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WO2015062481A1 - 替莫唑胺晶型及其制备方法 - Google Patents

替莫唑胺晶型及其制备方法 Download PDF

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WO2015062481A1
WO2015062481A1 PCT/CN2014/089713 CN2014089713W WO2015062481A1 WO 2015062481 A1 WO2015062481 A1 WO 2015062481A1 CN 2014089713 W CN2014089713 W CN 2014089713W WO 2015062481 A1 WO2015062481 A1 WO 2015062481A1
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Prior art keywords
temozolomide
crystal form
organic solvent
preparation
ray diffraction
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PCT/CN2014/089713
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English (en)
French (fr)
Inventor
王国成
刘文峥
高愚哲
杨海龙
侯庆伟
张宇
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天士力控股集团有限公司
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Application filed by 天士力控股集团有限公司 filed Critical 天士力控股集团有限公司
Priority to US15/033,242 priority Critical patent/US9714250B2/en
Priority to EP14858428.7A priority patent/EP3064499B1/en
Priority to AU2014344409A priority patent/AU2014344409B2/en
Priority to CA2928958A priority patent/CA2928958C/en
Priority to KR1020167012435A priority patent/KR20160077089A/ko
Priority to NZ719536A priority patent/NZ719536B2/en
Priority to JP2016550921A priority patent/JP2016535090A/ja
Priority to RU2016119773A priority patent/RU2669777C2/ru
Priority to ES14858428T priority patent/ES2827312T3/es
Publication of WO2015062481A1 publication Critical patent/WO2015062481A1/zh
Priority to ZA2016/03637A priority patent/ZA201603637B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of pharmacy, relates to a crystal form of a pharmaceutical compound, and particularly relates to a crystal form of an antitumor drug temozolomide and a preparation method thereof.
  • Temozolomide is an anti-tumor activity of an alkylating agent containing an imidazotetrazine ring. Its chemical structure is as follows:
  • Temozolomide itself is not active and belongs to the prodrug and must be converted to the active compound MITC (5-(3-methyltriazol-1-yl)imidazole-4-amide) by a non-enzymatic route at physiological pH. The latter is further hydrolyzed into active metabolites to visualize antitumor activity.
  • MITC 5-(3-methyltriazol-1-yl)imidazole-4-amide
  • MTIC the anti-tumor activity of MTIC is mainly through the main DNA alkylation (methylation) with the sixth oxygen atom of guanine, and also secondary to the seventh nitrogen atom of guanine. Additional alkylation, therefore, subsequent cytotoxicity is thought to be associated with these abnormally repaired methyl compounds.
  • the temozolomide compound has been synthesized for a long time, but in recent years, its new crystal form has been found to have excellent medicinal value.
  • the preparation method of temozolomide crystal form is disclosed in U.S. Patent No. 5,260,291, which uses acetone and water (3:1), acetone and water ( 1:3) Preparation with water; "China Pharmaceutical Industry” magazine reproduces the method of US Pat. No.
  • US20050187206 discloses a method for preparing various crystal forms of temozolomide using various solvents such as pyridine Preparation of ethanol, acetone, etc.
  • WO2008 111092 discloses a monohydrate of temozolomide using a solvent of acetone and water (3:1)
  • Chinese patent CN201110201186.3 discloses a crystalline form of temozolomide using acetone and acetonitrile. It is prepared by mixing with water.
  • the problem with the above method is that due to the solubility problem of TMZ, the amount of solvent required for dissolution is large, reaching several tens of times or even hundreds of times.
  • the amount of ethanol reaches 270 times (w/v) of TMZ, and The amount of acetone is more than 300 times (w / v); or, although the amount of solvent is more than ten times that of TMZ, the yield is low, which is not suitable for industrial production; in addition, the crystal form prepared by the above method is also unstable.
  • the problem such as in U.S. Patent No. 2,050,187,206, is to convert to crystalline form II, temozolomide Form I, upon heating to about 30 °C.
  • the solvent used in the recrystallization method of the existing temozolomide is lack of specificity, so that the obtained temozolomide crystal form contains a small amount of impurities, which affects the pharmaceutical application.
  • the present invention provides a novel method for preparing a temozolomide crystal form and a crystal form obtained by the method.
  • the method for preparing a crystalline form of temozolomide characterized in that the method comprises the steps of: dissolving temozolomide in dimethyl sulfoxide, and adding a second organic solvent for recrystallization to prepare the temozolomide crystal form
  • the second organic solvent is an alcohol, a ketone, a halogenated hydrocarbon or an ester.
  • the second organic solvent is ethanol, methanol, isopropanol, acetone, dichloromethane, ethyl acetate or ethylene glycol.
  • the preparation method of the temozolomide crystal form of the present invention comprises the steps of: taking temozolomide, adding 7-20 times (w/v) dimethyl sulfoxide, dissolving the temozolomide by stirring and heating, and adding 5-30 times The amount (w/v) of the second organic solvent is stirred, and after cooling, it is stirred and crystallized, filtered, washed with 2-10 times (w/v) of the second organic solvent, and dried under vacuum.
  • the temozolomide crystal form is obtained.
  • the preparation method of the temozolomide crystal form of the present invention more specifically: taking temozolomide, adding 7-15 times (w/v) of dimethyl sulfoxide, stirring and heating to 60-140 ° C to dissolve the temozolomide, Adding 7-20 times (w/v) of the second organic solvent, stirring for 5-15 minutes, cooling to 10-15 ° C, stirring and crystallization for 4 hours, filtering, using 2-5 times ( The second organic solvent of w/v) is washed and vacuum dried to obtain the temozolomide crystal form.
  • the formation of the three crystal forms has no special requirements for the stirring apparatus and the stirring speed, and the stirring apparatus and the stirring speed conventionally used in the preparation of the crystal form may be employed.
  • the crystal forms prepared by the method of the present invention were examined and confirmed to belong to three crystal forms: A crystal form, B crystal form, and C crystal form.
  • the second organic solvent when the second organic solvent is selected from the group consisting of ethanol or methanol, it is judged that the obtained crystal form is the same crystal form, and is named as A crystal form; when the second organic solvent is selected from isopropanol, In the case of acetone, dichloromethane or ethyl acetate, it is judged that the obtained crystal form is the same crystal form and is named as B crystal form; when the second organic solvent is ethylene glycol, the crystal form obtained is named C crystal form.
  • Temperature range room temperature - 300 ° C; heating rate: 10 ° C / min; DTA range: ⁇ 25 ⁇ v.
  • Instrument SHIMADZU FTIR-8400S FT/IR type infrared spectrometer, using the infrared spectrum absorption peak of polystyrene film to correct the wave number of the instrument; Method: KBr tablet method, record the spectrum of 4000-400cm -1 .
  • One embodiment of the present invention consists in that when the second organic solvent is ethanol, the temozolomide crystal form (referred to as A0 crystal form) is obtained, and the powder X-ray diffraction pattern is expressed in degrees of 2 ⁇ at 10.74 ⁇ . 0.2, 14.54 ⁇ 0.2, 26.40 ⁇ 0.2, 28.66 ⁇ 0.2, 29.74 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific X-ray diffraction data are shown in Table 1, and the X-ray diffraction pattern thereof is shown in Fig. 1.
  • thermogravimetry-differential thermal analysis map (TG-DTA) showed that the A0 crystal form had an exothermic peak at 206 °C, as shown in Fig. 8.
  • the infrared absorption spectrum data of the A0 crystal form showed characteristic absorption peaks at 3424.41, 3388.70, 3114.82, 1755.10, 1728.10, 1681.81, 1452.30, 1265.22, 948.91 cm -1 , see FIG.
  • the second organic solvent is methanol
  • the obtained temozolomide crystal form (Form A1) has a powder X-ray diffraction pattern of 2 ⁇ in degrees of 10.72 ⁇ 0.2. 14.58 ⁇ 0.2, 17.90 ⁇ 0.2, 26.44 ⁇ 0.2, 28.68 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific X-ray diffraction data are shown in Table 2, and the X-ray diffraction pattern thereof is shown in Fig. 2.
  • thermogravimetry-differential thermal analysis map (TG-DTA) showed that the A1 crystal form had an exothermic peak at 202 °C, as shown in Fig. 9.
  • thermogravimetry-differential heat data and the infrared absorption data of the A0 crystal form and the A1 crystal form it can be judged that the two crystal forms should be the same crystal form, collectively referred to as the A crystal form.
  • the second organic solvent is isopropanol
  • the temozolomide crystal form (B0 crystal form) obtained has a powder X-ray diffraction pattern expressed in degrees of 2 ⁇ at 7.34 ⁇ 0.2, 14.70 ⁇ 0.2, 22.98 ⁇ 0.2, 23.82 ⁇ 0.2, and 28.10 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific X-ray diffraction data is shown in Table 3, and the X-ray diffraction pattern thereof is shown in Fig. 3.
  • thermogravimetry-differential thermal analysis map (TG-DTA) showed that the B0 crystal form had an exothermic peak at 203 °C, as shown in FIG.
  • the infrared absorption spectrum data of the B0 crystal form showed characteristic absorption peaks at 3388.70, 3114.82, 1758.96, 1681.81, 1452.30, 1265.22, 950.84, and 736.76 cm -1 , as shown in FIG.
  • the second organic solvent is acetone
  • the obtained temozolomide crystal form (B1 crystal form) has a powder X-ray diffraction pattern in degrees of 2 ⁇ of 7.30 ⁇ 0.2. 14.70 ⁇ 0.2, 18.88 ⁇ 0.2, 23.76 ⁇ 0.2, 28.06 ⁇ 0.2, 29.42 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific X-ray diffraction data are shown in Table 4, and the X-ray diffraction pattern thereof is shown in Fig. 4.
  • thermogravimetry-differential thermal analysis map (TG-DTA) showed that the B1 crystal form had an exothermic peak at 202 °C, see Figure 11.
  • the infrared absorption spectrum data of the B1 crystal form showed characteristic absorption peaks at 3388.70, 3114.82, 1758.96, 1728.10, 1681.81, 1452.30, 1265.22, 952.77, and 736.76 cm -1 , as shown in FIG.
  • the second organic solvent is dichloromethane, the temozolomide crystal form (B2 crystal form) obtained, and the powder X-ray diffraction pattern thereof, expressed in degrees of 2 ⁇ at 7.32 Characteristic diffraction peaks were found at ⁇ 0.2, 14.02 ⁇ 0.2, 14.70 ⁇ 0.2, 22.94 ⁇ 0.2, and 23.78 ⁇ 0.2.
  • the specific X-ray diffraction data is shown in Table 5, and the X-ray diffraction pattern thereof is shown in Fig. 5.
  • thermogravimetry-differential thermal analysis map (TG-DTA) showed that the B2 crystal form had an exothermic peak at 205 °C, see Figure 12.
  • the infrared absorption spectrum data of the B2 crystal form showed characteristic absorption peaks at 3388.70, 3114.82, 1758.96, 1735.81, 1731.96, 1677.95, 1452.30, 1265.22, 952.77, and 736.76 cm -1 , as shown in FIG.
  • the second organic solvent is ethyl acetate
  • the obtained temozolomide crystal form (B3 crystal form) has a powder X-ray diffraction pattern expressed in degrees of 2 ⁇ at 7.36 ⁇ 0.2, 14.06 ⁇ 0.2, 14.74 ⁇ 0.2, 23.00 ⁇ 0.2, 23.86 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific X-ray diffraction data is shown in Table 6, and its X-ray diffraction pattern is shown in Fig. 6.
  • thermogravimetry-differential thermal analysis showed that the B3 crystal had an exothermic peak at 200 °C, see Figure 13.
  • the infrared absorption spectrum data of the B3 crystal form showed characteristic absorption peaks at 3388.70, 3114.82, 1751.24, 1735.81, 1728.10, 1674.10, 1452.30, 1265.22, 952.77, 730.97, and 711.68 cm -1 , as shown in FIG.
  • thermogravimetry-differential heat data and infrared absorption data of B0 crystal form, B1 crystal form, B2 crystal form and B3 crystal form it can be judged that the four crystal forms should be the same crystal form, collectively referred to as B. Crystal form.
  • the second organic solvent is ethylene glycol
  • the temozolomide crystal form (C crystal form) obtained has a powder X-ray diffraction pattern expressed in degrees of 2 ⁇ at 11.46 ⁇ 0.2, 13.20 ⁇ 0.2, 19.64 ⁇ 0.2, 24.58 ⁇ 0.2, 28.80 ⁇ 0.2 have characteristic diffraction peaks.
  • the specific X-ray diffraction data are shown in Table 7, and the X-ray diffraction pattern thereof is shown in Fig. 7.
  • thermogravimetry-differential thermal analysis map (TG-DTA) showed that the C crystal form had an exothermic peak at 201 ° C, as shown in FIG.
  • the infrared absorption spectrum data of Form C showed characteristic absorption peaks at 3388.70, 3112.89, 1758.96, 1731.96, 1674.10, 1454.23, 1267.14, 950.84, 736.76, and 698.18 cm -1 , as shown in FIG.
  • the invention also encompasses pharmaceutical compositions, in particular solid pharmaceutical compositions, comprising any of the temozolomide crystalline forms of the invention.
  • the pharmaceutically active substance in the pharmaceutical composition of the present invention is any of the temozolomide crystal forms of the present invention, which may be 0.01-99.99% by weight in the preparation, and the balance being a pharmaceutically acceptable carrier.
  • Preferred in the present invention are solid oral pharmaceutical preparation compositions such as tablets, capsules, granules, pills, dry powders and the like.
  • the pharmaceutical composition of the present invention determines the dosage according to the condition of the patient at the time of use, for example, it can be taken 1-3 times a day.
  • dimethyl sulfoxide is an aprotic polar solvent
  • solubility of temozolomide is large, the amount of the refining solvent is small, and the second organic solvent is added to greatly increase the product yield
  • dimethyl sulfoxide and the second organic solvent have high solubility to organic impurities in temozolomide, and in particular, can remove colored sensitized impurities which are difficult to remove with other solvents, so that the purity of the product is greatly improved;
  • the temozolomide crystal form obtained by the method of the present invention is superior to the prior art in purity and stability.
  • each of the crystal forms of the A crystal form, the B crystal form, and the C crystal form has similar solubility properties.
  • the applicant has selected A0, B0, and C crystal forms for specific description.
  • the solubility test of temozolomide A crystal form (specifically using the A0 crystal form prepared by the method of Example 1) was determined by using dimethyl sulfoxide, methanol, water, glacial acetic acid, 0.1 M HCl, 0.1 M NaOH and ethanol as solvents, respectively.
  • the solubility is shown in Table 8.
  • the solubility test of temozolomide C crystal form was determined by using dimethyl sulfoxide, methanol, water, glacial acetic acid, 0.1 M HCl, 0.1 M NaOH and ethanol as solvents, respectively.
  • the solubility is shown in Table 10.
  • Solvent Sample quantity (mg) Solvent (ml) required to dissolve the test sample Dissolve 1g of solvent required for the test (ml) Solubility Dimethyl sulfoxide 9.95 0.8 80 Slightly soluble Methanol 9.91 8.0 800 Slightly soluble water 10.08 8.0 800 Slightly soluble glacial acetic acid 10.21 3.0 300 Slightly soluble 0.1MHCl 10.11 8.0 800 Slightly soluble 0.1M NaOH 9.97 3.0 300 Slightly soluble Ethanol 10.17 60 6000 Very slightly soluble
  • the determination method of the related substances is as follows: the HPLC method is used for the measurement, and the column is prepared by using octadecylsilane-bonded silica gel as a filler and methanol-0.5% glacial acetic acid solution (10:90) as a mobile phase. Degree elution, detection wavelength is 254 nm.
  • each of the A crystal form, the B crystal form, and the C crystal form has similar stability.
  • the applicant has selected A0, B0, and C crystal forms for specific description.
  • the crystalline form of Mozolamide A (specifically, the A0 crystal form prepared by the method of Example 1) was irradiated under the conditions of a light intensity of 4500 ⁇ 500 Lx, and samples were taken for sampling at 5 and 10 days. The results are shown in Table 11.
  • the crystalline form of Mozolamide A (specifically, the A0 crystal form prepared by the method of Example 1) was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 12.
  • the temozolomide A crystal form (specifically, the A0 crystal form prepared by the method of Example 1) was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 13.
  • the temozolomide A crystal form (specifically, the A0 crystal form prepared by the method of Example 1) was sealed with a polyethylene film bag, and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 6 months, respectively. At the end of the month, samples were taken at the end of the first, second, third, and sixth months. The results are shown in Table 14.
  • the crystalline form of Mozolamide B (specifically, the B0 crystal form prepared by the method of Example 6) was irradiated under the conditions of a light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 15.
  • the crystalline form of Mozolamide B (specifically, the B0 crystal form prepared by the method of Example 6) was placed in a 60 ° C incubator, and samples were taken at 5 and 10 days. The results are shown in Table 16.
  • the temozolomide B crystal form (specifically, the B0 crystal form prepared by the method of Example 6) was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 17.
  • the crystalline form of temozolomide B (specifically, the B0 crystal form prepared by the method of Example 6) was sealed with a polyethylene film bag, and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 6 months, respectively. Samples were taken at the end of the first, second, third, and sixth months. The results are shown in Table 18.
  • the crystalline form of Mozolamide C (specifically, the crystal form C prepared by the method of Example 14) was irradiated under the conditions of a light intensity of 4500 ⁇ 500 Lx, and sampled at 5 and 10 days. The results are shown in Table 19.
  • the crystalline form of Mozolamide C (specifically, Form C prepared by the method of Example 14) was placed in a 60 ° C incubator, and samples were taken at 5 and 10 days. The results are shown in Table 20.
  • the temozolomide C crystal form (specifically, the C crystal form prepared by the method of Example 14) was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 21.
  • the crystalline form of temozolomide C (specifically, the crystal form C prepared by the method of Example 14) was sealed with a polyethylene film bag, and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 6 months, respectively. Samples were taken at the end of the first, second, third, and sixth months. The results are shown in Table 22.
  • Figure 1 is an X-ray diffraction pattern of A0 prepared by using ethanol as a second organic solvent.
  • Figure 2 is an X-ray diffraction pattern of the A1 crystal form prepared by using methanol as the second organic solvent.
  • Figure 3 is a B0 crystal form X-ray diffraction pattern prepared by using isopropanol as the second organic solvent.
  • Figure 4 is a B1 crystal form X-ray diffraction pattern prepared by using acetone as the second organic solvent.
  • Figure 5 is a B-type X-ray diffraction pattern prepared by using dichloromethane as the second organic solvent.
  • Figure 6 is a X-ray diffraction pattern of the B3 crystal form prepared by using ethyl acetate as the second organic solvent.
  • Figure 7 is a X-ray diffraction pattern of Form C prepared by using ethylene glycol as the second organic solvent.
  • Fig. 8 is a thermogravimetric-differential thermal analysis diagram of A0 crystal form prepared by using ethanol as a second organic solvent.
  • Fig. 9 is a thermogravimetric-differential thermal analysis diagram of the A1 crystal form prepared by using methanol as the second organic solvent.
  • Figure 10 is a thermogravimetric-differential thermal analysis diagram of B0 crystal form prepared by using isopropanol as the second organic solvent.
  • Figure 11 is a thermogravimetric-differential thermal analysis diagram of the B1 crystal form prepared by using acetone as the second organic solvent.
  • Figure 12 is a thermogravimetric-differential thermal analysis diagram of the B2 crystal form prepared by using dichloromethane as the second organic solvent.
  • Figure 13 is a thermogravimetric-differential thermal analysis diagram of the B3 crystal form prepared by using ethyl acetate as the second organic solvent.
  • Figure 14 is a thermogravimetric-differential thermal analysis diagram of Form C prepared by using ethylene glycol as the second organic solvent.
  • Figure 15 is an infrared absorption spectrum of A0 crystal form prepared by using ethanol as a second organic solvent.
  • Figure 16 is an infrared absorption spectrum of the A1 crystal form prepared by using methanol as the second organic solvent.
  • Figure 17 is an infrared absorption spectrum of a B0 crystal form prepared by using isopropanol as a second organic solvent.
  • Figure 18 is an infrared absorption spectrum of a B1 crystal form prepared by using acetone as a second organic solvent.
  • Figure 19 is an infrared absorption spectrum of a B2 crystal form prepared by using dichloromethane as a second organic solvent.
  • Figure 20 is an infrared absorption spectrum of a B3 crystal form prepared by using ethyl acetate as a second organic solvent.
  • Figure 21 is an infrared absorption spectrum of Form C prepared by using ethylene glycol as the second organic solvent.
  • the invention is further illustrated by the following examples.
  • the method of the present invention is intended to be illustrative only and not to limit the invention.
  • emozolomide 20 g was placed in a reaction flask, 250 ml of dimethyl sulfoxide was added, and the mixture was stirred and heated to 80 ° C to dissolve it. 300 ml of dichloromethane was added thereto, and the mixture was stirred for 5 minutes, cooled to 10-15 ° C, and stirred for 4 hours. It was filtered, washed with 50 ml of dichloromethane, and dried under vacuum at 45-50 ° C (vacuum degree ⁇ -0.07 Mpa) for 4 hours to obtain 19.1 g of temozolomide B2 crystal form, yield 95.5%.
  • emozolomide 20 g was placed in a reaction flask, 200 ml of dimethyl sulfoxide was added, and the mixture was stirred and heated to 80 ° C to dissolve it. 250 ml of dichloromethane was added thereto, and the mixture was stirred for 5 minutes, cooled to 10-15 ° C, and stirred for 4 hours. Filtration, washing with 60 ml of dichloromethane, drying under vacuum at 45-50 ° C (vacuum degree ⁇ -0.07 Mpa) for 4 hours, and obtaining 19.0 g of temozolomide B2 crystal form, yield 95%.
  • Example 16 Preparation of a Capsule Pharmaceutical Composition Containing Temozolomide A Form (Specific Form A0 Prepared Using the Method of Inventive Example 1)
  • the temozolomide A crystal form, lactose, microcrystalline cellulose, corn starch, sodium carboxymethyl starch were mixed in a high-efficiency wet granulator, and granulated by adding 2% polyvinylpyrrolidone ethanol solution (80%).
  • the wet granules were dried in a fluidized bed and sieved through a 18 mesh sieve.
  • the dry granules were mixed with magnesium stearate and then filled into capsules.
  • Example 17 Preparation of a capsule pharmaceutical composition containing a crystalline form of temozolomide B (specifically using a B0 crystal form prepared according to the method of Example 6 of the present invention)
  • the temozolomide B crystal form, lactose, microcrystalline cellulose, corn starch, sodium carboxymethyl starch were mixed in a high-efficiency wet granulator, and granulated by adding 2% polyvinylpyrrolidone ethanol solution (80%).
  • the wet granules were dried in a fluidized bed and sieved through a 18 mesh sieve.
  • the dry granules were mixed with magnesium stearate and then filled into capsules.
  • Example 18 Preparation of a capsule pharmaceutical composition containing a crystalline form of temozolomide C (specifically using Form C prepared by the method of Example 14 of the present invention)
  • the temozolomide C crystal form, lactose, microcrystalline cellulose, corn starch, sodium carboxymethyl starch were mixed in a high-efficiency wet granulator, and granulated by adding 2% polyvinylpyrrolidone ethanol solution (80%).
  • the wet granules were dried in a fluidized bed and sieved through a 18 mesh sieve.
  • the dry granules were mixed with magnesium stearate and then filled into capsules.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明提供了一种替莫唑胺晶型的新的制备方法以及由该方法所制得的三种替莫唑胺晶型。所述方法包括以下步骤：将替莫唑胺溶于二甲基亚砜中，再加入第二种有机溶剂进行重结晶制备所述替莫唑胺晶型，其中，所述第二种有机溶剂为醇、酮、卤代烃或酯。

Description

替莫唑胺晶型及其制备方法 技术领域
本发明属于药学领域，涉及药物化合物的晶型，特别涉及一种抗肿瘤药物替莫唑胺的晶型及其制备方法。
背景技术
替莫唑胺(Temozolomide，TMZ)是一个具有抗肿瘤活性的、含有咪唑四嗪环的烷化剂类抗肿瘤药物，其化学结构如下：
Figure PCTCN2014089713-appb-000001
替莫唑胺本身并没有活性，属于前体药物，须在生理水平pH下，经非酶途径转化为活性化合物MITC(5-(3-甲基三氮烯-1-基)咪唑-4-酰胺)，后者再进一步水解成活性代谢物，方能显现抗肿瘤活性。理论上，MTIC的抗肿瘤活性主要是通过与鸟嘌呤的第六位氧原子产生主要的DNA烷基化(甲基化)作用，同时也会与鸟嘌呤的第七位氮原子发生次要的附加性烷基化作用，因此，随后发生的细胞毒性被认为是与这些异常修复的甲基化合物有关。
替莫唑胺化合物早已合成，但近年不断发现其新的晶型具有优良的药用价值，例如美国专利US5260291中公开了替莫唑胺晶型的制备方法，为采用丙酮与水(3:1)、丙酮与水(1:3)和水进行制备；《中国医药工业》杂志重现了美国专利US5260291的方法，并报道了相应的数据；US20050187206公开了替莫唑胺多种晶型的制备方法，采用多种溶剂，例如吡啶、乙醇、丙酮等进行制备；WO2008 111092公开了替莫唑胺的一水合物，采用的溶剂为丙酮与水(3:1)进行制备；中国专利CN201110201186.3公开了一种替莫唑胺晶型，采用丙酮、乙腈和水的混合溶剂进行制备。
以上方法存在的问题是由于TMZ的溶解度的问题，溶解需要溶剂量很大，达到几十倍甚至几百倍，例如美国专利US20050187206中，乙醇的用量达到TMZ的270倍(w/v)，而丙酮的用量更是达到了300多倍(w/v)；或者，虽然溶剂量是TMZ的十几倍，但收率低，不适于工业化生产；此外，上述方法制备的晶型也存在不稳定的问题，例如美国专利US20050187206中，在加热到大约30℃的条件下，替莫唑胺晶型I就转化为晶型II。
因此，有必要找到一种稳定的晶型作为药物应用、特别是作为固体药物的有效成分使用。另外，现有替莫唑胺的重结晶方法使用的溶剂缺乏针对性，以致于使得到的替莫唑胺晶型中含有少量杂质，影响了药物应用。
发明内容
为了解决上述问题，本发明提供了一种新的替莫唑胺晶型的制备方法以及由该方法所制得的晶型。
本发明所提供的替莫唑胺晶型的制备方法，其特征在于，所述方法包括以下步骤：将替莫唑胺溶于二甲基亚砜中，再加入第二种有机溶剂进行重结晶制备所述替莫唑胺晶型，其中，所述第二种有机溶剂为醇、酮、卤代烃或酯。优选地，所述第二种有机溶剂为乙醇、甲醇、异丙醇、丙酮、二氯甲烷、乙酸乙酯或乙二醇。
本发明所述的替莫唑胺晶型的制备方法包括以下步骤：取替莫唑胺，加入7-20倍量(w/v)的二甲基亚砜，搅拌加热使所述替莫唑胺溶解，再加入5-30倍量(w/v)的所述第二种有机溶剂，搅拌，降温后，搅拌析晶，过滤，用2-10倍量(w/v)的所述第二种有机溶剂洗涤，真空干燥，得到所述替莫唑胺晶型。
本发明所述的替莫唑胺晶型的制备方法，更具体为：取替莫唑胺，加入7-15倍量(w/v)的二甲基亚砜，搅拌加热至60-140℃使所述替莫唑胺溶解，再加入7-20倍量(w/v)的所述第二种有机溶剂，搅拌5-15分钟，降温到10-15℃后，搅拌析晶4小时，过滤，用2-5倍量(w/v)的所述第二种有机溶剂洗涤，真空干燥，得到所述替莫唑胺晶型。
需要说明的是，本发明制备晶型的方法中，所述三种晶型的形成对于搅拌设备和搅拌速度并没有特殊的要求，可以采用晶型制备中常规采用的搅拌设备和搅拌速度。
用本发明的方法制备得到的晶型经过检测，确认分别属于三种晶型：A晶型、B晶型、C晶型。
其中，当所述第二种有机溶剂选自乙醇或者甲醇时，经判断，得到的晶型为同一种晶型，命名为A晶型；当所述第二种有机溶剂选自异丙醇、丙酮、二氯甲烷或者乙酸乙酯时，经判断，得到的晶型为同一种晶型，命名为B晶型；当所述第二种有机溶剂为乙二醇时，得到的晶型命名为C晶型。
具体实施方式
下面将用具体的参数说明采用本发明的方法得到的各种晶型。本发明中，XRPD、TG-DTA以及IR的测定条件如下：
XRPD：
仪器：Savitzkey-Golay型X射线衍射仪，测试条件：40kv 100mA；
狭缝：DS/SS＝1°，RS＝0.3mm；步长：0.02；靶型：铜靶，
Figure PCTCN2014089713-appb-000002
范围：3-50°；扫描速率：8°/min。
TG-DTA：
仪器：日本理学PTC-10A TG-DTA分析仪；量程：7mg；
温度范围：室温-300℃；升温速率：10℃/min；DTA量程：±25μv。
IR：
仪器：SHIMADZU FTIR-8400S FT/IR型红外光谱仪，用聚苯乙烯薄膜的红外光谱吸收峰对仪器波数进行校正；方法：KBr压片法，记录4000-400cm-1的谱图。
本发明的一种实施方式在于，当所述第二种有机溶剂为乙醇，所制得的替莫唑胺晶型(称为A0晶型)，其粉末X-射线衍射图以度表示的2θ在10.74±0.2、14.54±0.2、26.40±0.2、28.66±0.2、29.74±0.2有特征衍射峰。其具体的X-射线衍射数据如表1，其X-射线衍射图谱见图1。
表1 A0晶型的X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 5.320 16.5976 3
2 10.740 8.2306 49
3 13.060 6.7733 4
4 14.040 6.3026 6
5 14.540 6.0870 100
6 16.180 5.4735 15
7 16.660 5.3169 7
8 17.520 5.0578 4
9 17.880 4.9568 15
10 19.000 4.6670 15
11 19.480 4.5531 5
12 20.580 4.3121 4
13 21.260 4.1757 9
14 21.500 4.1297 14
15 23.640 3.7604 10
16 25.120 3.5421 5
17 26.400 3.3732 31
18 27.060 3.2924 5
19 27.640 3.2247 6
20 28.660 3.1122 33
21 29.440 3.0315 10
22 29.740 3.0016 20
23 30.220 2.9550 8
24 32.200 2.7776 8
25 32.520 2.7510 8
26 33.300 2.6884 4
27 34.460 2.6005 3
28 35.600 2.5198 6
29 36.140 2.4833 4
30 38.220 2.3528 4
31 39.580 2.2751 5
32 40.780 2.2109 4
33 41.740 2.1622 4
34 43.380 2.0842 5
35 44.260 2.0448 9
36 47.700 1.9050 5
37 48.600 1.8718 4
热重-差热分析图谱(TG-DTA)显示，A0晶型在206℃有放热峰，见图8。
A0晶型的红外吸收图谱数据显示，在3423.41、3388.70、3114.82、1755.10、1728.10、1681.81、1452.30、1265.22、948.91cm-1有特征吸收峰，见图15。
本发明的另一种实施方式在于，所述第二种有机溶剂为甲醇，所制得的替莫唑胺晶型(A1晶型)，其粉末X-射线衍射图以度表示的2θ在10.72±0.2、14.58±0.2、17.90±0.2、26.44±0.2、28.68±0.2有特征衍射峰。其具体的X-射线衍射数据如表2，其X-射线衍射图谱见图2。
表2 A1晶型的X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.420 11.9042 2
2 10.720 8.2459 10
3 13.260 6.6716 4
4 14.100 6.2759 6
5 14.580 6.0704 100
6 16.180 5.4735 4
7 16.680 5.3106 4
8 17.560 5.0464 2
9 17.900 4.9513 12
10 18.980 4.6719 7
11 19.480 4.5531 2
12 20.580 4.3121 2
13 21.300 4.1680 5
14 21.520 4.1259 5
15 22.120 4.0153 1
16 23.660 3.7573 5
17 25.120 3.5421 3
18 26.200 3.3985 8
19 26.440 3.3682 17
20 27.100 3.2877 3
21 27.640 3.2247 4
22 28.680 3.1100 15
23 29.480 3.0274 9
24 29.780 2.9976 8
25 30.220 2.9550 5
26 31.340 2.8519 3
27 32.240 2.7743 4
28 32.540 2.7494 3
29 33.360 2.6837 2
30 34.500 2.5975 2
31 35.620 2.5184 3
32 36.160 2.4820 2
33 39.580 2.2751 2
34 40.800 2.2098 2
35 41.760 2.1612 2
36 43.060 2.0989 2
37 47.700 1.9050 3
热重-差热分析图谱(TG-DTA)显示，A1晶型在202℃有放热峰，见图9。
A1晶型的红外吸收图谱数据显示，在3423.41、3388.70、3112.89、1755.10、1728.10、1674.10、1452.30、1265.22、948.91cm-1有特征吸收峰，见图16。
通过比较A0晶型与A1晶型的粉末X-射线衍射数据、热重-差热数据以及红外吸收数据，可以判断二者应为同一种晶型，统称为A晶型。
本发明的另一种实施方式在于，所述第二种有机溶剂为异丙醇，所制得的替莫唑胺晶型(B0晶型)，其粉末X-射线衍射图以度表示的2θ在7.34±0.2、14.70±0.2、22.98±0.2、23.82±0.2、28.10±0.2有特征衍射峰。其具体的X-射线衍射数据如表3，其X-射线衍射图谱见图3。
表3 B0晶型的X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.340 12.0338 92
2 10.800 8.1850 3
3 12.740 6.9427 2
4 14.020 6.3116 19
5 14.700 6.0211 100
6 16.080 5.5073 2
7 17.580 5.0407 3
8 17.920 4.9458 2
9 18.900 4.6915 6
10 19.440 4.5624 9
11 20.640 4.2997 2
12 22.160 4.0081 9
13 22.560 3.9380 4
14 22.980 3.8669 15
15 23.820 3.7324 25
16 24.420 3.6421 5
17 25.940 3.4320 11
18 26.480 3.3632 4
19 28.100 3.1729 24
20 28.740 3.1037 4
21 29.440 3.0315 5
22 29.760 2.9996 5
23 31.000 2.8824 12
24 32.920 2.7185 6
25 33.480 2.6743 9
26 34.000 2.6346 3
27 35.620 2.5184 3
28 37.360 2.4050 11
29 37.980 2.3672 3
30 40.300 2.2361 4
31 45.520 1.9910 8
32 47.480 1.9133 5
33 47.940 1.8960 4
34 48.340 1.8813 4
35 48.780 1.8653 4
热重-差热分析图谱(TG-DTA)显示，B0晶型在203℃有放热峰，见图10。
B0晶型的红外吸收图谱数据显示，在3388.70、3114.82、1758.96、1681.81、1452.30、1265.22、950.84、736.76cm-1有特征吸收峰，见图17。
本发明的另一种实施方式在于，所述第二种有机溶剂为丙酮，所制得的替莫唑胺晶型(B1晶型)，其粉末X-射线衍射图以度表示的2θ在7.30±0.2、14.70±0.2、18.88±0.2、23.76±0.2、28.06±0.2、29.42±0.2有特征衍射峰。其具体的X-射线衍射数据如表4，其X-射线衍射图谱见图4。
表4 B1晶型的X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.300 12.0996 100
2 10.740 8.2306 5
3 11.120 7.9502 3
4 12.680 6.9754 5
5 13.940 6.3476 30
6 14.700 6.0211 78
7 16.080 5.5073 3
8 17.600 5.0350 11
9 17.900 4.9513 4
10 18.880 4.6964 44
11 19.360 4.5810 19
12 20.000 4.4359 7
13 20.660 4.2956 9
14 22.140 4.0117 7
15 22.500 3.9483 11
16 22.880 3.8836 42
17 23.760 3.7417 75
18 24.340 3.6539 12
19 25.860 3.4424 10
20 26.380 3.3757 8
21 27.140 3.2829 4
22 28.060 3.1773 69
23 28.680 3.1100 12
24 29.420 3.0335 44
25 30.960 2.8860 32
26 31.500 2.8378 4
27 32.840 2.7250 6
28 33.140 2.7010 10
29 33.380 2.6821 18
30 33.900 2.6421 7
31 34.540 2.5946 5
32 35.560 2.5225 5
33 37.340 2.4062 10
34 37.640 2.3878 5
35 39.320 2.2895 4
36 40.220 2.2403 6
37 40.800 2.2098 4
38 41.820 2.1582 5
39 42.960 2.1036 5
40 43.540 2.0769 4
41 44.640 2.0282 4
42 45.420 1.9952 6
43 47.400 1.9164 7
44 48.280 1.8835 6
45 48.720 1.8675 5
热重-差热分析图谱(TG-DTA)显示，B1晶型在202℃有放热峰，见图11。
B1晶型的红外吸收图谱数据显示，在3388.70、3114.82、1758.96、1728.10、1681.81、1452.30、1265.22、952.77、736.76cm-1有特征吸收峰，见图18。
本发明的另一种实施方式在于，所述第二种有机溶剂为二氯甲烷，所制得的替莫唑胺晶型(B2晶型)，其粉末X-射线衍射图，以度表示的2θ在7.32±0.2、14.02±0.2、14.70±0.2、22.94±0.2、23.78±0.2有特征衍射峰。其具体的X-射线衍射数据如表5，其X-射线衍射图谱见图5。
表5 B2晶型的X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.320 12.0666 100
2 10.620 8.3234 1
3 12.720 6.9536 2
4 14.020 6.3116 14
5 14.700 6.0211 99
6 17.580 5.0407 3
7 18.900 4.6915 4
8 19.380 4.5764 6
9 22.120 4.0153 8
10 22.940 3.8736 11
11 23.780 3.7386 24
12 24.400 3.6450 5
13 25.880 3.4398 9
14 28.120 3.1707 7
15 29.500 3.0254 4
16 29.880 2.9878 5
17 30.960 2.8860 10
18 32.920 2.7185 7
19 33.420 2.6790 8
20 33.920 2.6406 2
21 35.580 2.5211 2
22 37.340 2.4062 10
23 37.940 2.3696 4
24 40.260 2.2382 3
25 42.880 2.1073 2
26 45.500 1.9919 6
27 47.440 1.9148 4
28 47.920 1.8968 4
29 48.280 1.8835 4
30 48.760 1.8661 3
热重-差热分析图谱(TG-DTA)显示，B2晶型在205℃有放热峰，见图12。
B2晶型的红外吸收图谱数据显示，在3388.70、3114.82、1758.96、1735.81、1731.96、1677.95、1452.30、1265.22、952.77、736.76cm-1有特征吸收峰，见图19。
本发明的另一种实施方式在于，所述第二种有机溶剂为乙酸乙酯，所制得的替莫唑胺晶型(B3晶型)，其粉末X-射线衍射图以度表示的2θ在7.36±0.2、14.06±0.2、14.74±0.2、23.00±0.2、23.86±0.2有特征衍射峰。其具体的X-射线衍射数据如表6，其X-射线衍射图谱见图6。
表6 B3晶型的X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.360 12.0011 100
2 11.200 7.8936 2
3 12.780 6.9210 3
4 14.060 6.2937 38
5 14.740 6.0049 93
6 16.120 5.4938 3
7 17.640 5.0237 5
8 18.940 4.6817 13
9 19.460 4.5577 13
10 20.080 4.4184 3
11 20.740 4.2792 3
12 22.180 4.0046 7
13 22.580 3.9345 6
14 23.000 3.8636 27
15 23.860 3.7263 38
16 24.500 3.6304 8
17 25.940 3.4320 12
18 26.560 3.3533 2
19 28.180 3.1641 21
20 28.800 3.0974 4
21 29.520 3.0234 8
22 31.040 2.8788 18
23 32.960 2.7153 6
24 33.480 2.6743 10
25 34.020 2.6331 3
26 35.660 2.5157 3
27 37.380 2.4038 7
28 37.980 2.3672 3
29 40.320 2.2350 4
30 44.640 2.0282 2
31 45.520 1.9910 5
32 47.480 1.9133 5
33 48.360 1.8805 4
34 48.800 1.8646 4
热重-差热分析图谱(TG-DTA)显示，B3晶型在200℃有放热峰，见图13。
B3晶型的红外吸收图谱数据显示，在3388.70、3114.82、1751.24、1735.81、1728.10、1674.10、1452.30、1265.22、952.77、730.97、711.68cm-1有特征吸收峰，见图20。
通过比较B0晶型与B1晶型、B2晶型、B3晶型的粉末X-射线衍射数据、热重-差热数据以及红外吸收数据，可以判断四者应为同一种晶型，统称为B晶型。
本发明的另一种实施方式在于，所述第二种有机溶剂为乙二醇，所制得的替莫唑胺晶型(C晶型)，其粉末X-射线衍射图以度表示的2θ在11.46±0.2、13.20±0.2、19.64±0.2、24.58±0.2、28.80±0.2有特征衍射峰。具体的X-射线衍射数据如表7，其X-射线衍射图谱见图7。
表7 C晶型的X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 10.860 8.1400 7
2 11.460 7.7151 100
3 12.140 7.2844 7
4 13.200 6.7018 19
5 14.680 6.0293 17
6 15.420 5.7415 4
7 16.260 5.4468 3
8 16.740 5.2917 2
9 17.120 5.1751 3
10 18.040 4.9132 6
11 19.100 4.6428 4
12 19.640 4.5164 22
13 21.540 4.1221 10
14 23.020 3.8603 14
15 23.900 3.7201 9
16 24.580 3.6187 23
17 25.400 3.5037 4
18 26.520 3.3582 10
19 26.860 3.3165 14
20 27.800 3.2065 6
21 28.800 3.0974 20
22 29.980 2.9781 9
23 30.900 2.8915 15
24 31.140 2.8697 10
25 31.480 2.8395 7
26 32.100 2.7861 7
27 33.600 2.6650 3
28 37.940 2.3696 4
29 38.600 2.3306 5
30 39.620 2.2729 3
31 41.340 2.1822 10
32 43.320 2.0869 4
33 43.580 2.0751 9
34 46.380 1.9561 4
35 46.920 1.9349 15
36 49.780 1.8302 5
热重-差热分析图谱(TG-DTA)显示，C晶型在201℃有放热峰，见图14。
C晶型的红外吸收图谱数据显示，在3388.70、3112.89、1758.96、1731.96、1674.10、1454.23、1267.14、950.84、736.76、698.18cm-1有特征吸收峰，见图21。
作为本发明的第二方面，本发明还包括含有本发明任何一种替莫唑胺晶型的药物组合物，特别是固体药物组合物。
本发明的药物组合物中的药物活性物质为本发明任一种替莫唑胺晶型，其在制剂中所占重量百分比可以是0.01-99.99％，其余为药物可接受的载体。
本发明优选的是固体口服用药物制剂组合物，如片剂、胶囊剂、颗粒剂、丸剂、干粉剂等。
本发明的药物组合物在使用时根据病人的情况确定用法用量，如可每日服用1-3次。
本发明的晶型和现有技术相比具有以下优点：
(1)由于二甲基亚砜是非质子极性溶剂，对替莫唑胺溶解度大，精制溶剂用量小，加入所述第二种有机溶剂，使产品收率大幅度提高；
(2)二甲基亚砜和所述第二种有机溶剂对替莫唑胺中的有机杂质溶解度较高，特别是能除掉用其它溶剂不易除去的有色致敏杂质，使产品纯度大幅度提高；
(3)用本发明的方法制得的替莫唑胺晶型，纯度和稳定性等均优于现有技术。
以下通过实验数据说明本发明的有益效果：
一、溶解性试验
需要说明的是，A晶型、B晶型和C晶型中的每一种晶型具有相似的溶解性质。以下，仅仅是为了说明的目的，申请人选用了A0、B0、C晶型进行具体说明。
1、替莫唑胺A晶型(具体使用实施例1的方法制备的A0晶型)溶解性试验，分别以二甲基亚砜、甲醇、水、冰醋酸、0.1MHCl、0.1MNaOH和乙醇作溶剂，测定其溶解度，结果见表8。
表8 替莫唑胺A晶型溶解性试验结果
溶剂 供试品量(mg) 溶解该供试品所需溶剂(ml) 溶解1g供试品所需溶剂(ml) 溶解度
二甲基亚砜 10.10 0.7 70 略溶
甲醇 9.98 7.0 700 微溶
水 9.84 8.0 800 微溶
冰醋酸 10.09 3.0 300 微溶
0.1MHCl 10.13 7 700 微溶
0.1MNaOH 9.95 3 300 微溶
乙醇 10.03 55 5500 极微溶
2、替莫唑胺B晶型(具体使用实施例6的方法制备的B0晶型)溶解性试验，分别以二甲基亚砜、甲醇、水、冰醋酸、0.1MHCl、0.1MNaOH和乙醇作溶剂，测定其溶解度，结果见表9。
表9 替莫唑胺B晶型溶解性试验结果
溶剂 供试品量(mg) 溶解该供试品所需溶剂(ml) 溶解1g供试品所需溶剂(ml) 溶解度
二甲基亚砜 10.07 0.6 70 略溶
甲醇 9.89 9.0 900 微溶
水 10.02 8.0 800 微溶
冰醋酸 9.99 3.0 300 微溶
0.1MHCl 9.93 8 800 微溶
0.1MNaOH 10.05 3 300 微溶
乙醇 10.13 57 5700 极微溶
3、替莫唑胺C晶型(具体使用实施例14的方法制备的C晶型)溶解性试验，分别以二甲基亚砜、甲醇、水、冰醋酸、0.1MHCl、0.1MNaOH和乙醇作溶剂，测定其溶解度，结果见表10。
表10 替莫唑胺C晶型溶解性试验结果
溶剂 供试品量(mg) 溶解该供试品所需溶剂(ml) 溶解1g供试品所需溶剂(ml) 溶解度
二甲基亚砜 9.95 0.8 80 略溶
甲醇 9.91 8.0 800 微溶
水 10.08 8.0 800 微溶
冰醋酸 10.21 3.0 300 微溶
0.1MHCl 10.11 8.0 800 微溶
0.1MNaOH 9.97 3.0 300 微溶
乙醇 10.17 60 6000 极微溶
二、稳定性试验
以下试验中，有关物质的测定方法如下：采用HPLC方法进行测定，色谱柱以十八烷基硅烷键合硅胶为填充剂，以甲醇-0.5％冰醋酸溶液(10:90)为流动相进行等度洗脱，检测波长为254nm。
需要说明的是，A晶型、B晶型和C晶型中的每一种晶型具有相似的稳定性。以下，仅仅是为了说明的目的，申请人选用了A0、B0、C晶型进行具体说明。
1.替莫唑胺A晶型的稳定性
1.1光照射试验
取替莫唑胺A晶型(具体使用实施例1的方法制备的A0晶型)置于光强度4500±500Lx的条件下照射，于5、10天取样检测，结果见表11。
表11 替莫唑胺A晶型强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质
0天 白色粉末 0.35 99.94 未检出
5天 白色粉末 0.33 99.93 未检出
10天 白色粉末 0.39 99.81 未检出
1.2高温试验
取替莫唑胺A晶型(具体使用实施例1的方法制备的A0晶型)置60℃恒温箱中，于5、10天取样检测，结果见表12。
表12 替莫唑胺A晶型高温试验结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质
0天 白色粉末 0.41 99.94 未检出
5天 白色粉末 0.38 99.63 未检出
10天 白色粉末 0.34 99.31 未检出
1.3高湿试验
将替莫唑胺A晶型(具体使用实施例1的方法制备的A0晶型)置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表13。
表13 替莫唑胺A晶型高湿试验结果
时间(天) 外观色泽 吸湿增重(％) 含量(％) 有关物质
0天 白色粉末 0 99.94 未检出
5天 白色粉末 0.32 99.73 未检出
10天 白色粉末 0.51 99.52 未检出
1.4加速试验
替莫唑胺A晶型(具体使用实施例1的方法制备的A0晶型)用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月的月末取样检测，结果见表14。
表14 替莫唑胺A晶型加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.94 未检出
1月 白色粉末 99.81 未检出
2月 白色粉末 99.64 未检出
3月 白色粉末 99.92 未检出
6月 白色粉末 99.62 未检出
结果表明：替莫唑胺A晶型在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、含量和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
2.替莫唑胺B晶型的稳定性
2.1光照射试验
取替莫唑胺B晶型(具体使用实施例6的方法制备的B0晶型)置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表15。
表15 替莫唑胺B晶型强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质
0天 白色粉末 0.38 99.97 未检出
5天 白色粉末 0.33 99.92 未检出
10天 白色粉末 0.29 99.95 未检出
2.2高温试验
取替莫唑胺B晶型(具体使用实施例6的方法制备的B0晶型)置60℃恒温箱中，于5、10天取样检测，结果见表16。
表16 替莫唑胺B晶型高温试验结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质
0天 白色粉末 0.33 99.97 未检出
5天 白色粉末 0.27 99.73 未检出
10天 白色粉末 0.29 99.61 未检出
2.3高湿试验
将替莫唑胺B晶型(具体使用实施例6的方法制备的B0晶型)置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表17。
表17 替莫唑胺B晶型高湿度试验结果
时间(天) 外观色泽 吸湿增重(％) 含量(％) 有关物质
0天 白色粉末 0 99.97 未检出
5天 白色粉末 0.37 99.63 未检出
10天 白色粉末 0.52 99.57 未检出
2.4加速试验
替莫唑胺B晶型(具体使用实施例6的方法制备的B0晶型)用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月月末取样检测，结果见表18。
表18 替莫唑胺B晶型加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.97 未检出
1月 白色粉末 99.71 未检出
2月 白色粉末 99.82 未检出
3月 白色粉末 99.73 未检出
6月 白色粉末 99.85 未检出
结果表明：替莫唑胺B晶型在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、含量和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
3.替莫唑胺C晶型的稳定性
3.1光照射试验
取替莫唑胺C晶型(具体使用实施例14的方法制备的C晶型)置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表19。
表19 替莫唑胺C晶型强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质
0天 白色粉末 0.27 99.91 未检出
5天 白色粉末 0.30 99.90 未检出
10天 白色粉末 0.32 99.96 未检出
3.2高温试验
取替莫唑胺C晶型(具体使用实施例14的方法制备的C晶型)置60℃恒温箱中，于5、10天取样检测，结果见表20。
表20 替莫唑胺C晶型高温试验稳定性结果
时间(天) 外观色泽 干燥失重(％) 含量(％) 有关物质
0天 白色粉末 0.35 99.91 未检出
5天 白色粉末 0.37 99.79 未检出
10天 白色粉末 0.34 99.69 未检出
3.3高湿试验
将替莫唑胺C晶型(具体使用实施例14的方法制备的C晶型)置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表21。
表21 替莫唑胺C晶型高湿度试验稳定性结果
时间(天) 外观色泽 吸湿增重(％) 含量(％) 有关物质
0天 白色粉末 0 99.91 未检出
5天 白色粉末 0.29 99.85 未检出
10天 白色粉末 0.47 99.63 未检出
3.4加速试验
替莫唑胺C晶型(具体使用实施例14的方法制备的C晶型)用聚乙烯薄膜袋密封，置于温度40±2℃、相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月月末取样检测，结果见表22。
表22 替莫唑胺C晶型加速试验结果
试验时间 外观色泽 含量(％) 有关物质
0月 白色粉末 99.91 未检出
1月 白色粉末 99.61 未检出
2月 白色粉末 99.87 未检出
3月 白色粉末 99.93 未检出
6月 白色粉末 99.65 未检出
结果表明：替莫唑胺C晶型在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、含量和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
附图说明
图1为采用乙醇作为第二种有机溶剂制备得到的A0晶型X-射线衍射图。
图2为采用甲醇作为第二种有机溶剂制备得到的A1晶型X-射线衍射图。
图3为采用异丙醇作为第二种有机溶剂制备得到的B0晶型X-射线衍射图。
图4为采用丙酮作为第二种有机溶剂制备得到的B1晶型X-射线衍射图。
图5为采用二氯甲烷作为第二种有机溶剂制备得到的B2晶型X-射线衍射图。
图6为采用乙酸乙酯作为第二种有机溶剂制备得到的B3晶型X-射线衍射图。
图7为采用乙二醇作为第二种有机溶剂制备得到的C晶型X-射线衍射图。
图8为采用乙醇作为第二种有机溶剂制备得到的A0晶型热重-差热分析图。
图9为采用甲醇作为第二种有机溶剂制备得到的A1晶型热重-差热分析图。
图10为采用异丙醇作为第二种有机溶剂制备得到的B0晶型热重-差热分析图。
图11为采用丙酮作为第二种有机溶剂制备得到的B1晶型热重-差热分析图。
图12为采用二氯甲烷作为第二种有机溶剂制备得到的B2晶型热重-差热分析图。
图13为采用乙酸乙酯作为第二种有机溶剂制备得到的B3晶型热重-差热分析图。
图14为采用乙二醇作为第二种有机溶剂制备得到的C晶型热重-差热分析图。
图15为采用乙醇作为第二种有机溶剂制备得到的A0晶型红外吸收图谱。
图16为采用甲醇作为第二种有机溶剂制备得到的A1晶型红外吸收图谱。
图17为采用异丙醇作为第二种有机溶剂制备得到的B0晶型红外吸收图谱。
图18为采用丙酮作为第二种有机溶剂制备得到的B1晶型红外吸收图谱。
图19为采用二氯甲烷作为第二种有机溶剂制备得到的B2晶型红外吸收图谱。
图20为采用乙酸乙酯作为第二种有机溶剂制备得到的B3晶型红外吸收图谱。
图21为采用乙二醇作为第二种有机溶剂制备得到的C晶型红外吸收图谱。
实施例
下面通过实施例来进一步说明本发明。本发明的实施例中的方法仅仅是用于说明本发明，而不是对本发明的限制。
实施例1 替莫唑胺A晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜200ml，搅拌加热到80℃使其溶解，加入乙醇300ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，40ml乙醇洗涤，45-50℃真空(真空度≤-0.07Mpa) 干燥4小时，得替莫唑胺A0晶型16.4g，收率82％。
实施例2 替莫唑胺A晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜140ml，搅拌加热到140℃使其溶解，加入乙醇140ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，60ml乙醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺A0晶型16.0g，收率80％。
实施例3 替莫唑胺A晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜300ml，搅拌加热到60℃使其溶解，加入乙醇400ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，100ml乙醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺A0晶型16.6g，收率83％。
实施例4 替莫唑胺A晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜140ml，搅拌加热到120℃使其溶解，加入甲醇100ml，搅拌10分钟，降温到10-15℃，搅拌析晶4小时。过滤，40ml甲醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺A1晶型16.7g，收率83.5％。
实施例5 替莫唑胺A晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜160ml，搅拌加热到110℃使其溶解，加入甲醇140ml，搅拌10分钟，降温到10-15℃，搅拌析晶4小时。过滤，60ml甲醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺A1晶型16.0g，收率80％。
实施例6 替莫唑胺B晶型的制备
取替莫唑胺10g置于反应瓶中，加入二甲基亚砜80ml，搅拌加热到110℃使其溶解，加入异丙醇200ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，30ml异丙醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B0晶型9.45g，收率94.5％。
实施例7 替莫唑胺B晶型的制备
取替莫唑胺10g置于反应瓶中，加入二甲基亚砜110ml，搅拌加热到80℃使其溶解，加入异丙醇300ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，20ml异丙醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B0晶型9.21g，收率92.1％。
实施例8 替莫唑胺B晶型的制备
取替莫唑胺5g置于反应瓶中，加入二甲基亚砜100ml，搅拌加热到60℃使其溶解，加入丙酮150ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，50ml丙酮洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B1晶型4.1g，收率82％。
实施例9 替莫唑胺B晶型的制备
取替莫唑胺5g置于反应瓶中，加入二甲基亚砜60ml，搅拌加热到70℃使其溶解，加入丙酮100ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，40ml丙酮洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B1晶型4.0g，收率80％。
实施例10 替莫唑胺B晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜250ml，搅拌加热到80℃使其溶解，加入二氯甲烷300ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，50ml二氯甲烷洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B2晶型19.1g，收率95.5％。
实施例11 替莫唑胺B晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜200ml，搅拌加热到80℃使其溶解，加入二氯甲烷250ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，60ml二氯甲烷洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B2晶型19.0g，收率95％。
实施例12 替莫唑胺B晶型的制备
取替莫唑胺10g置于反应瓶中，加入二甲基亚砜80ml，搅拌加热到130℃使其溶解，加入乙酸乙酯200ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，50ml乙酸乙酯洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B3晶型8.2g，收率82％。
实施例13 替莫唑胺B晶型的制备
取替莫唑胺10g置于反应瓶中，加入二甲基亚砜90ml，搅拌加热到110℃使其溶解，加入乙酸乙酯 150ml，搅拌5分钟，降温到10-15℃，搅拌析晶4小时。过滤，40ml乙酸乙酯洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺B3晶型8.0g，收率80％。
实施例14 替莫唑胺C晶型的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜150ml，搅拌加热到120℃使其溶解，加入乙二醇150ml，搅拌15分钟，降温到10-15℃，搅拌析晶4小时。过滤，50ml乙二醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺C晶型18g，收率90％。
实施例15 替莫唑胺C晶型物的制备
取替莫唑胺20g置于反应瓶中，加入二甲基亚砜180ml，搅拌加热到100℃使其溶解，加入乙二醇200ml，搅拌15分钟，降温到10-15℃，搅拌析晶4小时。过滤，70ml乙二醇洗涤，45-50℃真空(真空度≤-0.07Mpa)干燥4小时，得替莫唑胺C晶型17.6g，收率88％。
实施例16 含有替莫唑胺A晶型(具体使用本发明实施例1的方法制备的A0晶型)的胶囊剂药物组合物的制备
1、处方
Figure PCTCN2014089713-appb-000003
2、胶囊剂的制备方法
替莫唑胺A晶型、乳糖、微晶纤维素、玉米淀粉、羧甲基淀粉钠加入高效湿法制粒机中混合，加入2％聚乙烯吡咯烷酮乙醇溶液(80％)制粒。湿颗粒在流化床中干燥，经18目筛整粒。干颗粒中加入硬脂酸镁适当混合后装入胶囊。
实施例17 含有替莫唑胺B晶型(具体使用按照本发明实施例6的方法制备的B0晶型)的胶囊剂药物组合物的制备
1、处方
Figure PCTCN2014089713-appb-000004
2、胶囊剂的制备方法
替莫唑胺B晶型、乳糖、微晶纤维素、玉米淀粉、羧甲基淀粉钠加入高效湿法制粒机中混合，加入2％聚乙烯吡咯烷酮乙醇溶液(80％)制粒。湿颗粒在流化床中干燥，经18目筛整粒。干颗粒中加入硬脂酸镁适当混合后装入胶囊。
实施例18 含有替莫唑胺C晶型(具体使用本发明实施例14的方法制备的C晶型)的胶囊剂药物组合物的制备
1、处方
Figure PCTCN2014089713-appb-000005
Figure PCTCN2014089713-appb-000006
2、胶囊剂的制备方法
替莫唑胺C晶型、乳糖、微晶纤维素、玉米淀粉、羧甲基淀粉钠加入高效湿法制粒机中混合，加入2％聚乙烯吡咯烷酮乙醇溶液(80％)制粒。湿颗粒在流化床中干燥，经18目筛整粒。干颗粒中加入硬脂酸镁适当混合后装入胶囊。

Claims (11)

  1. 一种替莫唑胺晶型的制备方法，其特征在于，所述方法包括以下步骤：将替莫唑胺溶于二甲基亚砜中，再加入第二种有机溶剂进行重结晶制备所述替莫唑胺晶型，其中，所述第二种有机溶剂为醇、酮、卤代烃或酯。
  2. 根据权利要求1所述的制备方法，其特征在于，所述方法包括以下步骤：取替莫唑胺，加入7-20倍量(w/v)的二甲基亚砜，搅拌加热使所述替莫唑胺溶解，再加入5-30倍量(w/v)的所述第二种有机溶剂，搅拌，降温后，搅拌析晶，过滤，用2-10倍量(w/v)的所述第二种有机溶剂洗涤，真空干燥，得到所述替莫唑胺晶型。
  3. 根据权利要求1或2所述的制备方法，其特征在于，所述方法包括以下步骤：取替莫唑胺，加入7-15倍量(w/v)的二甲基亚砜，搅拌加热至60-140℃使所述替莫唑胺溶解，再加入7-20倍量(w/v)的所述第二种有机溶剂，搅拌5-15分钟，降温到10-15℃后，搅拌析晶4小时，过滤，用2-5倍量(w/v)的所述第二种有机溶剂洗涤，真空干燥，得到所述替莫唑胺晶型。
  4. 根据权利要求1至3任一项所述的制备方法，其特征在于，所述第二种有机溶剂为乙醇，所制得的替莫唑胺晶型的粉末X-射线衍射图以度表示的2θ在10.74±0.2、14.54±0.2、26.40±0.2、28.66±0.2、29.74±0.2有特征衍射峰；红外光谱在3423.41、3388.70、3114.82、1755.10、1728.10、1681.81、1452.30、1265.22、948.91cm-1有特征吸收峰；热重-差热分析曲线在206℃有放热峰。
  5. 根据权利要求1至3任一项所述的制备方法，其特征在于，所述第二种有机溶剂为甲醇，所制得的替莫唑胺晶型的粉末X-射线衍射图以度表示的2θ在10.72±0.2、14.58±0.2、17.90±0.2、26.44±0.2、28.68±0.2有特征衍射峰；红外光谱在3423.41、3388.70、3112.89、1755.10、1728.10、1674.10、1452.30、1265.22、948.91cm-1有特征吸收峰；热重-差热分析曲线在202℃有放热峰。
  6. 根据权利要求1至3任一项所述的制备方法，其特征在于，所述第二种有机溶剂为异丙醇，所制得的替莫唑胺晶型的粉末X-射线衍射图以度表示的2θ在7.34±0.2、14.70±0.2、22.98±0.2、23.82±0.2、28.10±0.2有特征衍射峰；红外光谱在3388.70、3114.82、1758.96、1681.81、1452.30、1265.22、950.84、736.76cm-1有特征吸收峰；热重-差热分析曲线在203℃有放热峰。
  7. 根据权利要求1至3任一项所述的制备方法，其特征在于，所述第二种有机溶剂为丙酮，所制得的替莫唑胺晶型的粉末X-射线衍射图以度表示的2θ在7.30±0.2、14.70±0.2、18.88±0.2、23.76±0.2、28.06±0.2、29.42±0.2有特征衍射峰；红外光谱在3388.70、3114.82、1758.96、1728.10、1681.81、1452.30、1265.22、952.77、736.76cm-1有特征吸收峰；热重-差热分析曲线在202℃有放热峰。
  8. 根据权利要求1至3任一项所述的制备方法，其特征在于，所述第二种有机溶剂为二氯甲烷，所制得的替莫唑胺晶型的粉末X-射线衍射图以度表示的2θ在7.32±0.2、14.02±0.2、14.70±0.2、22.94±0.2、23.78±0.2有特征衍射峰；红外光谱在3388.70、3114.82、1758.96、1735.81、1731.96、1677.95、1452.30、1265.22、952.77、736.76cm-1有特征吸收峰；热重-差热分析曲线在205℃有放热峰。
  9. 根据权利要求1至3任一项所述的制备方法，其特征在于，所述第二种有机溶剂为乙酸乙酯，所制得的替莫唑胺晶型的粉末X-射线衍射图以度表示的2θ在7.36±0.2、14.06±0.2、14.74±0.2、23.00±0.2、23.86±0.2有特征衍射峰；红外光谱在3388.70、3114.82、1751.24、1735.81、1728.10、1674.10、1452.30、1265.22、952.77、730.97、711.68cm-1有特征吸收峰；热重-差热分析曲线在200℃有放热峰。
  10. 根据权利要求1至3任一项所述的制备方法，其特征在于，所述第二种有机溶剂为乙二醇，所制得的替莫唑胺晶型的粉末X-射线衍射图以度表示的2θ在11.46±0.2、13.20±0.2、19.64±0.2、24.58±0.2、28.80±0.2有特征衍射峰；红外光谱在3388.70、3112.89、1758.96、1731.96、1674.10、1454.23、1267.14、950.84、736.76、698.18cm-1有特征吸收峰；热重-差热分析曲线在201℃有放热峰。
  11. 根据权利要求10所述的制备方法制备得到的替莫唑胺晶型，其特征在于，所制得的替莫唑胺晶型的粉末X-射线衍射图具有以下特征衍射峰：
    序号 2θ d值 相对强度I/I0 1 10.860 8.1400 7 2 11.460 7.7151 100
    3 12.140 7.2844 7 4 13.200 6.7018 19 5 14.680 6.0293 17 6 15.420 5.7415 4 7 16.260 5.4468 3 8 16.740 5.2917 2 9 17.120 5.1751 3 10 18.040 4.9132 6 11 19.100 4.6428 4 12 19.640 4.5164 22 13 21.540 4.1221 10 14 23.020 3.8603 14 15 23.900 3.7201 9 16 24.580 3.6187 23 17 25.400 3.5037 4 18 26.520 3.3582 10 19 26.860 3.3165 14 20 27.800 3.2065 6 21 28.800 3.0974 20 22 29.980 2.9781 9 23 30.900 2.8915 15 24 31.140 2.8697 10 25 31.480 2.8395 7 26 32.100 2.7861 7 27 33.600 2.6650 3 28 37.940 2.3696 4 29 38.600 2.3306 5 30 39.620 2.2729 3 31 41.340 2.1822 10 32 43.320 2.0869 4 33 43.580 2.0751 9 34 46.380 1.9561 4 35 46.920 1.9349 15 36 49.780 1.8302 5
    其红外光谱在3388.70、3112.89、1758.96、1731.96、1674.10、1454.23、1267.14、950.84、736.76、698.18cm-1有特征吸收峰；热重-差热分析曲线在201℃有放热峰。
PCT/CN2014/089713 2013-10-29 2014-10-28 替莫唑胺晶型及其制备方法 WO2015062481A1 (zh)

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