CN105330702B - A kind of lobaplatin crystal, preparation method and medicinal application - Google Patents
A kind of lobaplatin crystal, preparation method and medicinal application Download PDFInfo
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Abstract
The present invention relates to a kind of lobaplatin crystal, preparation method and medicinal application, the crystal form of the crystal is D, fusing point Tm.p..=218 ± 5 DEG C, there is diffraction maximum at 2 θ angle value is 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 in its X ray powder diffraction PXRD collection of illustrative plates, wherein 2 θ value error ranges are 0.2.The crystal form is that the lobaplatin compound of D is in lobaplatin dihydrate, it is added 1,2 dichloroethanes, suspend stirring at room temperature, and crystallization is precipitated, isolate the crystallization, it is obtained after drying, compared with existing lobaplatin and lobaplatin trihydrate, there is better stability, dissolubility, it is more suitable for preparing various forms of pharmaceutical preparations and storage, use, treating cancer can be preferably applied to and such as treat breast cancer, Small Cell Lung Cancer or chronic myelocytic leukemia.
Description
Technical field
The present invention relates to drug field, more particularly to a kind of novel crystal forms of lobaplatin and preparation method thereof and in drug
Using belonging to pharmaceutical technology field.
Technical background
Lobaplatin (Lobaplatin, D19466) also known as lobaplatin are that the third generation platinum class after cis-platinum, carboplatin is anti-swollen
Tumor medicine, its chemical name is：Cis--[anti-form-1,2- cyclobutane bis- (methylamine)-N, N']-[(2S)-lactic acid-O1, O2]-platinum
(II), molecular formula C9H18N2O3Pt, molecular weight 397.34, shown in chemical structural formula such as following formula (1)：
Lobaplatin has alkanisation, belongs to alkylating agent (broad sense).With good antitumor action, such as in vitro AH135- tumors,
B16- melanomas, colon cancer 115 have good inhibiting effect in body mouse P338 leukaemia etc..The characteristics of lobaplatin is anti-
Cancer activity is strong, and toxicity is low, no cumulative toxicity and renal toxicity, and smaller to bone marrow toxicity, and platelet-free reduces disease, at present
The injection lobaplatin of listing is mainly used for the treatment of breast cancer, Small Cell Lung Cancer and chronic granulocytic leukemia.
The drug original side of grinding is that German Ace reaches Pharmacy stock Co., Ltd (ASTA Medica AG), original patent
EP0324154 describes the preparation method of lobaplatin for the first time.In subsequent patent EP0611303, and disclose the hydration of lobaplatin three
The preparation method of object, the product are by being recrystallized lobaplatin anhydride, forming the crystallization aquatic products containing three hydrones
Object, in that patent, it is indicated that the lobaplatin that the preparation method (embodiment 1a) described in EP0324154 obtains has hygroscopy, is easy
It becomes sticky, it is difficult to preparation be made.
Invention content
The technical problem to be solved by the present invention is to, previous lobaplatin anhydrides there are hygroscopy, be difficult to that preparation, stabilization is made
Property difference problem.A kind of bioavilability of present invention offer is high, stability is good, solubility is high, good fluidity, is not easy moisture absorption change
Viscous, yield and the ideal lobaplatin of purity novel crystal forms.
One skilled in the art will appreciate that same drug, crystal form is different, and bioavilability may also can have difference,
Its stability, mobility, compressibility etc. may also can be different, these physicochemical properties generate certain shadow to the application of drug
It rings.The polymorphic of drug has become drug research process and drug at essential in yield and quality control and detection process
Important component contributes to the research of polymorph in pharmaceuticals the selection of new drug compound bioactivity, helps to provide biology
Availability increases clinical efficacy, contribute to drug administration approach selection and design and pharmaceutical preparation technology parameter really
It is fixed, to improve production quality.
We have invented a kind of novel crystal forms of lobaplatin and preparation method thereof and in drug by continuous Improvement
Application.
Specifically, in order to solve the above technical problem, the present invention provides following technical solutions：
A kind of lobaplatin compound crystal, which is characterized in that its crystal form is D, PXRD collection of illustrative plates 2 θ angle value be 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, there is diffraction maximum at 40.82,43.46, wherein 2 θ value error ranges are 0.2.
Wherein, fusing point Tm.p..=218 ± 5 DEG C.
Wherein the fusing point is measured with DSC, is assessed with peak-peak, the rate of heat addition：10 DEG C/minute.
On the other hand, the present invention also provides a kind of preparation methods of the lobaplatin crystal, which is characterized in that including as follows
Step b)：
In lobaplatin dihydrate, 1,2- dichloroethanes is added, suspend stirring at room temperature, and crystallization is precipitated, isolates this
Crystallization obtains white powder, as the novel crystal forms D of lobaplatin after dry.
Preferably, wherein the preparation method of the lobaplatin dihydrate includes the following steps a)：
Suspension crystallization solvent is added in lobaplatin trihydrate, suspend stirring, and crystallization is precipitated, and after removing solvent, uses ether
Washing, vacuum drying obtain lobaplatin dihydrate crystallization.
Preferably, wherein in step a), the mass volume ratio of the lobaplatin trihydrate and recrystallisation solvent is lobaplatin three
Hydrate：Recrystallisation solvent=1:15-30.
Preferably, wherein in step a), the recrystallisation solvent is selected from methyl tertiary butyl ether(MTBE), toluene, ether, acetic acid fourth
Ester, 1,4- dioxane or normal heptane.
Preferably, wherein in step b), after isolating crystallization, washed before the drying with ether, the drying is true
Sky is dry.
Preferably, wherein in step b), the suspension carries out at room temperature, and preferably suspend 45-50h.
Preferably, wherein the mass volume ratio of lobaplatin dihydrate and 1 in the step b), 2- dichloroethanes is lobaplatin
Dihydrate：Dichloroethanes=1 1,2-:15-30.
On the other hand, the present invention also provides a kind of pharmaceutical compositions, which is characterized in that with foregoing lobaplatin crystal
As active constituent.
Wherein it is preferred to amount containing lobaplatin crystal in described pharmaceutical composition minimum unit be 5mg, 10mg or
50mg。
Preferably, wherein described pharmaceutical composition is any clinically acceptable pharmaceutical dosage form.
Preferably, the dosage form is freeze-drying preparation for injection.
On the other hand, the present invention also provides the lobaplatin crystal or the pharmaceutical composition to prepare anticarcinogen
In application.
On the other hand, the present invention also provides the treating cancers of the lobaplatin crystal or the pharmaceutical composition
Using preferably it is used to treat breast cancer, Small Cell Lung Cancer or chronic granulocytic leukemia.
Raw material lobaplatin trihydrate used is prepared using the method for patent EP0611303 embodiments in the present invention.
Described pharmaceutical composition contains lobaplatin crystal form using lobaplatin crystal form above-mentioned as active constituent in minimum unit
Amount is 5mg, 10mg or 50mg.Medicine can be made with one or more pharmaceutically acceptable carriers or excipient in lobaplatin novel crystal forms
Compositions.Further, described pharmaceutical composition can be made into clinically any pharmaceutical dosage form suitable for raw material, including
Injection type, through non-stomaches such as skin form of administration, respiratory tract administration dosage form, cavity and other body parts mucosal drug delivery dosage forms
Intestinal canal administration dosage form.Preferably injection freeze-dried powder.
The pharmaceutical carrier or excipient can be selected from it is following in it is one or more：Water for injection, mannitol, lactose,
Polyethylene glycols, Tween-80, propylene glycol, tartaric acid, citric acid, ascorbic acid, natrium adetate, mosatil, sulfurous
Sour hydrogen sodium, glucose, sodium chloride, soybean oil, soybean lecithin, yolk phospholipid, Distearoyl Phosphatidylethanolamine, dextrose
Acid anhydride, glycine, glycerine.
The preparation method of above-mentioned composition and preparation is typically the known conventional method of those skilled in the art.The present invention
Lobaplatin crystal form and the lobaplatin agent activity form of listing be all lobaplatin, i.e., anhydrous lobaplatin, therefore the lobaplatin suitable for having listed
All diseases of product treatment.
Lobaplatin, that is, cis--[anti-form-1,2- cyclobutane bis- (methylamine)-N, N']-[(2S)-lactic acid-O1, O2]-platinum (II) belongs to
Alkylating agent, cytotoxic drug, also known as biological alkylating agent (BioalkylatingAgengts), can be formed in vivo carbon just from
Son or other compounds with active electrophilic groups, and then in the large biological molecule (DNA, RNA, enzyme) in cell
Covalent bond occurs for the group (such as amino, sulfydryl, hydroxyl, carboxyl, phosphate etc.) containing abundant electronics, makes its loss of activity
Or DNA molecular is made to be broken, lead to death of neoplastic cells, therefore antitumor activity is strong.Pharmacokinetic shows vein
After injecting lobaplatin, antitumor action is played in the form of total platinum and free platinum in serum, as anhydrous lobaplatin, which plays, effectively to be made
With unrelated with feed states.
The present invention lobaplatin novel crystal forms, be based on amorphous state lobaplatin be easy deliquesce become sticky, stability it is poor, be not easy to store
The defects of and the novel crystal forms developed, have bioavilability high, stability is good, the features such as being not easy to deliquesce, with lobaplatin trihydrate
It compares, it has surprisingly been found that it has solubility high compared to trihydrate, yield and purity is high, stability more preferably advantage.Cause
The exploitation of this novel crystal forms contributes to selection and design and the determination of pharmaceutical preparation technology parameter of drug administration approach,
To improve pharmaceutical production quality.The new lobaplatin compound of the present invention is highly stable at normal temperatures, is not easy the moisture absorption and becomes sticky, flows
Dynamic property is good, and the operability in storage, transport and preparation and processing is substantially better than unformed shape lobaplatin.
Description of the drawings
Fig. 1：The x-ray diffraction pattern of lobaplatin novel crystal forms D；
Fig. 2：The differential thermal analysis DSC figures of lobaplatin novel crystal forms D；
Fig. 3：The differential thermal analysis TGA figures of lobaplatin novel crystal forms D；
Fig. 4：Crystal form is the x-ray diffraction pattern of the lobaplatin dihydrate of A；
Fig. 5：Crystal form is the molecule stereo structure perspective view of the lobaplatin dihydrate of A；
Fig. 6：Crystal form is the differential thermal analysis DSC figures of the lobaplatin dihydrate of A；
Fig. 7：Crystal form is the differential thermal analysis TGA figures of the lobaplatin dihydrate of A.
Specific implementation mode
The present invention provides that a kind of solubility is high, lobaplatin novel crystal forms of excellent in stability, is named as crystal form D.
On the one hand, the present invention provides a kind of lobaplatin novel crystal forms of crystal habit.The Lip river that just preparative separation of the present invention goes out below
Platinum crystal form D is described as follows：
Use manufacturer for the X-ray diffractometer of Bruker, model Bruker D8advance XRD, to lobaplatin
Crystal form D is measured, and determination condition is：CuKa (40kv, 40mA), 2 °/min of sweep speed (2 θ values), 3 ° of scanning range-
45 ° (2 θ values), the absorption peak with following characteristics, see the table below 1, diffracting spectrum is as shown in Figure 1：
X-ray diffraction (PXRD) measurement result of 1 lobaplatin novel crystal forms D of table
| Peak sequence | 2 θ values (about) of the angle of diffraction | Crystal face is away from d (about) | Relative intensity (height is about) |
| 1 | 6.76 | 13.08 | 7 |
| 2 | 11.07 | 7.99 | 40.6 |
| 3 | 12.35 | 7.16 | 56.5 |
| 4 | 12.65 | 6.99 | 91.3 |
| 5 | 13.88 | 6.38 | 11.5 |
| 6 | 15.18 | 5.83 | 100 |
| 7 | 15.56 | 5.69 | 10.5 |
| 8 | 16.68 | 5.31 | 21.9 |
| 9 | 17.70 | 5.01 | 32.8 |
| 10 | 17.90 | 4.95 | 8.2 |
| 11 | 20.08 | 4.42 | 10.3 |
| 12 | 21.02 | 4.22 | 44.2 |
| 13 | 22.70 | 3.91 | 14.5 |
| 14 | 22.92 | 3.88 | 14.2 |
| 15 | 25.41 | 3.50 | 5.8 |
| 16 | 25.64 | 3.47 | 3.7 |
| 17 | 26.41 | 3.37 | 8.6 |
| 18 | 26.79 | 3.33 | 36.4 |
| 19 | 27.02 | 3.30 | 19 |
| 20 | 28.15 | 3.17 | 10.3 |
| 21 | 31.44 | 2.84 | 15.9 |
| 22 | 31.96 | 2.80 | 14 |
| 23 | 32.96 | 2.72 | 8 |
| 24 | 34.34 | 2.61 | 10.8 |
| 25 | 34.62 | 2.59 | 8.5 |
| 26 | 36.93 | 2.43 | 7 |
| 27 | 40.82 | 2.21 | 7.2 |
| 28 | 43.46 | 2.08 | 6 |
The novel crystal forms D of the lobaplatin is NETZSCH, model NETZSCH DSC 204F1, NETZSCH by manufacturer
The differential thermal analyzer of TG209F1 carries out differential thermal analysis (DSC-TGA), and DSC figures are as shown in Fig. 2, TGA figures are as shown in Figure 3.As a result
It has been shown that, is measured with DSC, is assessed with peak-peak, fusing point Tm.p..=218 ± 5 DEG C, the rate of heat addition：10 DEG C/minute.Specially：DSC
Collection of illustrative plates respectively has a wide endothermic peak in 91 DEG C, 113 DEG C or so, judges in conjunction with TGA data, which is to lose solvent to generate；218 ±
5 DEG C have an exothermic peak, judge in conjunction with TGA and 0611303 melting point data of European patent EP, which is fusion and decomposition peak, TGA figures
Spectrum has 9.27% weightlessness before 150 DEG C, judges it for dissolvent residual in conjunction with DSC data.
On the other hand, the present invention, which provides, a kind of preparing lobaplatin novel crystal forms that are simple, easily operated, being suitble to amplification production
Preparation method.
In a kind of preferred embodiment of the present invention, the preparation method of lobaplatin novel crystal forms of the present invention, including such as
Lower step：
A, lobaplatin dihydrate is prepared：Lobaplatin trihydrate is weighed in container, 15-30ml organic solvents are added, in room
Warm low suspension stirs 45-50h, and filtering is washed with ether, and white powder, as lobaplatin dihydrate are obtained after vacuum drying；
Wherein, the organic solvent be selected from methyl tertiary butyl ether(MTBE), toluene, ether, butyl acetate, Isosorbide-5-Nitrae-dioxane or
Normal heptane.
B, target crystal form is prepared：The lobaplatin dihydrate obtained by step a is weighed, is placed in container, 1,2-, bis- chloroethenes are added
Alkane, suspend stirring 45-50h at room temperature, and crystallization is precipitated, filters to isolate the crystallization, is washed with ether, after vacuum drying
White powder, as the novel crystal forms D of lobaplatin.
The mass volume ratio of lobaplatin dihydrate and 1,2- dichloroethanes is lobaplatin dihydrate in the step b：1,2-
Dichloroethanes=1:15-30.
Embodiment
By the following examples come illustrate the present invention lobaplatin crystal form D preparation method and each novel crystal forms sieve
Select separation process and its identification and performance measurement.
Embodiment one：The screening of each crystal form is analyzed
The volatilization crystallisation screening of 1.1 room temperature
It takes 20mg lobaplatin trihydrate samples to be put into 10ml sample bottles, 3ml absolute ethyl alcohols or absolute methanol is added, fills
It after dividing dissolving, is placed under 25 DEG C of environment and slowly volatilizees, obtain solid dried object, carry out PXRD measurement.As a result 2 be see the table below：
2 room temperature of table volatilization crystallization trial result
| Number | Solvent | PXRD (possible crystal form number) |
| 1-1 | Absolute ethyl alcohol | B |
| 1-2 | Absolute methanol | B |
The result shows that：The crystal form obtained in absolute methanol and absolute ethyl alcohol learns that it is same crystal form, temporarily through comparing
It is named as crystal form B.
1.2 suspended crystallization methods screen
It takes 20mg lobaplatin trihydrate samples to be put into 10ml sample bottles, the following organic solvents of 4ml is added, are prepared into outstanding
Supernatant liquid is placed under 25 DEG C of environment after shaking 1.5h and removes solvent, and PXRD measurement is carried out after solid drying.As a result 3 be see the table below：
3 suspension crystallization test result of table
The result shows that：Crystal form obtained by suspension crystallization has 9 kinds, is temporarily named as crystal form A, B, C, D, E, G, H, I, L.
1.3 solventing-out process screen
20mg lobaplatin trihydrate samples are taken, is dissolved in 3ml absolute methanols or absolute ethyl alcohol and is configured to solution, Xiang Qi
In be gradually added following organic solvents, until be precipitated solid, remove supernatant, solid drying after carry out PXRD measurement.As a result see
The following table 4：
4 dilution crystallization test result of table
The result shows that：Crystal form obtained by suspension crystallization has 7 kinds, is temporarily named as crystal form F, J, K, M, N, O, P.
The characterization of 1.4 each crystal forms
PXRD measurement and DCS, TGA characterization are carried out to crystal form A-P samples, wherein used each instrument title, model
It is as shown in table 5 below with producer.
Each instrument model when table 5 characterizes crystal form and manufacturer
Measurement result is as follows：
Crystal form A, it is characterised in that PXRD collection of illustrative plates 2 θ values be 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, there is diffraction maximum at 37.66,40.78,43.41, wherein 2 θ value error ranges are 0.2；
Crystal form A, it is characterised in that DSC collection of illustrative plates nearby has exothermic peak at 220 ± 5 DEG C.
Crystal form B, it is characterised in that PXRD collection of illustrative plates 2 θ values be 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、
There is diffraction maximum at 30.61, wherein 2 θ value error ranges are 0.2；
Crystal form B, it is characterised in that DSC collection of illustrative plates nearby has exothermic peak at 230 ± 5 DEG C.
Crystal form C, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 6.79,8.07,12.24,12.61,13.50,16.50,
17.83, have at 18.32,18.79,20.09,21.64,22.27,23.19,24.73,27.34,28.35,29.12,31.92
Diffraction maximum, wherein 2 θ value error ranges are 0.2；
Crystal form C, it is characterised in that DSC collection of illustrative plates nearby has exothermic peak at 228 ± 5 DEG C.
Crystal form D, it is characterised in that PXRD collection of illustrative plates 2 θ values be 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, there is diffraction maximum at 27.02,28.15,31.44,31.96,32.96,34.34,34.62,36.93,40.82,43.46,
Wherein 2 θ value error ranges are 0.2；
Crystal form D, it is characterised in that DSC collection of illustrative plates nearby has exothermic peak at 218 ± 5 DEG C.
Crystal form E, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 6.61,8.09,12.38,13.03,15.40,6.66,
17.47, there is diffraction maximum at 19.07, wherein 2 θ value error ranges are 0.2；
Crystal form E, it is characterised in that DSC collection of illustrative plates nearby has exothermic peak at 214 ± 5 DEG C.
Crystal form F, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 8.21,11.60,12.99,15.24,16.44,7.11,
17.55、18.42、19.01、19.20、19.42、21.81、22.17、22.42、23.33、23.85、 4.18、24.40、
24.77、25.46、25.98、26.13、27.89、28.42、29.03、30.32、31.17、 1.94、33.30、36.20、
37.62, there is diffraction maximum at 39.66, wherein 2 θ value error ranges are 0.2；
Crystal form F, it is characterised in that DSC collection of illustrative plates nearby has exothermic peak at 229 ± 5 DEG C.
Crystal form G, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 8.62,10.82,11.03,12.26,2.59,13.82,
15.12、15.57、16.59、17.43、17.65、18.48、19.46、20.11、20.37、 1.01、22.66、22.86、
24.60、25.40、26.33、26.77、27.00、28.11、29.79、31.42、 1.94、32.87、34.25、34.58、
36.06, there is diffraction maximum at 40.76,42.75,43.39, wherein θ values error range is 0.2.
Crystal form H, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 8.35,8.53,8.68,12.97,15.24,7.41,
18.40, there is diffraction maximum at 19.13,19.48,20.37,24.68,25.41,30.33,31.66,36.34, wherein 2 θ value errors
Ranging from 0.2.
Crystal form I, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 6.75,8.39,11.07,11.59,12.32,2.63,
12.99、15.20、16.80、17.07、17.57、19.14、19.46、21.00、22.13、22.84、 3.29、23.77、
24.22, there is diffraction maximum at 25.82,26.76,28.38,30.34,30.83,31.90,33.63,36.32,8.47, wherein 2 θ
It is 0.2 to be worth error range.
Crystal form J, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 5.94,8.35,9.87,13.05,15.28,6.66,
19.15, there is diffraction maximum at 22.22,22.68,25.09,30.71,33.56, wherein 2 θ value error ranges are 0.2.
Crystal form K, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 8.29,11.02,12.31,12.61,3.84,15.14,
15.53、16.70、17.66、19.05、20.06、20.98、22.68、22.90、25.60、 6.37、26.77、26.98、
27.68、28.23、29.75、31.40、31.88、32.90、33.81、34.29、 4.60、36.10、36.84、37.64、
39.93, there is diffraction maximum at 40.76,41.51,42.36,42.70,43.39, wherein 2 θ value error ranges are 0.2.
Crystal form L, it is characterised in that PXRD collection of illustrative plates 2 θ values be 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, there is diffraction maximum at 27.02,28.73,29.18,29.92,30.56,31.61,33.95,40.33,41.33, wherein 2 θ
It is 0.2 to be worth error range.
Crystal form M, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 8.05,13.03,15.20,16.19,17.47,
18.77, there is diffraction maximum at 19.32,24.06, wherein 2 θ value error ranges are 0.2.
Crystal form N, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 7.94,12.67,14.83,16.32,17.16,
18.71, there is diffraction maximum at 21.83,22.44,24.10,24.89,27.97,30.02,30.48, wherein 2 θ value error ranges are
0.2
Crystal form O, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 6.75,8.15,16.29,18.95,22.23,24.52,
There is diffraction maximum at 29.93, wherein 2 θ value error ranges are 0.2.
Crystal form P, it is characterised in that PXRD collection of illustrative plates 2 θ values be about 6.61,8.17,13.34,16.52,20.10,24.97,
27.02, there is diffraction maximum at 33.99,41.06, wherein 2 θ value error ranges are 0.2.
1.5 repetitions, amplification test
Crystal form A-P is further selected, 100mg amplifications is carried out respectively according to above-mentioned " screening of 1.2 suspended crystallization methods " and repeats to try
It tests, verifies the repeatability of crystal form.As a result 6 be see the table below：
Table 6 repeats test result
The result shows that：Crystal form A-F stablizes, and the amplification that crystal form G-P has is difficult, and some appearance crystal phenomenon are unsuitable for into one
Step is investigated.
That is, the methods of comprehensive room temperature volatilization, suspension crystallization, dilution crystallization carry out crystallization screening to raw material, use
By analysing and comparing to collection of illustrative plates after PXRD characterizations, there may be 16 kinds of crystal form A-P for preliminary judgement lobaplatin；By repeating, putting
Big verification, it is final to determine that crystal form A-F is repeatable preferable, for opposite stable crystal form；The yield that other crystal forms have is relatively low, it is difficult into
Row amplification production；Some appearance crystal phenomenon infer that it is unstable crystal form.Therefore, crystal form A-F is selected, is further carried out complete
It investigates in face.
Embodiment two：It is named as the preparation of the lobaplatin novel crystal forms of crystal form D
Preparation example 1
A, lobaplatin dihydrate is prepared：Lobaplatin trihydrate 2g is weighed in container, 30ml toluene is added, at room temperature
Suspend stirring 48h, and filtering is washed with ether, and white powder 1.73g, as lobaplatin dihydrate are obtained after vacuum drying；
B, target crystal form is prepared：The lobaplatin dihydrate 1g obtained by step a is weighed, is placed in container, 1,2- dichloros are added
Ethane 15ml, suspend stirring 50h at room temperature, and crystallization is precipitated, filters to isolate the crystallization, is washed with ether, after vacuum drying
Obtain white powder 0.65g, as the novel crystal forms D of lobaplatin.
Preparation example 2
A, lobaplatin dihydrate is prepared：Lobaplatin trihydrate 2g is weighed in container, 15ml methyl tertiary butyl ether(MTBE)s are added,
Suspend stirring 48h at room temperature, and filtering is washed with ether, and white powder 1.84g is obtained after vacuum drying, and as lobaplatin two is hydrated
Object；
B, target crystal form is prepared：The lobaplatin dihydrate 1g obtained by step a is weighed, is placed in container, 1,2- dichloros are added
Ethane 20ml, suspend stirring 48h at room temperature, and crystallization is precipitated, filters to isolate the crystallization, is washed with ether, after vacuum drying
Obtain white powder 0.62g, as the novel crystal forms D of lobaplatin.
Preparation example 3
A, lobaplatin dihydrate is prepared：Lobaplatin trihydrate 2g is weighed in container, 20ml butyl acetates are added, in room
Warm low suspension stirs 50h, and filtering is washed with ether, and white powder 1.68g, as lobaplatin dihydrate are obtained after vacuum drying；
B, target crystal form is prepared：The lobaplatin dihydrate 1g obtained by step a is weighed, is placed in container, 1,2- dichloros are added
Ethane 25ml, suspend stirring 45h at room temperature, and crystallization is precipitated, filters to isolate the crystallization, is washed with ether, after vacuum drying
Obtain white powder 0.61g, as the novel crystal forms D of lobaplatin.
Preparation example 4
A, lobaplatin dihydrate is prepared：Lobaplatin trihydrate 2g is weighed in container, addition 25ml1,4- dioxane,
Suspend stirring 45h at room temperature, and filtering is washed with ether, and white powder 1.76g is obtained after vacuum drying, and as lobaplatin two is hydrated
Object；
B, target crystal form is prepared：The lobaplatin dihydrate 1g obtained by step a is weighed, is placed in container, 1,2- dichloros are added
Ethane 30ml, suspend stirring 46h at room temperature, and crystallization is precipitated, filters to isolate the crystallization, is washed with ether, after vacuum drying
Obtain white powder 0.64g, as the novel crystal forms D of lobaplatin.
Preparation example 5
A, lobaplatin dihydrate is prepared：Lobaplatin trihydrate 2g is weighed in container, 30ml normal heptanes are added, in room temperature
Low suspension stirs 45h, and filtering is washed with ether, and white powder 1.75g, as lobaplatin dihydrate are obtained after vacuum drying；
B, target crystal form is prepared：The lobaplatin dihydrate 1g obtained by step a is weighed, is placed in container, 1,2- dichloros are added
Ethane 30ml, suspend stirring 46h at room temperature, and crystallization is precipitated, filters to isolate the crystallization, is washed with ether, after vacuum drying
Obtain white powder 0.64g, as the novel crystal forms D of lobaplatin.
Preparation example 6
A, lobaplatin dihydrate is prepared：Lobaplatin trihydrate 2g is weighed in container, 15ml ether is added, at room temperature
Suspend stirring 45h, and filtering is washed with ether, and white powder 1.78g, as lobaplatin dihydrate are obtained after vacuum drying；
B, target crystal form is prepared：The lobaplatin dihydrate 1g obtained by step a is weighed, is placed in container, 1,2- dichloros are added
Ethane 30ml, suspend stirring 46h at room temperature, and crystallization is precipitated, filters to isolate the crystallization, is washed with ether, after vacuum drying
Obtain white powder 0.64g, as the novel crystal forms D of lobaplatin.
The sample that step a) is prepared in embodiments above 1-6 is carried out according in above-described embodiment one 1.4 method
After XRD diffractions, the crystal form for being accredited as 6 kinds of samples is identical, which is A, and appraising datum is as follows.
The crystal form is A, and appraising datum is as follows.
The crystal form is the lobaplatin dihydrate of A, the absorption peak with feature shown in following table 7, diffraction spectrogram such as Fig. 4
It is shown.
7 crystal form of table is lobaplatin dihydrate X-ray diffraction (PXRD) measurement result of A
| Peak sequence | 2 θ values (about) of the angle of diffraction | Crystal face is away 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 |
Its characteristic peak is as follows in PXRD collection of illustrative plates：2 θ values be 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, there is diffraction maximum at 37.66,40.78,43.41, wherein 2 θ value error ranges are 0.2；
By carrying out X-ray single crystal diffraction experiment, crystal is in water white transparency column, belongs to rhombic system, space group is
P212121, cell parameter：A=10.601 (2), b=14.020 (3),, α=β=γ=90.0 °, structure cell
VolumeAsymmetry unit number Z=4 in structure cell；
Diffracted intensity data, CuK are collected with Bruker SMART APEX-II diffractometersαRadiation, graphite monochromator are single
Conduit diameter ф=0.50mm, crystal and ccd detector distance d=60.3mm, pipe press 40kV, pipe stream 30mA, scan mode：
φ/ω is scanned, and it is 5844 to collect total diffraction points, and independent diffraction points are 2376, observable points (| F | 2 >=2 σ | F |
2) it is 2376.
Crystal structure is parsed using direct method (Shelxs97), all 17 non-hydrogen atom positions is can get, uses minimum
Square law correcting principle parameter and differentiation atomic species, use geometric calculation and difference Fourier method to obtain whole hydrogen atoms
Position, final Reliability factor R1=0.0569, wR2=0.1491 (w=1/ σ | F |2), S=1.077.It is final to determine stoichiometry
Formula is C9H18N2O3Pt·2H2O, it is 433.36 to calculate molecular weight, calculates crystalline density 1.975g/cm3.It can be true through structure elucidation
Fixed lobaplatin novel crystal forms obtained are lobaplatin dihydrate, shown in molecular structure such as following formula (2)：
The crystal form is that the molecule stereo structure perspective view of the lobaplatin dihydrate of A is as shown in Figure 5.
In addition, the lobaplatin dihydrate that the crystal form is A by manufacturer is NETZSCH, model NETZSCH
The differential thermal analyzer progress differential thermal analysis (DSC-TGA) of DSC204F1, NETZSCH TG209F1, DSC scheme as shown in fig. 6, TGA
Figure is as shown in Figure 7.The results show that being measured with DSC, assessed with peak-peak, fusing point Tm.p..=220 ± 5 DEG C, the rate of heat addition：10
DEG C/minute.Specially：DSC collection of illustrative plates has a wide endothermic peak at 117 DEG C or so, judges in conjunction with monocrystalline and TGA data, which may
It is generated to lose 2 crystallizations water；There is an exothermic peak at 220 ± 5 DEG C, in conjunction with 0611303 melting point data of TGA and European patent EP
Judge, which is fusion and decomposition peak.TGA collection of illustrative plates has 9.49% weightlessness before 150 DEG C, is shown to be and loses 2 crystallization aquatic products
It is raw.
On the other hand, to the sample that is prepared in embodiments above 1-6 according in above-described embodiment one 1.4 side
After method carries out XRD diffractions, the crystal form for being accredited as 6 kinds of samples is identical, and characteristic peak is as follows：In 2 θ angle value in PXRD collection of illustrative plates
For 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, there is diffraction maximum at 36.93,40.82,43.46, wherein 2 θ value error ranges are 0.2.This crystal form is named as D types.
Embodiment three：Product property measures and comparative analysis
1, test specimen
Sample 1-6：1-6 preparation methods of the embodiment of the present invention obtain；
Contrast sample 1：It is as follows using lobaplatin, specific preparation method made from patent EP0324154 embodiment 1a methods：
3.8g (0.01mol) is cis--and [anti-form-1,2- cyclobutyl bis- (methylamine)-N, N']-dichloro platinum (II) is suspended in
In 20ml water, 40 DEG C are heated to, 3.39g (0.02mol) silver nitrate is added thereto.After stirring 1.5 hours, cooled down in refrigerator,
10ml water washings are used in combination in the silver nitride precipitation for filtering out precipitation, and filtrate is by containing 100ml basic ion exchange columns, with 150ml water
Washing.Then it is added drop-wise in the Pfansteihl of 4.5g (0.01mol, 20% aqueous solution).After stirring 3 days at room temperature, reaction is mixed
Object concentrate, after be dissolved in methanol and be added activated carbon stirring decoloration.Activated carbon is filtered off again, ether is added in filtrate, quickly
It is concentrated to give solid, as unformed shape lobaplatin.
Contrast sample 2：Using lobaplatin trihydrate, specific preparation method made from patent EP0611303 embodiment methods
It is as follows：
(3.8g 0.01mol) cis--and [anti-form-1,2- cyclobutyl bis- (methylamine)-N, N']-dichloro platinum (II) is suspended in
In 20ml water, 40 DEG C are heated to, 3.39g (0.02mol) silver nitrate is added thereto.After stirring 1.5 hours, cooled down in refrigerator,
10ml water washings are used in combination in the silver nitride precipitation for filtering out precipitation, and filtrate is by containing 100ml basic ion exchange columns, with 150ml water
Washing.Then it is added drop-wise in the Pfansteihl of 4.5g (0.01mol, 20% aqueous solution).After stirring 3 days at room temperature, reaction is mixed
Object is concentrated into about 20ml, is stood overnight in refrigerator.The crystallization that suction strainer is precipitated, filtrate concentration, refrigerator is stood overnight, and is precipitated
Crystallization, then collection is filtered, it after merging crystallization, is recrystallized with 20ml water/acetone (1/1, V/V), gained crystal is that lobaplatin three is hydrated
Object.
2, Morphological Identification
Contrast sample 1：Obtained lobaplatin is amorphous state；
Contrast sample 2：By X-ray diffraction, PXRD collection of illustrative plates 2 θ values be 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、
There are diffraction maximum, 2 θ value error ranges to be less than 0.2 at 30.79, its fusing point (divides for 210 DEG C described in patent EP0611303
Solution)；
Inventive samples 1-6：By X-ray diffraction, PXRD collection of illustrative plates 2 θ values be 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、
There are diffraction maximum, 2 θ value error ranges to be less than 0.2 at 43.46；DSC collection of illustrative plates, which is shown at 218 ± 5 DEG C, exothermic peak, in conjunction with
TGA and document melting point data judge that the peak is fusion and decomposition peak, show that sample 1-6 is same crystal form, and also as lobaplatin is new
Crystal form D.
3, solubility is investigated
Compound concentration is 60 μ g/ml respectively, the lobaplatin three of 80 μ g/ml, 200 μ g/ml, 400 μ g/ml, 800 μ g/ml are hydrated
Object reference substance solution makes standard curve by HPLC legal systems, and gained calibration curve equation is Y=4.8641X+20.5794, R=
0.9998.Saturated aqueous solution (suspension) is made in the sample 1 of lobaplatin novel crystal forms and contrast sample 2, sets 25 DEG C of shaking table concussions
Then 6h is filtered, dilute suitable multiple, carries out HPLC analyses.Solubility results such as the following table 8：
8 solubility of table investigates result
| Crystal form | Sample 1 | Contrast sample 2 |
| Solubility (mg/ml) | 22.6837 | 10.3271 |
The result shows that：Lobaplatin compound dissolubility produced by the present invention is better than lobaplatin trihydrate.
4, lobaplatin novel crystal forms quality versus studies
Sample 1-6, each 20mg of contrast sample 1-2 are taken, with product moisture, impurity content, active component content, yield etc.
For index, product quality and yield are investigated.As a result 9 be see the table below：
9 lobaplatin novel crystal forms quality versus of table studies
The above results show compared with lobaplatin anhydride and lobaplatin trihydrate, the lobaplatin novel crystal forms C that the present invention obtains
Have the characteristics 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：With octadecylsilane bonded silica
Glue is filler, with potassium dihydrogen phosphate：Acetonitrile=92:8 be mobile phase, Detection wavelength 210nm, 40 DEG C of column temperature, theory
Plate number should be mended by the calculating of lobaplatin peak less than 1000, and lobaplatin peak meets the requirements with impurity peaks separating degree；The preparation of reference substance solution：
Lobaplatin trihydrate reference substance 10mg is taken, it is accurately weighed to set in 50ml measuring bottles, it is diluted with water to scale, shakes up to obtain the final product；Test sample
The preparation of solution：Sample each 20mg is taken, it is accurately weighed, it sets respectively in 100ml measuring bottles, is diluted with water to scale, shake up to obtain the final product；
Measurement and result：Precision measures reference substance and each 10 μ l of sample solution, is injected separately into liquid chromatograph, records chromatogram, presses
External standard method is calculated to obtain the final product with calculated by peak area by anhydride, critical field 97.0%-102%.
Note 2：Determination of foreign matter method：Lobaplatin, 1,2- diaminomethyls cyclobutane (CBMA), lactic acid etc. are measured with thin-layer chromatography
Known and unknown impurity content.Solvent：Ethyl alcohol：Chloroform：25% ammonium hydroxide：Water=53： 39：15：1.5 (volume ratios) are thin
Layer chromatoplate：Silica gel 60F25410 × 10 lamellaes.After expansion in iodine vapor with 0.3% ninhydrin reagent and to nitroso two
Toluidines reagent colour development checks impurity CBMA and unknown impuritie.
Note 3：Determination of moisture method：It is measured using KarlFischer methods.Dihydrate moisture content theoretical amount is
8.77%, trihydrate moisture content theoretical amount is 11.96%.
5, study on the stability
Sample made from the embodiment of the present invention 1, contrast sample 2 are respectively placed in 60 DEG C of baking ovens, relative humidity is about
In the environment of 95%, in the light stability test case (the conventional insulating box with lighting function) that illumination is about 4500lux, respectively
Sample is taken out after 5 days, 10 days and carries out PXRD tests and HPLC analyses, to investigate the stability of sample under the high temperature conditions.
As a result 10 be see the table below：
10 estimation of stability result of table
Above-mentioned test result show lobaplatin of the invention be novel crystal forms, solubility be higher than lobaplatin trihydrate, yield and
Purity is ideal, and from the point of view of result is investigated in high temperature, high humidity, illumination, lobaplatin novel crystal forms stability is good, and no crystal phenomenon occurs,
HPLC and significant change does not occur, illustrates that lobaplatin of the present invention is newly brilliant the result shows that active constituent content is better than lobaplatin trihydrate
Type stability is good.
Claims (21)
1. a kind of lobaplatin compound crystal, which is characterized in that its crystal form be D, PXRD collection of illustrative plates 2 θ angle value be 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, there is diffraction maximum at 43.46, wherein 2 θ value error ranges are 0.2.
2. lobaplatin compound crystal as described in claim 1, which is characterized in that fusing point Tm.p..=218 ± 5 DEG C.
3. the method for preparing lobaplatin compound crystal described in claims 1 or 2, which is characterized in that include the following steps 1)：
In lobaplatin dihydrate, 1,2- dichloroethanes is added, crystallization is precipitated in suspension stirring, isolates the crystallization, is obtained after dry
White powder, as the crystal form D of lobaplatin；
Wherein, the preparation method of the lobaplatin dihydrate includes the following steps a)：
Suspension crystallization solvent is added in lobaplatin trihydrate, suspend stirring, and crystallization is precipitated, and after removing solvent, is washed with ether,
Vacuum drying obtains lobaplatin dihydrate crystallization, and the recrystallisation solvent is selected from methyl tertiary butyl ether(MTBE), toluene, ether, acetic acid
Butyl ester, 1,4- dioxane or normal heptane.
4. method as claimed in claim 3, wherein in step a), the mass body of the lobaplatin trihydrate and recrystallisation solvent
Product is than being lobaplatin trihydrate：Recrystallisation solvent=1:(15-30)g/ml.
5. method as described in claim 3 or 4, wherein in step 1), after isolating crystallization, washed before the drying with ether
It washs, the drying is vacuum drying.
6. method as described in claim 3 or 4, wherein in step 1), the suspension carries out at room temperature.
7. method as claimed in claim 5, wherein in step 1), the suspension carries out at room temperature.
8. method as described in claim 3 or 4, wherein in step 1), described suspend is suspension 45-50h.
9. method as claimed in claim 5, wherein in step 1), described suspend is suspension 45-50h.
10. method as described in claim 3 or 4, wherein lobaplatin dihydrate and 1 in the step 1), 2- dichloroethanes
Mass volume ratio is lobaplatin dihydrate：Dichloroethanes=1 1,2-:(15-30)g/ml.
11. method as claimed in claim 5, wherein lobaplatin dihydrate and 1 in the step 1), the matter of 2- dichloroethanes
Amount volume ratio is lobaplatin dihydrate：Dichloroethanes=1 1,2-:(15-30)g/ml.
12. method as claimed in claim 6, wherein lobaplatin dihydrate and 1 in the step 1), the matter of 2- dichloroethanes
Amount volume ratio is lobaplatin dihydrate：Dichloroethanes=1 1,2-:(15-30)g/ml.
13. the method for claim 7, wherein lobaplatin dihydrate and 1 in the step 1), the matter of 2- dichloroethanes
Amount volume ratio is lobaplatin dihydrate：Dichloroethanes=1 1,2-:(15-30)g/ml.
14. method as claimed in claim 8, wherein lobaplatin dihydrate and 1 in the step 1), the matter of 2- dichloroethanes
Amount volume ratio is lobaplatin dihydrate：Dichloroethanes=1 1,2-:(15-30)g/ml.
15. method as claimed in claim 9, wherein lobaplatin dihydrate and 1 in the step 1), the matter of 2- dichloroethanes
Amount volume ratio is lobaplatin dihydrate：Dichloroethanes=1 1,2-:(15-30)g/ml.
16. a kind of pharmaceutical composition, which is characterized in that using lobaplatin compound crystal as claimed in claim 1 or 2 as activity at
Point.
17. pharmaceutical composition as claimed in claim 16, which is characterized in that contain Lip river in described pharmaceutical composition minimum unit
The amount of platinum compounds crystal is 5mg, 10mg or 50mg.
18. the pharmaceutical composition as described in claim 16 or 17, which is characterized in that described pharmaceutical composition be it is any clinically
Acceptable pharmaceutical dosage form.
19. the pharmaceutical composition as described in claim 16 or 17, which is characterized in that the dosage form of described pharmaceutical composition is injection
Use lyophilized preparation.
20. lobaplatin compound crystal as claimed in claim 1 or 2 or claim 16-19 any one of them pharmaceutical compositions
Application of the object in preparing anticarcinogen.
21. the application described in claim 20, wherein the cancer refers to that breast cancer, Small Cell Lung Cancer or chronic granulocytic are white
Blood disease.
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| CN103467528A (en) * | 2013-08-21 | 2013-12-25 | 江苏奥赛康药业股份有限公司 | Preparation method of lobaplatin |
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| US5023335A (en) * | 1988-01-09 | 1991-06-11 | Asta Pharma Aktiengesellschaft | 1,2-bis (aminomethyl) cyclobutane-platinum complexes |
| CN1120046A (en) * | 1994-04-15 | 1996-04-10 | Asta药物股份公司 | Lobaplatin-Trihydrat |
| CN102020679A (en) * | 2010-11-24 | 2011-04-20 | 贵州益佰制药股份有限公司 | Method for preparing lobaplatin trihydrate by usingoxalate |
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