CN105198933A - Lobaplatin crystal, preparing method and medicine application - Google Patents
Lobaplatin crystal, preparing method and medicine application Download PDFInfo
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- CN105198933A CN105198933A CN201410279601.0A CN201410279601A CN105198933A CN 105198933 A CN105198933 A CN 105198933A CN 201410279601 A CN201410279601 A CN 201410279601A CN 105198933 A CN105198933 A CN 105198933A
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Abstract
The invention relates to a lobaplatin crystal, a preparing method and a medicine application. The crystal form of the lobaplatin crystal is C, and the melting point Tm.p.. is 228+/-5 DEG C; in a PXRD pattern of the lobaplatin crystal, diffraction peaks exist when the 2theta value is 6.79, 8.07, 12.24, 12.61, 13.50, 16.50, 17.83, 18.32, 18.79, 20.09, 21.64, 22.27, 23.19, 24.73, 27.34, 28.35, 29.12 and 31.92, and the error range of the 2theta value is 0.2. The preparing method for the crystal form C includes the steps that isobutanol or normal propyl alcohol is added into lobaplatin dihydrate, the mixture is stirred in a suspension mode, and the crystal is dissolved out, separated out, dried and then obtained. Compared with existing lobaplatin and lobaplatin trihydrate, better stability and better solubility are achieved, and the lobaplatin crystal can be better suitable for preparing medicine preparations in various forms, can be better stored and used and can be better used for treating cancers such as the breast cancer, the small cell lung cancer and the chronic granulocytic leukemia.
Description
Technical field
The present invention relates to pharmaceutical field, particularly a kind of new crystal and preparation method thereof of lobaplatin and the application in medicine, belong to medical art.
Background technology
Lobaplatin (Lobaplatin, D19466), have another name called lobaplatin, it is the third generation platinum series antineoplastic medicament after cis-platinum, carboplatin, its chemical name is: cis-[anti-form-1, two (methylamine)-N, the N' of 2-tetramethylene]-[(2S)-lactic acid-O1, O2]-platinum (II), molecular formula is C
9h
18n
2o
3pt, molecular weight is 397.34, and chemical structural formula is as shown in the formula shown in (1):
Lobaplatin tool alkanisation, belongs to alkylating agent (broad sense).There is good antitumor action, as in vitro AH135-knurl, B16-melanoma, colorectal carcinoma 115, in body mouse P338 leukemia etc., there is good restraining effect.The feature of lobaplatin is that antitumour activity is strong, and toxicity is low, without cumulative toxicity and renal toxicity, and less to bone marrow toxicity, platelet-free reduces disease, and the injection lobaplatin gone on the market at present is mainly used in the treatment of mammary cancer, small cell lung cancer and chronic myelocytic leukemia.
The former side of grinding of this medicine reaches Pharmacy stock Co., Ltd (ASTAMedicaAG) for German Ace, and its original patent EP0324154 describes the preparation method of lobaplatin first.In patent EP0611303 subsequently, again disclose the preparation method of lobaplatin trihydrate, this product is by lobaplatin anhydride is carried out recrystallization, form the crystal water product containing three water moleculess, in that patent, point out that the lobaplatin that the preparation method (embodiment 1a) described in EP0324154 obtains has deliquescence, easily become sticky, be difficult to make preparation.
Summary of the invention
The technical problem to be solved in the present invention is, lobaplatin anhydride existed deliquescence, is difficult to make the problem of preparation, poor stability in the past.The invention provides that a kind of bioavailability is high, good stability, solubleness are high, good fluidity, the not easily moisture absorption become sticky, the new crystal of yield and all ideal lobaplatin of purity.
One skilled in the art will appreciate that same medicine, crystal formation is different, and its bioavailability also may exist difference, and its stability, mobility, compressibility etc. also may be different, and the application of these physico-chemical properties on medicine produces certain impact.The polymorphic of medicine has become drug research process and has become with medicine yield and quality to control and requisite important component part in testing process, the bioactive selection of new drug compound is contributed to the research of polymorph in pharmaceuticals, contribute to providing bioavailability, increase clinical efficacy, contribute to selection and the design of drug administration approach, and the determination of pharmaceutical preparation technology parameter, thus improve products production quality.
We, by continuous Improvement, have invented new crystal of a kind of lobaplatin and preparation method thereof and the application in medicine.
Specifically, in order to solve the problems of the technologies described above, the invention provides following technical scheme:
A kind of lobaplatin compound crystal, it is characterized in that, its crystal formation is C, PXRD collection of illustrative plates is about 6.79,8.07,12.24,12.61,13.50,16.50,17.83,18.32,18.79,20.09,21.64,22.27,23.19,24.73,27.34,28.35,29.12,31.92 places in 2 θ angle value diffraction peak, and wherein 2 θ value limit of error are 0.2.
Wherein, fusing point Tm.p..=228 ± 5 DEG C of this crystal.
Wherein, the fusing point of this crystal measures with DSC, with peak-peak assessment, and heating rate: 10 DEG C/minute.
On the other hand, the present invention also provides the preparation method of described lobaplatin crystal, it is characterized in that, comprises the steps b):
In lobaplatin dihydrate, add isopropylcarbinol or n-propyl alcohol, suspend and stir, crystallization, isolates this crystallization, obtains white powder, be the crystal C of lobaplatin after drying.
Preferably, wherein, the preparation method of described lobaplatin dihydrate comprises the steps a):
In lobaplatin trihydrate, add suspension crystallization solvent, suspend and stir, crystallization, after removing solvent, with washed with diethylether, vacuum-drying obtains this lobaplatin dihydrate crystallization.
Preferably, wherein, step a) in, the mass volume ratio of described lobaplatin trihydrate and recrystallisation solvent is lobaplatin trihydrate: recrystallisation solvent=1:15-30.
Preferably, wherein, step a) in, described recrystallisation solvent is selected from methyl tertiary butyl ether, toluene, ether, butylacetate, Isosorbide-5-Nitrae-dioxane or normal heptane.
Preferably, wherein, step b) in, after isolating crystallization, use washed with diethylether before the drying, described drying is vacuum-drying.
Preferably, wherein, step b) in, described in be suspended in room temperature under carry out, preferably suspend 45-50h.
Preferably, wherein, described step b) in the mass volume ratio of lobaplatin dihydrate and isopropylcarbinol be lobaplatin dihydrate: isopropylcarbinol=1:15-30; The mass volume ratio of lobaplatin dihydrate and n-propyl alcohol is lobaplatin dihydrate: n-propyl alcohol=1:15-30.
On the other hand, the present invention also provides a kind of pharmaceutical composition, it is characterized in that, using described lobaplatin crystal as activeconstituents.
Preferably, the amount containing lobaplatin crystal in described pharmaceutical composition minimum unit is 5mg, 10mg or 50mg.
Preferably, described pharmaceutical composition is any acceptable pharmaceutical dosage form clinically.
Preferably, described formulation is freeze-drying preparation for injection.
On the other hand, the present invention also provides described lobaplatin crystal or described pharmaceutical composition preparing the application in anticarcinogen.
On the other hand, the present invention also provides described lobaplatin crystal or described pharmaceutical composition to be used for the treatment of the application of cancer, and it is used for the treatment of mammary cancer, small cell lung cancer or chronic myelocytic leukemia.
The present invention still further provides the application of lobaplatin new crystal in pharmaceutical compositions and pharmaceutical preparation.
Raw material lobaplatin trihydrate used in the present invention adopts the method for patent EP0611303 embodiment to prepare.
Described pharmaceutical composition, using aforesaid lobaplatin crystal formation as activeconstituents, in minimum unit containing lobaplatin crystal formation amount be 5mg, 10mg or 50mg.Lobaplatin new crystal can make pharmaceutical composition with one or more pharmaceutically acceptable carriers or vehicle.Further, described pharmaceutical composition can be made into any clinically pharmaceutically useful formulation being suitable for raw material, comprises injection type, through parenteral administration formulations such as other position mucosal drug delivery formulations of percutaneous drug delivery formulation, respiratory tract administration formulation, cavity and health.Be preferably injection freeze-dried powder.
Described pharmaceutical carrier or vehicle can be selected from following in one or more: water for injection, N.F,USP MANNITOL, lactose, polyethylene glycols, tween-80, propylene glycol, tartrate, Citric Acid, xitix, Zonon D, Calcium Disodium Edetate, sodium bisulfite, glucose, sodium-chlor, soybean oil, soybean lecithin, egg phospholipids, DSPE, dextran, glycine, glycerine.
The preparation method of above-mentioned composition and preparation normally those skilled in the art knows conventional method.The lobaplatin agent activity form of lobaplatin crystal formation of the present invention and listing is all lobaplatin, i.e. anhydrous lobaplatin, therefore is applicable to all diseases of the lobaplatin product treatment of now having gone on the market.
Lobaplatin and cis-[anti-form-1, two (the methylamine)-N of 2-tetramethylene, N']-[(2S)-lactic acid-O1, O2]-platinum (II), belong to alkylating agent, cytotoxic drug, also known as biological alkylating agent (BioalkylatingAgengts), carbonium ion can be formed in vivo or other have the compound of active electrophilic groups, and then with the biomacromolecule (DNA in cell, RNA, enzyme) in containing enriching the group of electronics (as amino, sulfydryl, hydroxyl, carboxyl, phosphate etc.) there is covalent attachment, make its loss of activity or DNA molecular is ruptured, cause death of neoplastic cells, therefore anti-tumor activity is strong.Pharmacokinetic shows, after intravenous injection lobaplatin, in serum, plays antitumor action with the form of total platinum and free platinum, is anhydrous lobaplatin and plays useful effect, have nothing to do with feed states.
Lobaplatin new crystal of the present invention, be become sticky based on the easy deliquescence of amorphous state lobaplatin, poor stability, the not easily defect such as storage and the new crystal developed, there is bioavailability high, good stability, the not easily feature such as deliquescence, compared with lobaplatin trihydrate, also surprisingly find it to compare trihydrate to have solubleness high, yield and the advantage that purity is high, stability is more excellent.Therefore the exploitation of this new crystal, contributes to selection and the design of drug administration approach, and the determination of pharmaceutical preparation technology parameter, thus improves pharmaceutical production quality.The new lobaplatin compound of the present invention is highly stable at normal temperatures, its not easily the moisture absorption become sticky, good fluidity, storing, transport and preparation and process time operability be obviously better than unformed shape lobaplatin.
Accompanying drawing explanation
Fig. 1: the x-ray diffraction pattern of lobaplatin new crystal C;
The differential thermal analysis DSC figure of Fig. 2: lobaplatin new crystal C;
The differential thermal analysis TGA figure of Fig. 3: lobaplatin new crystal C.
Fig. 4: crystal formation is the x-ray diffraction pattern of the lobaplatin dihydrate of A;
Fig. 5: crystal formation is the molecule stereo structure sciagraph of the lobaplatin dihydrate of A;
Fig. 6: crystal formation is the differential thermal analysis DSC figure of the lobaplatin dihydrate of A;
Fig. 7: crystal formation is the differential thermal analysis TGA figure of the lobaplatin dihydrate of A.
Embodiment
The invention provides that a kind of solubleness is high, the lobaplatin new crystal of excellent in stability, called after crystal C.
On the one hand, the invention provides a kind of lobaplatin new crystal of crystal habit.The lobaplatin crystal C that just preparative separation of the present invention goes out below is described as follows:
Employing manufacturer is Bruker, model is the X-ray diffractometer of BrukerD8advanceXRD, lobaplatin crystal C is measured, its condition determination is: CuKa (40kv, 40mA), scanning speed 2 °/min (2 θ value), sweep limit 3 °-45 ° (2 θ value), has the absorption peak of following characteristics, see the following form 1, its diffracting spectrum as shown in Figure 1:
X-ray diffraction (PXRD) measurement result of table 1 lobaplatin new crystal C
| Peak sequence | Diffraction angle 2 θ value (about) | Crystal face is apart from d (about) | Relative intensity (highly about %) |
| 1 | 6.79 | 13.01 | 100 |
| 2 | 8.07 | 10.94 | 22.5 |
| 3 | 12.24 | 7.23 | 4.5 |
| 4 | 12.61 | 7.01 | 3.6 |
| 5 | 13.50 | 6.55 | 7 |
| 6 | 16.50 | 5.37 | 29.4 |
| 7 | 17.83 | 4.97 | 2.8 |
| 8 | 18.32 | 4.84 | 7 |
| 9 | 18.79 | 4.72 | 8.2 |
| 10 | 20.09 | 4.42 | 3.1 |
| 11 | 21.64 | 4.10 | 15.8 |
| 12 | 22.27 | 3.99 | 5.1 |
| 13 | 23.19 | 3.83 | 3.4 |
| 14 | 24.73 | 3.60 | 5.2 |
| 15 | 27.34 | 3.26 | 11.2 |
| 16 | 28.35 | 3.15 | 4.3 |
| 17 | 29.12 | 3.06 | 4.4 |
| 18 | 31.92 | 2.80 | 4.3 |
The new crystal C of this lobaplatin by manufacturer be NETZSCH, model is that the differential thermal analyzer of NETZSCHDSC204F1, NETZSCHTG209F1 carries out differential thermal analysis (DSC-TGA), as shown in Figure 2, TGA figure is as shown in Figure 3 for DSC figure.Result shows, and measures with DSC, with peak-peak assessment, and fusing point T
m.p..=228 ± 5 DEG C, heating rate: 10 DEG C/minute.Be specially: DSC collection of illustrative plates has an exothermic peak at 228 ± 5 DEG C, judge in conjunction with TGA and European patent EP 0611303 melting point data, this peak is fusion and decomposition peak, and TGA collection of illustrative plates had the weightlessness of 3.89% before 150 DEG C, judges that it is dissolvent residual in conjunction with DSC data.
On the other hand, the invention provides a kind of preparation method preparing simple, easy handling, be applicable to amplifying the lobaplatin new crystal produced.
In a preferred embodiment, the preparation method of lobaplatin new crystal of the present invention, comprises the steps:
A, prepare lobaplatin dihydrate: take lobaplatin trihydrate in container, add 15-30ml organic solvent, stir 45-50h in room temperature low suspension, filter, with washed with diethylether, after vacuum-drying white powder, be lobaplatin dihydrate;
Wherein, described organic solvent is selected from methyl tertiary butyl ether, toluene, ether, butylacetate, Isosorbide-5-Nitrae-dioxane or normal heptane.
B, preparation target crystal formation: the lobaplatin dihydrate taking step a gained, is placed in container, adds isopropylcarbinol or n-propyl alcohol, stir 45-50h in room temperature low suspension, crystallization, filters to isolate this crystallization, with washed with diethylether, obtain white powder after vacuum-drying, be the new crystal C of lobaplatin.
In described step b, the mass volume ratio of lobaplatin dihydrate and isopropylcarbinol is lobaplatin dihydrate: isopropylcarbinol=1:15-30; The mass volume ratio of lobaplatin dihydrate and n-propyl alcohol is lobaplatin dihydrate: n-propyl alcohol=1:15-30.
Embodiment
Illustrate the preparation method of lobaplatin crystal C of the present invention and the screening and separating process of each new crystal and qualification thereof and performance measurement by the following examples.
Embodiment one: the screening strength of each crystal formation
1.1 normal temperature volatilization crystallization process screenings
Get 20mg lobaplatin trihydrate sample and put into 10ml sample bottle, add 3ml dehydrated alcohol or anhydrous methanol, after fully dissolving, slowly volatilize under being placed in 25 DEG C of environment, obtain solid drying thing, carry out PXRD mensuration.The results are shown in following table 2:
Table 2 normal temperature volatilization crystallization trial result
| Numbering | Solvent | PXRD (possible crystal formation numbering) |
| 1-1 | Dehydrated alcohol | B |
| 1-2 | Anhydrous methanol | B |
Result shows: the crystal formation obtained in anhydrous methanol and dehydrated alcohol, learns that it is same crystal formation, temporary called after crystal form B through comparing.
1.2 suspended crystallization method screenings
Get 20mg lobaplatin trihydrate sample and put into 10ml sample bottle, add the following organic solvent of 4ml, be prepared into suspension, remove solvent after shaking 1.5h under being placed in 25 DEG C of environment, after solid drying, carry out PXRD mensuration.The results are shown in following table 3:
Table 3 suspension crystallization test-results
Result shows: the obtainable crystal formation of suspension crystallization has 9 kinds, temporary called after crystal form A, B, C, D, E, G, H, I, L.
1.3 solventing-out process screenings
Get 20mg lobaplatin trihydrate sample, be dissolved in 3ml anhydrous methanol or dehydrated alcohol and be mixed with solution, progressively add following organic solvent wherein, until separate out solid, removing supernatant liquor, carries out PXRD mensuration after solid drying.The results are shown in following table 4:
Table 4 dilution crystallization test-results
Result shows: the obtainable crystal formation of suspension crystallization has 7 kinds, temporary called after crystal formation F, J, K, M, N, O, P.
The sign of 1.4 each crystal formations
Carry out PXRD mensuration and DCS, TGA sign to crystal form A-P sample, wherein, each instrument title adopted, model and producer are as shown in table 5 below.
Each INSTRUMENT MODEL when table 5 pair crystal formation characterizes and manufacturer
Measurement result is as follows:
Crystal form A, it is characterized in that PXRD collection of illustrative plates is about 11.04,12.32,12.61,13.85,15.14,15.55,16.68,17.67,17.86,19.03,20.06,21.00,22.68,22.92,23.76,25.39,25.58,26.37,26.77,27.00,27.71,28.13,29.71,31.42,31.94,32.89,34.29,34.60,36.10,36.93,37.66,40.78,43.41 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2;
Crystal form A, is characterized in that DSC collection of illustrative plates has exothermic peak near 220 ± 5 DEG C.
Crystal form B, it is characterized in that PXRD collection of illustrative plates is about 8.25,9.77,11.70,13.13,15.28,16.48,17.22,17.74,19.01,19.56,22.28,23.72,24.04,24.30,25.62,26.20,28.57,30.22,30.61 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2;
Crystal form B, is characterized in that DSC collection of illustrative plates has exothermic peak near 230 ± 5 DEG C.
Crystal C, it is characterized in that PXRD collection of illustrative plates is about 6.79,8.07,12.24,12.61,13.50,16.50,17.83,18.32,18.79,20.09,21.64,22.27,23.19,24.73,27.34,28.35,29.12,31.92 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2;
Crystal C, is characterized in that DSC collection of illustrative plates has exothermic peak near 228 ± 5 DEG C.
Crystal formation D, it is characterized in that PXRD collection of illustrative plates is about 6.76,11.07,12.35,12.65,13.88,15.18,15.56,16.68,17.70,17.90,20.08,21.02,22.70,22.92,25.41,25.64,26.41,26.79,27.02,28.15,31.44,31.96,32.96,34.34,34.62,36.93,40.82,43.46 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2;
Crystal formation D, is characterized in that DSC collection of illustrative plates has exothermic peak near 218 ± 5 DEG C.
Crystal formation E, it is characterized in that PXRD collection of illustrative plates is about 6.61,8.09,12.38,13.03,15.40,16.66,17.47,19.07 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2;
Crystal formation E, is characterized in that DSC collection of illustrative plates has exothermic peak near 214 ± 5 DEG C.
Crystal formation F, it is characterized in that PXRD collection of illustrative plates is about 8.21,11.60,12.99,15.24,16.44,17.11,17.55,18.42,19.01,19.20,19.42,21.81,22.17,22.42,23.33,23.85,24.18,24.40,24.77,25.46,25.98,26.13,27.89,28.42,29.03,30.32,31.17,31.94,33.30,36.20,37.62,39.66 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2;
Crystal formation F, is characterized in that DSC collection of illustrative plates has exothermic peak near 229 ± 5 DEG C.
Crystal formation G, it is characterized in that PXRD collection of illustrative plates is about 8.62,10.82,11.03,12.26,12.59,13.82,15.12,15.57,16.59,17.43,17.65,18.48,19.46,20.11,20.37,21.01,22.66,22.86,24.60,25.40,26.33,26.77,27.00,28.11,29.79,31.42,31.94,32.87,34.25,34.58,36.06,40.76,42.75,43.39 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal formation H, it is characterized in that PXRD collection of illustrative plates is about 8.35,8.53,8.68,12.97,15.24,17.41,18.40,19.13,19.48,20.37,24.68,25.41,30.33,31.66,36.34 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal formation I, it is characterized in that PXRD collection of illustrative plates is about 6.75,8.39,11.07,11.59,12.32,12.63,12.99,15.20,16.80,17.07,17.57,19.14,19.46,21.00,22.13,22.84,23.29,23.77,24.22,25.82,26.76,28.38,30.34,30.83,31.90,33.63,36.32,38.47 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal formation J, it is characterized in that PXRD collection of illustrative plates is about 5.94,8.35,9.87,13.05,15.28,16.66,19.15,22.22,22.68,25.09,30.71,33.56 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal form K, it is characterized in that PXRD collection of illustrative plates is about 8.29,11.02,12.31,12.61,13.84,15.14,15.53,16.70,17.66,19.05,20.06,20.98,22.68,22.90,25.60,26.37,26.77,26.98,27.68,28.23,29.75,31.40,31.88,32.90,33.81,34.29,34.60,36.10,36.84,37.64,39.93,40.76,41.51,42.36,42.70,43.39 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal formation L, it is characterized in that PXRD collection of illustrative plates is about 6.71,7.91,10.75,11.84,14.06,14.29,15.85,16.78,17.29,19.76,20.20,20.63,21.08,21.58,21.89,22.17,23.87,25.09,26.83,27.02,28.73,29.18,29.92,30.56,31.61,33.95,40.33,41.33 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal form M, it is characterized in that PXRD collection of illustrative plates is about 8.05,13.03,15.20,16.19,17.47,18.77,19.32,24.06 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal formation N, it is characterized in that PXRD collection of illustrative plates is about 7.94,12.67,14.83,16.32,17.16,18.71,21.83,22.44,24.10,24.89,27.97,30.02,30.48 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2
Crystal formation O, it is characterized in that PXRD collection of illustrative plates is about 6.75,8.15,16.29,18.95,22.23,24.52,29.93 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
Crystal form P, it is characterized in that PXRD collection of illustrative plates is about 6.61,8.17,13.34,16.52,20.10,24.97,27.02,33.99,41.06 places in 2 θ values and has diffraction peak, wherein 2 θ value limit of error are 0.2.
1.5 repetitions, amplification test
Further selection crystal form A-P, carries out 100mg respectively according to above-mentioned " 1.2 suspended crystallization method screening " and amplifies revision test, the repeatability of checking crystal formation.The results are shown in following table 6:
Table 6 revision test result
Result shows: crystal form A-F stablizes, and the amplification difficulty that crystal formation G-P has, some appearance turn brilliant phenomenon, are unsuitable for further investigation.
That is, the methods such as comprehensive normal temperature volatilization, suspension crystallization, dilution crystallization carry out crystallization screening to raw material, and by analysing and comparing to collection of illustrative plates after adopting PXRD to characterize, preliminary judgement lobaplatin may exist 16 kinds of crystal form A-P; By repeating, amplifying checking, finally determining that crystal form A-F can repeat better, is relatively stable crystal formation; The yield that other crystal formations have is lower, is difficult to carry out amplification and produces; Some appearance turn brilliant phenomenon, infer that it is unstable crystal formation.Therefore, select crystal form A-F, investigate further comprehensively.
Embodiment two: the preparation of the lobaplatin new crystal of called after crystal C
Preparation example 1
A, prepare lobaplatin dihydrate: take lobaplatin trihydrate 2g in container, add 30ml toluene, stir 48h in room temperature low suspension, filter, with washed with diethylether, after vacuum-drying white powder 1.73g, be lobaplatin dihydrate;
B, preparation target crystal formation: the lobaplatin dihydrate 1g taking step a gained, is placed in container, adds 15ml isopropylcarbinol, stir 50h in room temperature low suspension, crystallization, filters to isolate this crystallization, with washed with diethylether, obtain white powder 0.64g after vacuum-drying, be the new crystal C of lobaplatin.
Preparation example 2
A, prepare lobaplatin dihydrate: take lobaplatin trihydrate 2g in container, add 15ml methyl tertiary butyl ether, stir 48h in room temperature low suspension, filter, with washed with diethylether, after vacuum-drying white powder 1.84g, be lobaplatin dihydrate;
B, preparation target crystal formation: the lobaplatin dihydrate 1g taking step a gained, is placed in container, adds 20ml isopropylcarbinol, stir 48h in room temperature low suspension, crystallization, filters to isolate this crystallization, with washed with diethylether, obtain white powder 0.68g after vacuum-drying, be the new crystal C of lobaplatin.
Preparation example 3
A, prepare lobaplatin dihydrate: take lobaplatin trihydrate 2g in container, add 20ml butylacetate, stir 50h in room temperature low suspension, filter, with washed with diethylether, after vacuum-drying white powder 1.68g, be lobaplatin dihydrate;
B, preparation target crystal formation: the lobaplatin dihydrate 1g taking step a gained, is placed in container, adds 25ml isopropylcarbinol, stir 45h in room temperature low suspension, crystallization, filters to isolate this crystallization, with washed with diethylether, obtain white powder 0.67g after vacuum-drying, be the new crystal C of lobaplatin.
Preparation example 4
A, prepare lobaplatin dihydrate: take lobaplatin trihydrate 2g in container, add 25ml1,4-dioxane, stir 45h in room temperature low suspension, filter, with washed with diethylether, after vacuum-drying white powder 1.76g, be lobaplatin dihydrate;
B, preparation target crystal formation: the lobaplatin dihydrate 1g taking step a gained, is placed in container, adds 30ml isopropylcarbinol, stir 46h in room temperature low suspension, crystallization, filters to isolate this crystallization, with washed with diethylether, obtain white powder 0.65g after vacuum-drying, be the new crystal C of lobaplatin.
Preparation example 5
A, prepare lobaplatin dihydrate: take lobaplatin trihydrate 2g in container, add 30ml normal heptane, stir 45h in room temperature low suspension, filter, with washed with diethylether, after vacuum-drying white powder 1.75g, be lobaplatin dihydrate;
B, preparation target crystal formation: the lobaplatin dihydrate 1g taking step a gained, is placed in container, adds 30ml n-propyl alcohol, stir 46h in room temperature low suspension, crystallization, filters to isolate this crystallization, with washed with diethylether, obtain white powder 0.67g after vacuum-drying, be the new crystal C of lobaplatin.
Preparation example 6
A, prepare lobaplatin dihydrate: take lobaplatin trihydrate 2g in container, add 15ml ether, stir 45h in room temperature low suspension, filter, with washed with diethylether, after vacuum-drying white powder 1.78g, be lobaplatin dihydrate;
B, preparation target crystal formation: the lobaplatin dihydrate 1g taking step a gained, is placed in container, adds 15ml n-propyl alcohol, stir 46h in room temperature low suspension, crystallization, filters to isolate this crystallization, with washed with diethylether, obtain white powder 0.65g after vacuum-drying, be the new crystal C of lobaplatin.
The sample that in each embodiment 1-6, step a) prepares above according in above-described embodiment one 1.4 method carry out XRD diffraction after, the crystal formation being accredited as 6 kinds of samples is identical, and this crystal formation is A, and its appraising datum is as follows.
This crystal formation is the lobaplatin dihydrate of A, and have with the absorption peak of feature shown in following table 7, its diffraction spectrogram as shown in Figure 4.
Table 7 crystal formation is lobaplatin dihydrate X-ray diffraction (PXRD) measurement result of A
| Peak sequence | Diffraction angle 2 θ value (about) | Crystal face is apart from d (about) | Relative intensity (about) |
| 1 | 11.04 | 8.01 | 66.9 |
| 2 | 12.32 | 7.18 | 86.3 |
| 3 | 12.61 | 7.01 | 51.3 |
| 4 | 13.85 | 6.39 | 22.2 |
| 5 | 15.14 | 5.85 | 100 |
| 6 | 15.55 | 5.69 | 17.4 |
| 7 | 16.68 | 5.31 | 35 |
| 8 | 17.67 | 5.02 | 54.5 |
| 9 | 19.03 | 4.66 | 4.8 |
| 10 | 20.06 | 4.42 | 16.8 |
| 11 | 21.00 | 4.23 | 75.9 |
| 12 | 22.68 | 3.92 | 25.4 |
| 13 | 22.92 | 3.88 | 28.2 |
| 14 | 23.76 | 3.74 | 2 |
| 15 | 25.58 | 3.48 | 7.8 |
| 16 | 26.77 | 3.33 | 37.4 |
| 17 | 27.00 | 3.30 | 22.9 |
| 18 | 27.71 | 3.22 | 8.3 |
| 19 | 28.13 | 3.17 | 19.2 |
| 20 | 29.71 | 3.00 | 8.4 |
| 21 | 31.42 | 2.84 | 33.5 |
| 22 | 31.94 | 2.80 | 25.1 |
| 23 | 32.89 | 2.72 | 8.9 |
| 23 | 34.60 | 2.59 | 17.3 |
| 25 | 36.93 | 2.43 | 10.3 |
| 26 | 37.66 | 2.39 | 7.3 |
| 27 | 40.78 | 2.21 | 12.3 |
| 28 | 43.41 | 2.08 | 9.8 |
In PXRD collection of illustrative plates, its characteristic peak is as follows: being about 11.04,12.32,12.61,13.85,15.14,15.55,16.68,17.67,17.86,19.03,20.06,21.00,22.68,22.92,23.76,25.39,25.58,26.37,26.77,27.00,27.71,28.13,29.71,31.42,31.94,32.89,34.29,34.60,36.10,36.93,37.66,40.78,43.41 places in 2 θ values has diffraction peak, and wherein 2 θ value limit of error are 0.2;
By carrying out the experiment of X-ray single crystal diffraction, crystal is water white transparency column, belongs to rhombic system, and spacer is P2
12
12
1, unit cell parameters: a=10.601 (2), b=14.020 (3), c=9.759 (2)
α=β=γ=90.0 °, unit cell volume V=1450.5 (5)
asymmetry unit number Z=4 in structure cell;
Diffracted intensity data are collected, CuK with BrukerSMARTAPEX-II diffractometer
αradiation, graphite monochromator, single conduit diameter ф=0.50mm, crystal and ccd detector distance d=60.3mm, pipe pressure 40kV, pipe stream 30mA, scan mode: φ/ω scans, collecting that total diffraction counts is 5844, and it is 2376 that independent diffraction is counted, observable is counted (| F|2>=2 σ | F|2) be 2376.
Direct method (Shelxs97) is adopted to resolve crystalline structure, whole 17 non-hydrogen atom positions can be obtained, use least-squares refinement structural parameter and differentiate atomic species, geometric calculation and difference Fourier method is used to obtain whole hydrogen atom position, final Reliability factor R1=0.0569, wR
2=0.1491 (w=1/ σ | F|
2), S=1.077.Finally determine that stoichiometric equation is C
9h
18n
2o
3pt2H
2o, calculating molecular weight is 433.36, calculates crystalline density 1.975g/cm
3.Can determine that the lobaplatin new crystal obtained is lobaplatin dihydrate through structure elucidation, its molecular structure is as shown in the formula shown in (2):
This crystal formation be the molecule stereo structure sciagraph of the lobaplatin dihydrate of A as shown in Figure 5.
In addition, this crystal formation be A lobaplatin dihydrate by manufacturer be NETZSCH, model is that the differential thermal analyzer of NETZSCHDSC204F1, NETZSCHTG209F1 carries out differential thermal analysis (DSC-TGA), as shown in Figure 6, TGA figure as shown in Figure 7 for DSC figure.Result shows, and measures with DSC, with peak-peak assessment, and fusing point T
m.p..=220 ± 5 DEG C, heating rate: 10 DEG C/minute.Be specially: DSC collection of illustrative plates has a wide endotherm(ic)peak at about 117 DEG C, judge in conjunction with monocrystalline and TGA data, this peak may produce for losing 2 crystal water; Have an exothermic peak at 220 ± 5 DEG C, judge in conjunction with TGA and European patent EP 0611303 melting point data, this peak is fusion and decomposition peak.TGA collection of illustrative plates had the weightlessness of 9.49% before 150 DEG C, was indicated as and lost 2 crystal water generations.
On the other hand, to step b in embodiment 1-6 above) in the final sample for preparing, according in above-described embodiment one 1.4 method carry out XRD diffraction after, its characteristic peak is as follows: be that 6.79,8.07,12.24,12.61,13.50,16.50,17.83,18.32,18.79,20.09,21.64,22.27,23.19,24.73,27.34,28.35,29.12,31.92 places have diffraction peak in 2 θ angle value in PXRD collection of illustrative plates, wherein 2 θ value limit of error are 0.2.By this crystal formation called after C type.
Embodiment three: product property measures and comparative analysis
1, test sample
Sample 1-6: embodiment of the present invention 1-6 preparation method obtains;
Comparative sample 1: adopt the lobaplatin that patent EP0324154 embodiment 1a method is obtained, concrete preparation method is as follows:
3.8g (0.01mol) cis-[anti-form-1, two (methylamine)-N, the N' of 2-cyclobutyl]-dichloro platinum (II) is suspended in 20ml water, is heated to 40 DEG C, adds 3.39g (0.02mol) Silver Nitrate wherein.Stir after 1.5 hours, in refrigerator cooling, the silver nitride precipitation that filtering is separated out, and use 10ml water washing, filtrate, by containing 100ml basic ion exchange column, uses 150ml water washing.Then be added drop-wise in the Pfansteihl of 4.5g (0.01mol, 20% aqueous solution).Reaction mixture, after 3 days, concentrates by stirred at ambient temperature, after to be dissolved in methyl alcohol and to add gac and stir decolouring.Again by gac elimination, add ether in filtrate, rapid concentration obtains solid, is unformed shape lobaplatin.
Comparative sample 2: adopt the lobaplatin trihydrate that patent EP0611303 embodiment method is obtained, concrete preparation method is as follows:
3.8g (0.01mol) cis-[anti-form-1, two (methylamine)-N, the N' of 2-cyclobutyl]-dichloro platinum (II) is suspended in 20ml water, is heated to 40 DEG C, adds 3.39g (0.02mol) Silver Nitrate wherein.Stir after 1.5 hours, in refrigerator cooling, the silver nitride precipitation that filtering is separated out, and use 10ml water washing, filtrate, by containing 100ml basic ion exchange column, uses 150ml water washing.Then be added drop-wise in the Pfansteihl of 4.5g (0.01mol, 20% aqueous solution).Reaction mixture, after 3 days, is concentrated into about 20ml by stirred at ambient temperature, places and spend the night in refrigerator.The crystallization that suction strainer is separated out, filtrate concentrates, and refrigerator is placed and spent the night, crystallization again, then filters collection, and after merging crystallization, with 20ml water/acetone (1/1, V/V) recrystallization, gained crystal is lobaplatin trihydrate.
2, identification of morphology
Comparative sample 1: the lobaplatin obtained is amorphous state;
Comparative sample 2: pass through X-ray diffraction, PXRD collection of illustrative plates is about 6.71,8.35,12.89,15.14,16.74,17.45,19.01,19.40,22.07,22.76,23.16,24.30,25.21,25.74,27.08,30.26,30.79 places in 2 θ values diffraction peak, its 2 θ value limit of error is less than 0.2, and describing its fusing point in patent EP0611303 is 210 DEG C (decomposition);
Inventive samples 1-6: pass through X-ray diffraction, PXRD collection of illustrative plates is about 6.79,8.07,12.24,12.61,13.50,16.50,17.83,18.32,18.79,20.09,21.64,22.27,23.19,24.73,27.34,28.35,29.12,31.92 places in 2 θ values diffraction peak, and its 2 θ value limit of error is less than 0.2; DSC collection of illustrative plates is presented at 228 ± 5 DEG C of places exothermic peak, and judge in conjunction with TGA and document melting point data, this peak is fusion and decomposition peak, shows that sample 1-6 is same crystal formation, is also the new crystal C of lobaplatin.
3, solubleness is investigated
Compound concentration is the lobaplatin trihydrate reference substance solution of 60 μ g/ml, 80 μ g/ml, 200 μ g/ml, 400 μ g/ml, 800 μ g/ml respectively, typical curve is made by HPLC legal system, gained typical curve equation is Y=4.8641X+20.5794, R=0.9998.The sample 1 of lobaplatin new crystal and comparative sample 2 are made saturated aqueous solution (suspension), and put 25 DEG C of shaking table concussion 6h, then filter, dilution suitable multiple, carries out HPLC analysis.Solubility results is as following table 8:
Table 8 solubleness investigates result
| Crystal formation | Sample 1 | Comparative sample 1 |
| Solubleness (mg/ml) | 19.8169 | 10.3271 |
Result shows: the lobaplatin compound dissolution that the present invention obtains is better than lobaplatin trihydrate.
4, lobaplatin new crystal quality versus research
The each 20mg of sample thief 1-6, comparative sample 1-2, with product moisture, foreign matter content, active component content, yield etc. for index, investigates quality product and yield.The results are shown in following table 9:
Table 9 lobaplatin new crystal quality versus studies
The above results shows, compared with lobaplatin anhydride and lobaplatin trihydrate, the lobaplatin new crystal C that the present invention obtains has the advantages that content is high, impurity is low, yield is good.
Note 1: content assaying method: according to high effective liquid chromatography for measuring: chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica, with potassium dihydrogen phosphate: acetonitrile=92:8 is moving phase, determined wavelength is 210nm, column temperature 40 DEG C, number of theoretical plate calculates by lobaplatin peak and should mend lower than 1000, and lobaplatin peak and impurity peaks resolution meet the requirements; The preparation of reference substance solution: get lobaplatin trihydrate reference substance 10mg, accurately weighedly puts in 50ml measuring bottle, is diluted with water to scale, shakes up and get final product; The preparation of need testing solution: each 20mg of sample thief, accurately weighed, put respectively in 100ml measuring bottle, be diluted with water to scale, shake up and get final product; Measure and result: precision measures reference substance and each 10 μ l of sample solution, respectively injection liquid chromatography, record color atlas, by external standard method with calculated by peak area, calculate and get final product by anhydride, standard range is 97.0%-102%.
Note 2: determination of foreign matter method: with thin-layer chromatography measure lobaplatin, 1,2-diaminomethyl tetramethylene (CBMA), lactic acid etc. known with the foreign matter content of the unknown.Developping agent: ethanol: chloroform: 25% ammoniacal liquor: water=53:39:15:1.5 (volume ratio), thin layer chromatography board: silica gel 60F
25410 × 10 thin layer plates.After expansion to iodine vapor with 0.3% ninhydrin reagent and NDMA reagent colour development, check impurity CBMA and unknown impuritie.
Note 3: moisture determination method: adopt KarlFischer method to measure.Dihydrate moisture content theoretical amount is 8.77%, and trihydrate moisture content theoretical amount is 11.96%.
5, study on the stability
The sample 1 embodiment of the present invention obtained, comparative sample 2 are placed in 60 DEG C of baking ovens respectively, relative humidity be about the environment of 95% under, illumination is about in the light stability test case (thermostat container of routine of band lighting function) of 4500lux, after 5 days, 10 days, PXRD test and HPLC analysis are carried out in sample taking-up, to investigate sample stability under the high temperature conditions.The results are shown in following table 10:
Table 10 estimation of stability result
Above-mentioned test-results shows, lobaplatin of the present invention is new crystal, solubleness higher than lobaplatin trihydrate, yield and purity ideal, from high temperature, high humidity, illumination investigate result, lobaplatin new crystal good stability, occur without turning brilliant phenomenon, HPLC result shows that active constituent content is better than lobaplatin trihydrate, and considerable change does not occur, illustrate that lobaplatin new crystal stability of the present invention is better than existing lobaplatin, not easily deliquescence become sticky, good fluidity.
Claims (14)
1. a lobaplatin compound crystal, it is characterized in that, its crystal formation is C, PXRD collection of illustrative plates is about 6.79,8.07,12.24,12.61,13.50,16.50,17.83,18.32,18.79,20.09,21.64,22.27,23.19,24.73,27.34,28.35,29.12,31.92 places in 2 θ angle value diffraction peak, and wherein 2 θ value limit of error are 0.2.
2. lobaplatin crystal as claimed in claim 1, is characterized in that, fusing point T
m.p..=228 ± 5 DEG C.
3. prepare the method for lobaplatin crystal described in claim 1 or 2, it is characterized in that, comprise the steps b):
In lobaplatin dihydrate, add isopropylcarbinol or n-propyl alcohol, suspend and stir, crystallization, isolates this crystallization, obtains white powder, be the crystal C of lobaplatin after drying.
4. method as claimed in claim 3, wherein, the preparation method of described lobaplatin dihydrate comprises the steps a):
In lobaplatin trihydrate, add suspension crystallization solvent, suspend and stir, crystallization, after removing solvent, with washed with diethylether, vacuum-drying obtains this lobaplatin dihydrate crystallization.
5. method as claimed in claim 4, wherein, step a) in, described recrystallisation solvent is selected from methyl tertiary butyl ether, toluene, ether, butylacetate, 1,4-dioxane or normal heptane, the mass volume ratio of described lobaplatin trihydrate and recrystallisation solvent is lobaplatin trihydrate: recrystallisation solvent=1:15-30.
6. the method as described in any one of claim 3-5, wherein, step b) in, after isolating crystallization, use washed with diethylether before the drying, described drying is vacuum-drying.
7. the method as described in any one of claim 3-6, wherein, step b) in, described in be suspended in room temperature under carry out, preferably suspend 45-50h.
8. as described in any one of claim 3-7, prepare the method for crystal, it is characterized in that, described step b) in the mass volume ratio of lobaplatin dihydrate and isopropylcarbinol be lobaplatin dihydrate: isopropylcarbinol=1:15-30; The mass volume ratio of lobaplatin dihydrate and n-propyl alcohol is lobaplatin dihydrate: n-propyl alcohol=1:15-30.
9. a pharmaceutical composition, is characterized in that, using the lobaplatin crystal described in claim 1 or 2 as activeconstituents.
10. pharmaceutical composition as claimed in claim 9, is characterized in that, the amount containing lobaplatin crystal in described pharmaceutical composition minimum unit is 5mg, 10mg or 50mg.
11. pharmaceutical compositions as described in claim 9 or 10, it is characterized in that, described pharmaceutical composition is any acceptable pharmaceutical dosage form clinically.
12. pharmaceutical compositions as described in any one of claim 9-11, it is characterized in that, described formulation is freeze-drying preparation for injection.
Lobaplatin crystal described in 13. claims 1 or 2 or the pharmaceutical composition described in any one of claim 9-12 are preparing the application in anticarcinogen.
Lobaplatin crystal described in 14. claims 1 or 2 or the pharmaceutical composition described in any one of claim 9-12, it is used for the treatment of mammary cancer, small cell lung cancer or chronic myelocytic leukemia.
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| CN110790791A (en) * | 2018-08-02 | 2020-02-14 | 贵州益佰制药股份有限公司 | Anhydrous crystal of lobaplatin, preparation method and pharmaceutical application |
| CN113173953A (en) * | 2021-04-12 | 2021-07-27 | 昆明贵研药业有限公司 | Purification method of high-purity lobaplatin trihydrate for preparing antitumor drugs |
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| US5023335A (en) * | 1988-01-09 | 1991-06-11 | Asta Pharma Aktiengesellschaft | 1,2-bis (aminomethyl) cyclobutane-platinum complexes |
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| US4482569A (en) * | 1980-01-03 | 1984-11-13 | Nederlandse Centrale Organisatie Voor Toegepastnatuurweten-Schappelijk Onderzoek | Platinum (IV)-diamine complexes, a process for the preparation of pharmaceutical compositions and a method of treating malignant tumors in mice |
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|---|---|---|---|---|
| CN110790791A (en) * | 2018-08-02 | 2020-02-14 | 贵州益佰制药股份有限公司 | Anhydrous crystal of lobaplatin, preparation method and pharmaceutical application |
| CN113173953A (en) * | 2021-04-12 | 2021-07-27 | 昆明贵研药业有限公司 | Purification method of high-purity lobaplatin trihydrate for preparing antitumor drugs |
| CN113173953B (en) * | 2021-04-12 | 2022-06-10 | 昆明贵研药业有限公司 | Purification method of high-purity lobaplatin trihydrate for preparing antitumor drugs |
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