferably, in described pharmaceutical composition, the crystal form J of lenalidomide can be mixed with one or more pharmaceutically acceptable solids or liquid diluent and/or excipient, and Galenic formula is made.
Also on the one hand, the crystal form J of present invention offer lenalidomide is preparing the purposes in anti-tumor drug.
Further, the invention further relates to the crystal form J of the lenalidomide for treating tumor disease.
In even further aspect, the present invention also provides a kind of methods for treating tumor disease, and the method includes the crystal form J of a effective amount of lenalidomide is administered to individual in need.
The tumour includes but is not limited to Huppert's disease and lymphoma mantle cell.
Fig. 1 is the X-ray powder diffraction collection of 1 gained lenalidomide crystal form J of embodiment.
Fig. 2 is the infrared absorption spectrum of 1 gained lenalidomide crystal form J of embodiment.
Fig. 3 is the DSC map of 1 gained lenalidomide crystal form J of embodiment.
Fig. 4 is the TGA map of 1 gained lenalidomide crystal form J of embodiment.
Fig. 5 is x-ray diffraction pattern of the 1 gained lenalidomide crystal form J of embodiment after 60 DEG C of stability inferiors are investigated 10 days.
Fig. 6 is DSC figure of the 1 gained lenalidomide crystal form J of embodiment after 60 DEG C of stability inferiors are investigated 10 days.
Fig. 7 is the x-ray diffraction pattern under 1 gained lenalidomide crystal form J of embodiment is 75 ± 5% in relative humidity after 10 days.
Fig. 8 is the DSC figure under 1 gained lenalidomide crystal form J of embodiment is 75 ± 5% in relative humidity after 10 days.
Fig. 9 is the TGA figure under 1 gained lenalidomide crystal form J of embodiment is 75 ± 5% in relative humidity after 10 days.
Figure 10 is the hygroscopicity empirical curve comparison diagram of crystal form J and crystal form E, whereinCrystal form J is represented,Represent crystal form E.
Figure 11 be crystal form E stability keep sample transformation after DSC figure.
Figure 12 is to scheme crystal form E and crystal form J according to the DSC obtained after the concussion mixing of 1: 1 ratio.
Figure 13 is the Dissolution profiles comparison diagram of crystal form J and crystal form E, whereinCrystal form J is represented,Represent crystal form E.
The present invention is described in more detail below, it should be appreciated that the term is intended to describe purpose, is not intended to limit the present invention.
General definition and term
Unless otherwise indicated, the technical and scientific term used herein has the identical meaning being generally understood with those skilled in the art of the invention.Contradiction if it exists, then be subject to definition provided by the present application.When stating some amount, concentration or other values or parameter in the form of range, preferred scope or preferred numerical upper limits and preferred numerical lower limits, it should be understood that any range specifically disclosed by combining any pair of range limit or preferred value with any range lower limit or preferred value is equivalent to, without considering whether the range specifically discloses.Unless otherwise indicated, the endpoint and all integers and score (decimal) within the scope of this that numberical range listed herein is intended to include range.
Term " about ", " about " are when with numerical variable and the used time, all numerical value of the numerical value and the variable that are often referred to the variable are in experimental error (such as in the confidence interval of average value 95%) or in ± the 10% of specified numerical value or in wider range.
It is open for stating "comprising" or the similar statement " comprising " synonymous with its, " containing " and " having " etc., however not excluded that additional unlisted element, step or ingredient.It states " Consists of " and excludes unspecified any element, step or ingredient.Statement "consisting essentially of ..." how is limited in specified element, step or ingredient, in addition appointing
Element, step or the ingredient of the basic and new feature of theme claimed will not be substantially influenced existing for choosing.It should be appreciated that statement "comprising" covers statement "consisting essentially of ..." and " Consists of ".
Term as used herein " optional " " optionally " refers to that the event then described or situation may occur or may not occur, which includes that the event or situation occurs and the event or situation does not occur.Such as prepare lenalidomide crystal form J method in " optional, filtering ... " indicate to be filtered or without filtering.
Unless otherwise indicated, the percentage of this paper, number etc. be all by weight.
As used herein, term " crystal form " or " crystal " refer to any solid matter that three-dimensional sequence is presented, with amorphous solid substance on the contrary, it generates the characteristic X-ray powder diffracting spectrum with the peak of clear border.
As used herein, term " amorphous " refers to any solid matter in three-dimensional without sequence.
As used herein, the solvate of water of term " hydrate " description comprising drug and stoichiometry or non-stoichiometry amount.
As used herein, term " X-ray powder diffraction (XRPD) map " refers to the diffraction pattern of Germicidal efficacy or parameter, data or value derived from it.XRPD map is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
As used herein, term " 2 θ " refers to based on the peak position indicated with degree (°) being arranged in x-ray diffraction experiment, and is usually the abscissa unit in diffracting spectrum.If reflection is diffracted when incident beam and certain lattice plane shape into θ angle, experimental setup needs to record reflecting bundle with 2 angles θ.It should be appreciated that the specific 2 θ value for the specific crystal formation mentioned herein is intended to indicate using 2 θ values (being indicated with degree) measured by x-ray diffraction experiment condition as described herein.For example, as described herein, using Cu-K α, (K α 1 is) it is used as radiation source.XRPD map herein can be acquired for example on Rigaku D/max-2200X- ray powder diffraction analysis instrument.Illustrative test condition can be 4 °/min of scanning speed, scan 0.01 ° of step width.
As used herein, the term " substantially " at X-ray diffraction peak is meant to take into account representative peak position and Strength Changes.For example, it will be understood by those skilled in the art that peak position (2 θ) can show some variations, usual up to 0.1-0.2 degree (± 0.1 to ± 0.2 degree), and the instrument for measuring diffraction also results in some variations.In addition, it will be understood by those skilled in the art that relative peak intensities can because between instrument difference and crystallinity degree, preferred orientation, preparation sample surfaces and other factors well known by persons skilled in the art due to change, and should be regarded as only observational measurement.
As used herein, differential scanning calorimetric analysis (DSC) measurement is when crystal since its crystal structure changes or crystal melting and transition temperature when absorbing or discharge heat.For the crystal form of the same race of same compound, in continuous analysis, thermal transition temperature and fusing point error are typically within about 5 DEG C.When describing some compound has a certain given peak DSC or fusing point, the peak DSC or fusing point ± 5 DEG C are referred to." substantially " also the variation of this temperature is taken into account.DSC provides a kind of householder method for distinguishing different crystal forms.Different crystal habits can be identified according to its different transition temperature feature.It is to be noted that the peak DSC or fusing point may change in the larger context for mixture.Further, since with decomposition during material melts, therefore fusion temperature is related to heating rate.DSC map can be for example in model such as NETZSCH DSC200 F3 Jaia
Instrument on measure.Illustrative test condition is 10 DEG C/min of heating rate, temperature range: 25-300 DEG C.
As used herein, infrared absorption spectrum (FTIR) can be used for studying the structure and chemical bond of molecule, can also be used as characterization and identifies the method for chemical species.Herein, FTIR is used to characterize the molecular structure and crystal form of lenalidomide crystal form J.The method that KBr tabletting usually can be used is measured the compound of solid form.FTIR can be acquired for example on the infrared spectrophotometer of model BRWKER JECTOR 22.Illustrative test condition is using KBr pressed disc method, scanning range 400-4000cm-1。
As used herein, thermogravimetric analysis (TGA) is to measure the common methods of the thermal stability of compound.Herein, TGA also is used to measure the hydration status of compound.Heating rate can generate certain influence to map in test process.Such as excessively high heating rate is unfavorable for measuring for intermediate product.TGA map can be measured for example in the model such as instrument of PerkinElmer TGA400.Illustrative test condition is 10 DEG C/min of heating rate, and temperature range is 30-300 DEG C.
The crystal form J of lenalidomide
In one embodiment, the crystal form J of present invention offer lenalidomide, it is radiated using Cu-K α, its X-ray powder diffraction (XRPD) map, 2 θ being expressed in degrees have characteristic peak at 12.0 ± 0.2 °, 13.6 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
In a specific embodiment, lenalidomide crystal form J of the present invention, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees have characteristic peak at 12.0 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 18.6 ± 0.2 °, 20.0 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
In a more specific embodiment, lenalidomide crystal form J of the invention, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees are at 12.0 ± 0.2 °, 12.6 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 17.5 ± 0.2 °, 18.6 ± 0.2 °, 20.0 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, 28.7 ± 0.2 °, 29.9 ± 0.2 °, 30.5 ± 0.2 °, 3 There is characteristic peak at 2.0 ± 0.2 °, 34.7 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
In a more specific embodiment, lenalidomide crystal form J of the invention, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees are at 12.0 ± 0.2 °, 12.6 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 17.5 ± 0.2 °, 18.6 ± 0.2 °, 20.0 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, 28.7 ± 0.2 °, 29.9 ± 0.2 °, 30.5 ± 0.2 °, 3 There is characteristic peak at 2.0 ± 0.2 °, 33.1 ± 0.2 °, 33.6 ± 0.2 °, 34.2 ± 0.2 °, 34.7 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
In a further embodiment, lenalidomide crystal form J of the present invention, is radiated using Cu-K α, and X-ray powder diffraction collection has 2 θ values, d value and relative intensity (L/L as shown in table 1 below0):
Table 1
In a further embodiment, lenalidomide crystal form J of the present invention has the peak at the angle of diffraction (2 θ) substantially the same with shown in Fig. 1.In another embodiment, crystal form J has X-ray powder diffraction spectrogram substantially as shown in.
In a further embodiment, lenalidomide crystal form J of the present invention has the peak at the angle of diffraction (2 θ) same as shown in Figure 1.In another embodiment, crystal form J has X-ray powder diffraction spectrogram as shown in Figure 1.
In another embodiment, lenalidomide crystal form J of the present invention, the infrared absorption figure measured with KBr tabletting
Spectrum is in about 3448.7cm-1、3356.7cm-1、3267.8cm-1、3057.0cm-1、2852.7cm-1、1738.9cm-1、1690.4cm-1、1638.4cm-1、1492.6cm-1、1460.4cm-1、1446.0cm-1、1422.6cm-1、1367.1cm-1、1351.7cm-1、1302.0cm-1、1234.6cm-1、1207.0cm-1、1179.3cm-1、1055.7cm-1、920.2cm-1、894.4cm-1、790.4cm-1、759.4cm-1、607.6cm-1、470.6cm-1、420.4cm-1There is absorption peak at place.
In specific embodiments, lenalidomide crystal form J of the present invention, the infrared absorption pattern measured with KBr tabletting is in about 3448.7cm-1、3356.7cm-1、3267.8cm-1、3057.0cm-1、2852.7cm-1、1738.9cm-1、1690.4cm-1、1638.4cm-1、1492.6cm-1、1460.4cm-1、1446.0cm-1、1422.6cm-1、1367.1em-1、1351.7cm-1、1302.0cm-1、1261.7cm-1、1234.6cm-1、1207.0cm-1、1179.3cm-1、1089.9cm-1、1055.7cm-1、997.0cm-1、920.2cm-1、894.4cm-1、833.3cm-1、814.4cm-1、790.4cm-1、759.4cm-1、699.0cm-1、607.6cm-1、558.1em-1、488.0cm-1、470.6cm-1、420.4cm-1There is characteristic peak at place.
In preferred embodiments, the crystal form J of lenalidomide of the present invention has the characteristic peak of the peak position substantially the same with shown in Fig. 2.In a further embodiment, the crystal form J of lenalidomide have basically as in Figure 2 shown in infrared absorption spectra.
In a further embodiment, the crystal form J of lenalidomide has the characteristic peak of peak position same as shown in Figure 2.In further embodiment, crystal form J has infrared absorption spectra as shown in Figure 2.
In one embodiment, differential scanning calorimetry (DSC) map of lenalidomide crystal form J of the present invention has the first endothermic peak at 110-117 DEG C, there is the second endothermic peak at 266-271 DEG C.
In preferred embodiments, lenalidomide crystal form J of the present invention has the characteristic peak at the temperature substantially the same with shown in Fig. 3.In another embodiment, the crystal form J of lenalidomide has DSC map substantially as shown in Figure 3.
In a further preferred embodiment, lenalidomide crystal form J of the present invention has the characteristic peak at temperature same as shown in Figure 3.In further embodiment, the crystal form J of lenalidomide has DSC map as shown in Figure 3.
In one embodiment, the crystal form J of lenalidomide of the present invention has the weight-loss curve substantially the same with shown in Fig. 4.In preferred embodiments, the crystal form J of lenalidomide has TGA map substantially as shown in Figure 4.
In a more preferred embodiment, lenalidomide crystal form J of the present invention has weight-loss curve same as shown in Figure 4.In a further preferred embodiment, the crystal form J of lenalidomide has TGA map as shown in Figure 4.According to the TGA map of Fig. 4 it is found that the crystal form J of lenalidomide is dihydrate crystal form.
The preparation method of the crystal form J of lenalidomide
The present invention also provides the methods of crystal form J for preparing lenalidomide a kind of comprising crystallizes lenalidomide from phosphate aqueous solution, to obtain the crystal form J of the lenalidomide.
In preferred embodiments, the present invention provides the method for crystal form J for preparing lenalidomide a kind of, and described method includes following steps:
(1) lenalidomide is added in phosphate aqueous solution, heating stirring makes it dissolve, and obtains the phosphate aqueous solution of lenalidomide；
(2) optionally, filtration step (1) acquired solution；
(3) step (1) or (2) acquired solution are cooled to -5-5 DEG C, crystallization；
(4) isolated lenalidomide crystal form J.
In a preferred embodiment, the w/v (g/ml) of lenalidomide and phosphate aqueous solution is 1: 20-1: 500, preferably 1: 30-1: 60.Such selection can make method of the invention obtain excellent yield when preparing crystal form J.
In a preferred embodiment, the concentration of the phosphate aqueous solution is 0.1%-50% (ml/ml), preferably 1%-5% (ml/ml).
Unless otherwise indicated, " heating " is to promote compound to dissolve in preparation method.The temperature of heating is not particularly limited, as long as being lower than the boiling point of recrystallisation solvent.Preferred heating temperature is room temperature to 90 DEG C, more preferable 60-90 DEG C, such as 60 DEG C, 70 DEG C, 80 DEG C, 85 DEG C, 90 DEG C.
Unless otherwise indicated, the speed of " stirring " and time are not particularly limited in the step of lenalidomide addition recrystallisation solvent, as long as can be completely dissolved lenalidomide.Preferred mixing time is 20-40min, more preferably 30min.
Crystallization temperature in preparation method should make the crystal form J that can form lenalidomide.Preferred crystallization temperature is -10 DEG C to 5 DEG C, preferably -5 DEG C to 5 DEG C, such as -8 DEG C, -6 DEG C, -5 DEG C, -3 DEG C, 0 DEG C, 3 DEG C, 5 DEG C.
Unless otherwise indicated, " crystallization " can also carry out during standing during stirring in preparation method.Crystallization can carry out about 6-60h, for example, about 48h, 36h, for 24 hours, 12h.
The crystal form of preparation by including decantation, centrifugation, evaporation, gravity filtration, suction filtration or under elevated pressure or under reduced pressure it is any other for solid separation technology including method separated and recovered, preferably filter or be centrifugated.Crystal form J after separation is optionally dried.Drying can carry out at about 60 DEG C or less, about 50 DEG C or less, about 45 DEG C or less, about 40 DEG C or less, about 35 DEG C or less, about 20 DEG C of temperature below or any other suitable temperature.Drying can carry out for example, about 1min, 1h, 2h, 4h, 8h, 12h, for 24 hours or any other suitable time.
Pharmaceutical composition and administration
In one embodiment, the present invention provides a kind of pharmaceutical composition, and the composition includes lenalidomide crystal form J and one or more pharmaceutically acceptable carriers.
" pharmaceutically acceptable carrier " refers to the solid being administered together with therapeutic agent or liquid diluent, adjuvant, excipient or medium as used herein, the term, and its tissue that the mankind and/or other animals are adapted for contact in the range of reasonable medical judgment is without excessive toxicity, stimulation, allergic reaction or corresponding other problems or complication compared with reasonable benefit/risk.
Workable pharmaceutically acceptable carrier includes but is not limited to sterile liquid, such as water and oil, oil including those petroleum, animal, plant or synthesis source, such as soybean oil, peanut oil, mineral oil etc. in pharmaceutical composition of the invention.When described pharmaceutical composition is administered intravenously (IV, water is exemplary carrier.Physiological saline and glucose and glycerine water solution can also be used as liquid-carrier, be especially used for injection.Suitable drug excipient includes glucose, starch, lactose, gelatin, maltose, sucrose, chalk, silica gel, glycerin monostearate, odium stearate, talcum, sodium chloride, glycerol, propylene glycol, water, ethyl alcohol etc..The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffer.Oral preparation may include standard vector, such as mannitol, lactose, starch, magnesium stearate, cellulose, saccharin sodium, the magnesium carbonate of pharmaceutical grade.The example of suitable pharmaceutically acceptable carrier is as described in Remington ' s Pharmaceutical Sciences (1990).
Composition of the invention can be acted on systematically and/or locally be acted on.For this purpose, the approach administration that they can be suitble to, for example, by injection, intra-arterial, subcutaneous, intravenous, peritonaeum, intramuscular or percutaneous dosing；Or oral, intranasal, it is buccal, transmucosal, local, in the form of eye-drops preparations or pass through inhalation.
For these administration routes, composition of the invention is administered in the dosage form that can be suitble to.The dosage form includes but is not limited to tablet, pill, capsule, pastille, hard candy agent, powder, spray, cream, ointment, suppository, gelling agent, aqueous suspension, injection, elixir, syrup.
Pharmaceutical composition of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolution, granulation, the processing such as sweet tablet, mill, emulsify, be lyophilized and prepare." therapeutically effective amount " refers to as used herein, the term be administered after can alleviate to a certain extent treated illness one or more symptoms compound amount.
Dosage regimen be can adjust to provide optimal required response.For example, single bolus can be administered, several divided doses can be administered at any time, or dosage can be proportionally reduced or increased as indicated in the urgent need for the treatment of condition.It it should be noted that dose value can change with the type and seriousness for the patient's condition to be mitigated, and may include single or multiple dosage.It further understands, for any particular individual, specific dosage regimen should adjust at any time according to the professional judgement of individual need and administration composition or the personnel for the administration for supervising composition.
Unless otherwise stated, otherwise as used herein, term " treatment " means to reverse, mitigates, inhibits illness applied by such term or the patient's condition perhaps one or more symptoms of the progress of one or more symptoms of such illness or the patient's condition or the such illness of prevention or the patient's condition or such illness or the patient's condition.
" individual " includes people or non-human animal as used herein.Exemplary individual human includes individual human (referred to as patient) or normal individual with disease (such as disease as described herein)." non-human animal " includes all vertebrates in the present invention, such as nonmammalian (such as amphibian, reptile, birds) and mammal, such as non-human primates, domestic animal and/or domesticated animal (such as dog, cat, sheep, milk cow, pig etc.).
Lenalidomide novel crystal forms J favorable solubility of the invention, crystallization processes are simple, convenient for operate, pollute it is small, can be real
Existing industrialized production, and crystal form drug of the invention is provided simultaneously with that product purity is high, physicochemical property is excellent, high temperature/high humidity and chemically and physically have good stability, process (filtering, it is dry, dissolve out and tabletting) adaptability is excellent, reproducible advantage, and there is good solubility, dissolution rate, dissolution time and biology release, there is good market application prospect.
Embodiment
The present invention is further explained by the following examples, and purpose, which is only that, more fully understands the contents of the present invention, they do not constitute a limitation on the scope of protection of the present invention or limit.
The preparation and characterization of lenalidomide crystal form J
The lenalidomide crude product used is not particularly limited in the preparation method of lenalidomide crystal form J described in the embodiment of the present invention, can be commercially available, or according to known methods, such as documented method is prepared in patent document US5635517A.
Lenalidomide crystal form B described in the embodiment of the present invention, crystal form E can be prepared according to method disclosed in CN101838261B.The patent document and non-patent literature that the present invention refers to are by quoting addition herein.
Test equipment information and method
X-ray powder diffraction instrument according to the present invention and test condition are as follows: X- diffraction apparatus model Rigaku D/max-2200Cu target；Operating method: 4 °/min of scanning speed scans 0.01 ° of step width.
Infrared spectrophotometer according to the present invention and test condition are as follows: infrared spectrophotometer model: BRWKER JECTOR 22；Operating method: KBr pressed disc method, scanning range 400-4000em are used-1。
DSC test condition of the present invention are as follows: DSC detector model are as follows: NETZSCH DSC200 F3 Jaia；Operating method: 10 DEG C/min of heating rate, temperature range: 25-300 DEG C.
TGA test condition of the present invention are as follows: TGA detector model are as follows: PerkinElmer TGA400；Operating method: 10 DEG C/min of heating rate, temperature range: 30-300 DEG C.
High performance liquid chromatography (HPLC) test condition of the present invention are as follows: chromatographic column is Agilent Zorbax SB-CN；4.6 × 250mm, 5 μm or equivalent chromatographic column；Mobile phase: buffer (takes perfluorooctane sulfonate 2.16g, water 1000ml is added to make to dissolve, add phosphatase 11 ml, mix, with 0.1mol/L sodium hydroxide tune pH value to 2.50): acetonitrile=92: 8；Detection wavelength: 210nm；Flow velocity: 1.0ml/min；Sample volume: 10 μ l；Column temperature: 25 DEG C.
Ion chromatography test condition of the present invention are as follows: chromatographic column is lonpac AG11；LonpacAS11-HC5 μm of 4.0 × 50mm, Guard；4.0×250mm；Mobile phase: 30 mmoles sodium hydroxide solutions；Dilution: 30 mmoles sodium hydroxide solutions；Detection wavelength: 210nm；Flow velocity: 1.5ml/min；Sample volume: 25 μ l；Column temperature: 30 DEG C.
Dissolution test method of the present invention are as follows: dissolution rate instrument model Agilent 708-DS；Method is slurry processes, revolving speed 50rpm, pH=6.8,37 DEG C of temperature.
Embodiment 1
Lenalidomide crude product 10g (HPLC purity=98%) is added in the phosphate aqueous solution of 200ml 50% (ml/ml),
60 DEG C are heated to, 30min is persistently stirred, is dissolved to clearly, obtains lenalidomide solution.Acquired solution is cooled to 5 DEG C, and stirring and crystallizing 48h at 5 DEG C, filtering, it is dried in vacuo at 20 DEG C, 8.1g crystal is obtained, measuring its purity through HPLC is 99.8%, and ion chromatography shows phosphate anion are as follows: 20ppm, the X-ray powder diffraction collection of the crystal form, infrared absorption pattern, DSC map and TGA map difference are as shown in Figs 1-4, and are defined as lenalidomide crystal form J.According to TGA map it is found that crystal form J is dihydrate.
Embodiment 2
Lenalidomide crude product 10g (HPLC purity=98%) is added in the phosphate aqueous solution of 5L 0.1% (ml/ml), 90 DEG C is heated to, persistently stirs 30min, is dissolved to clearly, obtains lenalidomide solution.Acquired solution is cooled to 0 DEG C, and stands crystallization 48h at 0 DEG C, is filtered, is dried in vacuo at 35 DEG C, obtains 7.1g crystal, measuring its purity through HPLC is 99.7%, and X-ray powder diffraction detection shows it for novel crystal forms J.
Embodiment 3
Lenalidomide crude product 10g (HPLC purity=98%) is added in the phosphate aqueous solution of 600ml 1% (ml/ml), 85 DEG C is heated to, persistently stirs 30min, is dissolved to clearly, obtains lenalidomide solution.Filtering, gained filtrate are cooled to -5 DEG C, and the stirring and crystallizing 36h at -5 DEG C, filter, and are dried in vacuo at 45 DEG C, obtain 7.8g crystal, and measuring its purity through HPLC is 99.9%, and X-ray powder diffraction detection shows it for novel crystal forms J.
Embodiment 4
Lenalidomide crude product 10g (HPLC purity=98%) is added in the phosphate aqueous solution of 600ml 1% (ml/ml), 80 DEG C is heated to, persistently stirs 30min, is dissolved to clearly, obtains lenalidomide solution.Filtering, gained filtrate are cooled to 0 DEG C, and stirring and crystallizing for 24 hours, filters at 0 DEG C, is dried in vacuo at 50 DEG C, obtains 7.8g crystal, and measuring its purity through HPLC is 99.8%, and X-ray powder diffraction detection shows it for novel crystal forms J.
Embodiment 5
Lenalidomide crude product 10g (HPLC purity=98%) is added in the phosphate aqueous solution of 300ml 5% (ml/ml), is heated to 70 DEG C, persistently stirs 30min, is dissolved to clearly, obtain lenalidomide solution.Filtering, gained filtrate are cooled to 0 DEG C, and the stirring and crystallizing 12h at 0 DEG C, filter, and are dried in vacuo at 40 DEG C, obtain 8.8g crystal, and measuring its purity through HPLC is 99.8%, and X-ray powder diffraction detection shows it for novel crystal forms J.
Stability test
High temperature experiment
Lenalidomide crystal form J made from embodiment 1 is placed in sealing clean vial, is placed in 60 DEG C of thermostatic drying chambers, respectively at 5,10 days sample detections, and is compareed with 0 day result.It the results are shown in Table 2.Table 2 shows that after placing 5 days and 10 days, sample of the content of the appearance of the crystal form J of lenalidomide, fusing point and crystal form J with 0 day is essentially identical.Crystal form J after investigating 10 days at 60 DEG C is tested, x-ray diffraction pattern is shown in Fig. 5, and XRPD data are as shown in table 3, and DSC map is shown in Fig. 6.DSC map has the first endothermic peak at 110-117 DEG C, in 266-271
There is the second endothermic peak at DEG C.Lenalidomide crystal form J placed 10 days at 60 DEG C after XRPD map, data and DSC map and 0 day it is essentially identical, show good high-temperature stability.
Table 2
Table 3
High humidity experiment
Lenalidomide crystal form J made from embodiment 1 and crystal form E are uniformly shared into open culture dish respectively, thickness≤5mm, it is subsequently placed in room temperature (25 DEG C), in the constant temperature and humidity incubator that relative humidity is 75 ± 5%, it is measured respectively at sampling in the 5th, 10 day, and is compareed with 0 day result.Wherein, the hygroscopicity of lenalidomide crystal form J the results are shown in Table 4, it can be seen that crystal form J only has moisture absorption weight gain slightly after 5 days, 10 days, and the content of appearance, fusing point and crystal form J and 0 day sample are essentially identical.Relative humidity be 75 ± 5%, (25 DEG C) of room temperature place 10 days after the x-ray diffraction pattern of crystal form J see Fig. 7, XRPD data are as shown in table 5, and DSC figure is shown in that Fig. 8, TGA figure are shown in Fig. 9.DSC figure shows that it has the first endothermic peak at 110-117 DEG C, there is the second endothermic peak at 266-271 DEG C.Lenalidomide crystal form J placed 10 days under high humidity environment after XRPD map, data, DSC map and TGA curve and 0 day it is essentially identical, show good high wet stability.
Table 4
Table 5
The hygroscopicity contrast and experiment of lenalidomide crystal form J and lenalidomide crystal form E is shown in Figure 10, from fig. 10 it can be seen that the hygroscopicity of lenalidomide crystal form J is significantly lower than known crystal form E, shows that crystal form J has higher stability.
Stability of crystal form test
Keep sample condition: by the crystal form B prepared, the closed preservation of crystal form E, crystal form J and under the conditions of 25 DEG C, keeping sample 6 months, investigates the variation of crystal form.
Table 6
As can be seen from Table 6, crystal form J has excellent stability.Crystal form B with crystal form J the DSC map after keeping sample 6 months respectively before keep sample compared with almost without apparent variation.Crystal form E is unstable, crystal form E transformation after DSC map it is as shown in figure 11, with keep sample before DSC map differ obvious.
Crystal form comparative test
After crystal form E and crystal form J is mixed according to the concussion of 1: 1 ratio, the crystal form state of mixture is observed.
Figure 12 show the DSC map measured after crystal form E is mixed with crystal form J.The DSC map of mixture and the DSC map (Fig. 3) of crystal form J are inconsistent, and the endothermic peak independent of crystal form E and crystal form J as we can see from the figure, further prove that crystal form E and crystal form J is not same crystal form.
Solubility test
The method for measuring solubility is as follows:
Chromatographic column: 5 μm of 250mm × 4.6mm of Agilent ZORBAX SB-C18
Detection wavelength: 215nm, flow velocity: 1.0ml/min, sample volume: 10 μ l, column temperature: 25 DEG C
Runing time: 14 minutes
Diluent: diluent 1: acetonitrile: water=40: 60, diluent 2:0.01NHCl
Mobile phase: buffer (takes 4.33g octane -1- sodium sulfonate in 1L water, 1ml phosphoric acid is added to mix, filtering): methanol=70: 30, it mixes, ultrasound.
Reference substance solution is prepared: the lenalidomide reference substance that precision weighs about 25mg is set in 50ml measuring bottle, is dissolved with diluent 1 and is diluted to scale, is mixed.Precision pipettes 5.0ml into 25ml measuring bottle, is diluted to scale with diluent 2, mixes, and obtains reference substance solution (containing lenalidomide 0.1mg/ml).
Sample solution: take appropriate test sample (about 0.3g) to 25ml measuring bottle, 5ml solvent (pH=1.2, pH=2, pH=4.5, pH=6.8, pH=7.5) is added to mix, it sets to take out after 37 DEG C of water-baths shake 24 hours and filter immediately, after discarding primary filtrate 1-2ml, collect subsequent filtrate, precision pipette subsequent filtrate it is appropriate and with diluent 2 be diluted to the solution of about 0.1mg/ml to get.
Table 7
As can be seen from Table 7, the solubility of crystal form J is better than crystal form B.
Dissolution experiments
Use the dissolution rate of the crystal form J of the capsule form measurement lenalidomide of that degree amine crystal form J.
The prescription of lenalidomide crystal form J capsule:
Table 8
| Ingredient | Weight |
| Lenalidomide crystal form J | 10mg |
| Lactose | 300mg |
| Microcrystalline cellulose | 50mg |
| Croscarmellose sodium | 15mg |
| Magnesium stearate | 3mg |
The preparation method of lenalidomide crystal form J capsule:
Lenalidomide crystal form J of the present invention, the lactose, microcrystalline cellulose, croscarmellose sodium for taking recipe quantity, are made softwood with 95% ethanol solution, sieving, 50-60 DEG C of forced air drying, whole grain sieving, filling capsule after stiffened fatty acid magnesium mixes.
The prescription of lenalidomide crystal form E capsule:
Table 9
| Ingredient | Weight |
| Lenalidomide crystal form E | 10mg |
| Lactose | 300mg |
| Microcrystalline cellulose | 50mg |
| Croscarmellose sodium | 15mg |
| Magnesium stearate | 3mg |
The preparation method of lenalidomide crystal form E capsule:
Lenalidomide crystal form E, lactose, the microcrystalline cellulose, croscarmellose sodium for taking recipe quantity, are made softwood with 95% ethanol solution, sieving, 50-60 DEG C of forced air drying, whole grain sieving, filling capsule after stiffened fatty acid magnesium mixes.
Lenalidomide Dissolution Rate Testing method:
Test apparatus: agitating paddle, stripping rotor, sedimentation basket, motor.
Test process:
(1) adjusting instrument makes agitating paddle bottom away from bottom 25mm ± 2mm in stripping rotor；
(2) sample is thrown, the 900ml by degassing process is taken, 0.01N hydrochloric acid solution is placed in stripping rotor, puts into lenalidomide capsule；
(3) start instrument, revolving speed is controlled in 50rpm；
(4) dissolution rate is surveyed.
The Dissolution profiles comparison diagram of lenalidomide crystal form J and crystal form E is shown in Figure 13.The results are shown in Table 10 for the Dissolution experiments of lenalidomide crystal form J and crystal form E:
Table 10
From Dissolution experiments result it is found that lenalidomide crystal form J of the invention is compared with known crystal form E, there is better dissolution rate, be more suitable for formulation application.
Skilled artisans appreciate that; numerical value or numerical end point involved in technical solution of the present invention; its meaning or desired protection scope are not limited to the number itself; they contain those by the well accepted permissible error range in this field; such as experimental error, measurement error, statistical error and random error etc., and these error ranges are included within the scope of the present invention.
It will be clear for a person skilled in the art that many modifications and variations of the present invention can be carried out without departing from its spirit and scope.Specific embodiment as described herein is only provided by way of example, is not meant to limit in any way.True scope and spirit of the invention are shown by the appended claims, and description and embodiments are merely exemplary.
Claims (13)
- A kind of lenalidomide crystal form J, it is characterized in that, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees have characteristic peak at 12.0 ± 0.2 °, 13.6 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
- Lenalidomide crystal form J according to claim 1, it is characterized in that, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees have characteristic peak at 12.0 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 18.6 ± 0.2 °, 20.0 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
- Lenalidomide crystal form J according to claim 1 or 2, it is characterized in that, it is radiated using Cu-K α, its X-ray powder diffraction collection, 2 θ being expressed in degrees are at 12.0 ± 0.2 °, 12.6 ± 0.2 °, 13.6 ± 0.2 °, 15.3 ± 0.2 °, 17.5 ± 0.2 °, 18.6 ± 0.2 °, 20.0 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 °, 22.1 ± 0.2 °, 22.6 ± 0.2 °, 23.2 ± 0.2 °, 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, 28.7 ± 0.2 °, 29.9 ± 0.2 °, 30.5 ± 0.2 °, There is characteristic peak at 32.0 ± 0.2 °, 34.7 ± 0.2 °, and 2 θ only have a diffraction maximum between 13.0-14.0 °.
- Lenalidomide crystal form J according to any one of claim 1-3, which is characterized in that its X-ray powder diffraction collection is substantially as shown in.
- Lenalidomide crystal form J described in any one of -4 according to claim 1, which is characterized in that its DSC map has the first endothermic peak at 110-117 DEG C, there is the second endothermic peak at 266-271 DEG C.
- Lenalidomide crystal form J according to any one of claims 1-5, which is characterized in that its DSC map is substantially as shown in Figure 3.
- Lenalidomide crystal form J according to claim 1 to 6 is dihydrate crystal form.
- A method of it prepares such as lenalidomide crystal form J of any of claims 1-7, which is characterized in that the method includes crystallizing lenalidomide from phosphate aqueous solution, to obtain the crystal form J of the lenalidomide.
- A method of it prepares such as lenalidomide crystal form J of any of claims 1-7, the method includes Following steps:(1) lenalidomide is added in phosphate aqueous solution, heating stirring makes it dissolve, and obtains the phosphate aqueous solution of lenalidomide；(2) optionally, filtration step (1) acquired solution；(3) step (1) or (2) acquired solution are cooled to -5 to 5 DEG C, crystallization；(4) isolated lenalidomide crystal form J.
- Method according to claim 8 or claim 9, which is characterized in that the w/v of the lenalidomide and phosphate aqueous solution is 1: 20-1: 500 (g/ml), preferably 1: 30-1: 60 (g/ml).
- The method according to any one of claim 8-10, which is characterized in that the concentration of the phosphate aqueous solution is 0.1%-50% (ml/ml), preferably 1%-5% (ml/ml).
- The method according to any one of claim 9-11, which is characterized in that solution is cooled to -5 DEG C, 0 DEG C or 5 DEG C crystallizations in step (3).
- According to claim 1, lenalidomide crystal form J described in any one of -7 is preparing the purposes in anti-tumor drug.
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