WO2016127684A1 - 一种泮托拉唑钠化合物新晶型及其制剂和制备方法 - Google Patents

一种泮托拉唑钠化合物新晶型及其制剂和制备方法 Download PDF

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WO2016127684A1
WO2016127684A1 PCT/CN2015/095231 CN2015095231W WO2016127684A1 WO 2016127684 A1 WO2016127684 A1 WO 2016127684A1 CN 2015095231 W CN2015095231 W CN 2015095231W WO 2016127684 A1 WO2016127684 A1 WO 2016127684A1
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pantoprazole sodium
crystal form
product
crystal
preparation
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PCT/CN2015/095231
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English (en)
French (fr)
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郝红勋
陶灵刚
姜琛
王永莉
王静康
吕军
尹秋响
侯宝红
徐昭
谢闯
王召
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天津大学
海南灵康制药有限公司
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Priority to US15/304,861 priority Critical patent/US20170197937A1/en
Publication of WO2016127684A1 publication Critical patent/WO2016127684A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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

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  • the invention belongs to the technical field of medicine separation, and particularly relates to a novel crystal form of a pantoprazole sodium compound and a preparation method thereof.
  • Pantoprazole sodium is a white or off-white crystalline powder that is readily soluble in water or methanol and is almost insoluble in chloroform or diethyl ether.
  • the chemical name of pantoprazole sodium is 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl-1H-benzimidazole sodium salt.
  • the molecular formula is C 16 H 14 F 2 N 3 NaO 4 S, the molecular weight is 405.36, and the structural formula is as shown in formula (I).
  • Pantoprazole sodium is a proton pump inhibitor, which is suitable for the treatment of acute upper gastrointestinal bleeding such as duodenal ulcer, gastric ulcer, acute gastric mucosal lesions, complex gastric ulcer, etc.
  • the main pharmacological effect is through the stomach wall.
  • the proton pump (ie, H+/K+-ATPase) of the cells binds and inhibits gastric acid secretion.
  • Pantoprazole sodium has a crystalline form with a different crystal structure.
  • WO 91/19710 discloses a monohydrate of pantoprazole sodium.
  • W02004100949A discloses complex crystals of pantoprazole sodium, including acetone solvate A1-A4, methyl acetate solvate B1-B3, methyl ethyl ketone solvate C1-C2, diethyl ketone solvent Compound D1.
  • US20040186139 A1 discloses an improved process for the preparation of pantoprazole sodium sesquilate sodium crystals comprising preparing pantoprazole sodium free base and stoichiometric sodium hydroxide in tetrahydrofuran, acetic acid or ethyl acetate solution, adding an anti-solvent, cooling The solution was formed until a precipitate formed and the precipitate was isolated.
  • US20050245578A1 discloses a new crystalline form of pantoprazole sodium monohydrate and monosolvate with a ketone solvent such as acetone, methyl ethyl ketone, diethyl ketone and methyl isobutyl ketone, which is prepared by Pantoprazole sodium is contacted with the above solvent.
  • ZL201110228921.X discloses a pantoprazole sodium crystalline hydrate which is obtained by dissolving pantoprazole sodium powder in a water/methanol mixed solution and then adding diethyl ether. Out of the
  • pantoprazole sodium As a commonly used drug, extensive and intensive research on pantoprazole sodium has been carried out, and some crystalline compounds of pantoprazole sodium have been developed.
  • the crystalline forms of these pantoprazole sodium which have been reported in the patent are mostly in the form of hydrates or solvates, and there is a general problem of poor thermal stability or low crystallinity, in the subsequent preparation or storage process, due to the outside world.
  • the change in conditions makes it difficult to ensure the reduction or removal of the solvent in the hydrate or solvent compound. Therefore, it is possible to cause fluctuations in product quality.
  • the present inventors have found a new crystal form of pantoprazole sodium compound and its corresponding crystal preparation method in production and scientific research practice.
  • the invention discloses a new crystalline form of pantoprazole sodium compound and a preparation method thereof, and the new crystal form is named M crystal form.
  • the new crystalline form of the pantoprazole sodium compound has an X-ray powder diffraction pattern at a diffraction angle of 2 ⁇ of 5.62 ⁇ 0.2, 11.62 ⁇ 0.2, 12.16 ⁇ 0.2, 13.80 ⁇ 0.2, 17.18 ⁇ 0.2, 18.80 ⁇ 0.2. , 21.72 ⁇ 0.2, 23.44 ⁇ 0.2, 25.16 ⁇ 0.2, 26.88 ⁇ 0.2 degrees with characteristic peaks, as shown in Figure 1.
  • the DSC analysis of the crystalline pantoprazole sodium crystal showed an endothermic peak at 192 ⁇ 2 ° C, as shown in FIG. 2 .
  • the crystalline pantoprazole sodium crystal has an appearance of a short and thick rod as shown in FIG.
  • pantoprazole sodium crystal of the present invention is as follows:
  • pantoprazole sodium solid is added to the alcohol solvent to prepare a suspension of 0.05-0.2 g/mL; the antioxidant is added to the suspension, and the solid is completely dissolved at 15 to 35 ° C; under the condition of applying ultrasonic waves
  • the eluent is added dropwise to the solution, and the amount of the eluent is 3 to 10 times the volume of the alcohol solvent; then the temperature is lowered to 0 to 5 ° C, and the stirring is continued for 1 to 3 hours; the suspension formed by suction filtration is 50 to 60 ° C. After drying, a fresh crystalline crystal product of pantoprazole sodium compound is obtained.
  • the alcohol solvent in the method is selected from a mixed solvent of one or more of n-butanol, isobutanol, n-pentanol, isoamyl alcohol or n-hexanol.
  • the antioxidant in the method is selected from one of BHA (butylhydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), TBHQ (te-butyl hydroquinone) or Several mixtures.
  • the amount of the antioxidant in the method is from 0.1% to 0.5% by mass of the pantoprazole sodium added.
  • the leaching agent in the method is selected from a mixed solvent of one or more of n-heptane, n-hexane, n-pentane, cyclohexane, and n-octane.
  • the dropping rate of the dissolution agent in the method is from 0.2% to 2% by volume of the eluting agent per minute.
  • the ultrasonic wave in the method has a frequency of 20 to 50 KHz and a power of 50 to 100 W.
  • the cooling rate of the suspension in the process is 0.2 to 2 ° C / min.
  • the drying conditions in the method are carried out at 50 to 60 ° C under normal pressure for 24 to 48 hours.
  • the pantoprazole sodium compound M crystal form of the present invention is characterized by being free of any crystallizing solvent, and the melting point of the new crystal form product is 192 ⁇ 2 ° C, and the melting point is higher than that of the conventional crystal form.
  • the new crystal form has a short, thick rod shape with higher bulk density and fluidity.
  • the crystal form product has a greater advantage in subsequent preparation processes such as preparation of pantoprazole sodium tablets, powder injections and the like due to the improvement of stability, fluidity and bulk density.
  • the product is also of better quality during filtration, washing, drying, packaging and storage due to the above-mentioned properties.
  • the operating conditions of the preparation method of the new crystalline form of the pantoprazole sodium compound of the invention are simple and easy to control, the product crystal slurry is easy to be filtered, washed and dried, and the single pass molar yield of the crystallization process is above 90%, and the product purity is More than 99%.
  • the toxicity of the pantoprazole sodium new crystalline form compound obtained by the present invention indicates that the toxicity is lower than that of the existing pantoprazole sodium.
  • Figure 1 X-ray powder diffraction pattern of a new crystalline form M of pantoprazole sodium compound
  • Figure 3 Micrograph of a new crystalline form M of pantoprazole sodium compound.
  • the X-ray powder diffraction pattern of the new Form M product is shown in Figure 1. It has characteristic peaks at diffraction angles 2 ⁇ of 5.62, 11.62, 12.16, 13.80, 17.18, 18.80, 21.72, 23.44, 25.16, 26.88 degrees.
  • the DSC analysis of the new crystal form M is shown in Fig. 2. It has a characteristic endothermic peak at 192.61 °C. The product has no change in crystal form, purity and appearance after 15 days at 60 ° C and 90% relative humidity.
  • the crystal form, purity and color of the product did not change; the appearance of the new crystal M product is as shown in Fig. 3, which is short and thick, and has higher bulk density and fluidity.
  • the purity of the new crystalline product obtained by the method is 99.5%, and the single pass molar yield of the crystallization process is higher than 91.2%.
  • pantoprazole sodium solid 2 g was added to 30 mL of isoamyl alcohol to form a suspension, and 0.008 g of equal mass ratio of BHA and BHT was added to the suspension under stirring, and the suspension was heated to 20 ° C to make a solid.
  • the X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2 ⁇ of 5.64, 11.42, 12.18, 13.80, 17.16, 18.82, 21.68, 23.02, 25.18, 26.98 degrees.
  • the DSC analysis of the new crystal form M showed that it has a characteristic endothermic peak at 192.12 ° C.
  • the product has no change in crystal form, purity and appearance after 15 days at 60 ° C and 90% relative humidity. Normal temperature and air humidity conditions After 100 days of storage, the crystal form, purity and color of the product did not change; the new crystal M product showed a short and thick rod shape with higher bulk density and fluidity.
  • the purity of the new crystalline product obtained by the method is 99.3%, and the single pass molar yield of the crystallization process is 91.5%.
  • the crystal slurry was dried at 55 ° C under normal pressure for 30 hours to a constant weight to obtain a M crystalline pantoprazole sodium product.
  • the X-ray powder diffraction pattern of the product had characteristic peaks at diffraction angles 2 ⁇ of 5.74, 11.56, 12.26, 13.92, 17.28, 18.88, 21.78, 23.24, 25.22, 27.08 degrees.
  • the DSC analysis of the new crystal form M shows that it has a characteristic endothermic peak at 192.80 ° C.
  • the product has no change in crystal form, purity and appearance after 15 days at 60 ° C and 90% relative humidity.
  • the crystal form, purity and color of the product did not change; the new crystal M product showed a short and thick rod shape with higher bulk density and fluidity.
  • the purity of the new crystalline product obtained by the method is 99.6%, and the single pass molar yield of the crystallization process is 92.1%.
  • pantoprazole sodium solid was added to 20 mL of isobutanol to form a suspension.
  • 0.004 g of TBHQ was added to the suspension under stirring, and the suspension was heated to 35 ° C to dissolve all the solids at a constant temperature to 1 ml.
  • 200 mL of an equal volume of n-hexane and n-heptane was added dropwise to the solution to obtain a suspension, while applying a frequency of 50 kHz, a power of 100 W of ultrasonication, and then cooling to 5 ° C at a rate of 2 ° C/min, and stirring was continued.
  • the crystal slurry was vacuum-filtered, and the product was dried at 60 ° C under normal pressure for 24 h to constant weight to obtain M-type pantoprazole sodium product.
  • the X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2 ⁇ of 5.62, 11.42, 12.14, 13.80, 17.12, 18.70, 21.64, 23.40, 25.20, 26.84 degrees.
  • the DSC analysis of the new crystal form M shows that it has a characteristic endothermic peak at 192.46 ° C.
  • the product has no change in crystal form, purity and appearance after 15 days at 60 ° C and 90% relative humidity.
  • pantoprazole sodium new crystal form compound obtained by the present invention was subjected to the following toxicity test (taking the crystalline form of pantoprazole sodium compound obtained in Example 1 as an example):
  • mice Acute toxicity experiments in mice were performed using the median lethal dose method. 50 ICR mice that met the test requirements were randomly divided into 5 dose groups according to body weight, 10 animals in each group, half male and half female. The dose was set to 600, 492, 403.4, 330.8, 271.3 mg/kg. The concentration of pantoprazole sodium was 30, 24.6, 20.2, 16.5, and 13.6 mg/mL, and was administered by tail vein injection. The toxic reaction of the mice during the administration and after administration was observed. As a result, during the administration, the animal was struggling, shortness of breath, softening of the limbs, difficulty in breathing, and severe death, with an LD 50 of 391.52 mg/kg.
  • pantoprazole sodium was administered at 44, 67, 100, 150, and 225 mg/kg. There were 3 animals per dose group. The toxicity of each group of animals after administration was observed. As a result, at a dose of 150 mg/kg, it exhibited tremor, increased salivation, softness, vomiting, and then died after 20 minutes, and the LD 50 was 70 mg/kg.
  • Pantoprazole sodium was divided into 5, 3, 1g/kg groups according to high, medium and low doses. The test period was 13wk, and 80 healthy Wistar rats, male and female, were randomly divided into 4 groups according to body weight.
  • the drug was administered once a day, and was administered for 13 weeks and stopped for 2 weeks, and routine toxicological observation and index detection were performed. As a result, no significant difference occurred in the middle and low dose groups, and the administration of the high dose group ended, the granulocyte (GR) was significantly decreased, and the alanine aminotransferol (ALT) was significantly increased. Histopathological examination revealed an animal liver cell degeneration. At the end of drug withdrawal, no significant abnormalities were observed in each dose group. The long-term toxicity test of pantoprazole sodium in rats was 3g ⁇ kg -1 .
  • pantoprazole sodium crystal form disclosed and proposed by the invention and the preparation method thereof can be realized by those skilled in the art by referring to the content of the paper, appropriately changing raw materials, process parameters and the like.
  • the method and product of the present invention have been described by way of a preferred embodiment, and it is obvious that those skilled in the art can make modifications or appropriate changes and combinations of the methods and products described herein without departing from the scope of the invention.
  • the technology of the present invention It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the spirit, scope and content of the invention.

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Abstract

本发明公开了一种泮托拉唑钠化合物新晶型及其制备方法，该新晶型命名为M晶型。用X-射线粉末衍射图谱的衍射角2θ°和DSC的特征峰进行定义。将泮托拉唑钠固体加入醇类溶剂中，配制成0.05～0.2g/mL的悬浮液，向悬浮液中加入抗氧化剂，在15～35℃使固体完全溶解，在施加超声波作用的条件下向溶液中滴加溶析剂，溶析剂用量是醇类溶剂体积的3～10倍，然后降温至0～5℃，继续搅拌1～3h，抽滤所形成的悬浮液，干燥泮托拉唑钠晶体产品至恒重得到新晶型。产品热稳定性测试表明，该晶型产品具有更高的热稳定性。同时，该晶型产品具有更高的堆密度和更好的流动性，更有利于后续的制剂过程和产品储存、运输等。

Description

一种泮托拉唑钠化合物新晶型及其制剂和制备方法 技术领域
本发明属于医药分离技术领域，特别涉及一种泮托拉唑钠化合物的新晶型及其制备方法。
背景技术
泮托拉唑钠(Pantoprazole sodium)为白色或类白色结晶性粉末，在水中或甲醇中易溶，在三氯甲烷或***中几乎不溶。泮托拉唑钠的化学名为5-二氟甲氧基-2-[(3,4-二甲氧基-2-吡啶基)甲基]亚硫酰基-1H-苯并咪唑钠盐，分子式为C16H14F2N3NaO4S，分子量为405.36，结构式如式(I)。泮托拉唑钠作为一种质子泵抑制剂，它适用于十二指肠溃疡、胃溃疡、急性胃粘膜病变，复合性胃溃疡等急性上消化道出血的治疗，主要药理作用是通过与胃壁细胞的质子泵(即H+/K+-ATP酶)结合，抑制胃酸分泌。
Figure PCTCN2015095231-appb-000001
泮托拉唑钠具有不同晶体结构的结晶形式。WO91/19710公开了泮托拉唑钠的一水合物。W02004100949A公开了泮托拉唑钠的络合物结晶，包括丙酮溶剂合物A1-A4，乙酸甲酯溶剂合物B1-B3，甲基乙基酮溶剂合物C1-C2，二乙基酮溶剂合物D1。US20040186139A1公开了一种制备倍半水合泮托拉唑钠结晶的改进方法，包括制备泮托拉唑钠游离碱和化学计量的氢氧化钠的四氢呋喃、乙酸或乙酸乙酯溶液，加入反溶剂，冷却该溶液直至形成沉淀，分离沉淀，即得。US20050245578A1公开了一种泮托拉唑钠单水合物和单溶剂化物与酮溶剂如丙酮、甲基乙基酮、二乙基酮和甲基异丁基酮的新结晶形式，其制备方法为将泮托拉唑钠与上述溶剂接触。ZL201110228921.X公开了一种泮托拉唑钠结晶水合物，是通过将泮托拉唑钠粉末溶于水/甲醇混合溶液，然后加***来析 出晶体的。
综上所述，作为一种常用的药物，人们对泮托拉唑钠进行了广泛而深入的研究，已经开发了泮托拉唑钠的一些结晶化合物。但是，专利已经报道的这些泮托拉唑钠的结晶形式多为水合物或者溶剂化物的形式，普遍存在热稳定性不好或者结晶度不高的问题，在后续制剂或者存放过程中，由于外界条件的改变，很难保证水合物或溶剂化合物中溶剂的减少或者脱除。因此，就有可能造成产品质量的波动。为解决上述问题，本发明人在生产和科研实践中，发现了泮托拉唑钠化合物的一种新晶型及其相应的结晶制备方法。
发明内容
本发明公开了一种泮托拉唑钠化合物新晶型及其制备方法，该新晶型命名为M晶型。
所述的泮托拉唑钠化合物新晶型，其X-射线粉末衍射图谱中，在衍射角2θ为5.62±0.2，11.62±0.2，12.16±0.2，13.80±0.2，17.18±0.2，18.80±0.2，21.72±0.2，23.44±0.2，25.16±0.2，26.88±0.2度处有特征峰，如图1所示。
所述的晶型泮托拉唑钠晶体，其DSC分析结果显示，在192±2℃有一个吸热峰，如图2所示。
所述的晶型泮托拉唑钠晶体，其外观如图3所示，为短粗的棒状。
本发明所述的泮托拉唑钠晶体的晶型的制备方法如下：
将泮托拉唑钠固体加入醇类溶剂中，配制成0.05～0.2g/mL的悬浮液；向悬浮液中加入抗氧化剂，在15～35℃使固体完全溶解；在施加超声波作用的条件下向溶液中滴加溶析剂，溶析剂用量是醇类溶剂体积的3～10倍；然后降温至0～5℃，继续搅拌1～3h；抽滤所形成的悬浮液，50～60℃干燥后得到泮托拉唑钠化合物新晶型晶体产品。
所述方法中的醇类溶剂选自正丁醇、异丁醇、正戊醇、异戊醇或正己醇中的一种或几种的混合溶剂。
所述方法中的抗氧化剂选自BHA(丁基羟基茴香醚)、BHT(二丁基羟基甲苯)、PG(没食子酸丙酯)、TBHQ(特丁基对苯二酚)中的一种或几种的混合物。
所述方法中的抗氧化剂用量为加入的泮托拉唑钠质量的0.1％～0.5％。
所述方法中的溶析剂选自正庚烷、正己烷、正戊烷、环己烷、正辛烷中的一种或几种的混合溶剂。
所述方法中的溶析剂的滴加速率是每分钟滴加溶析剂体积的0.2％～2％。
所述方法中的超声波作用频率为20～50KHz，功率为50～100W。
所述方法中的悬浮液的降温速率是0.2～2℃/min。
所述方法中的干燥条件是在50～60℃、常压的条件下进行24～48h。
本发明的泮托拉唑钠化合物M晶型的特点是不含任何结晶溶剂，新晶型产品熔点为192±2℃，熔点较传统晶型高。通过60℃，90％相对湿度的条件下的热稳定性试验发现，15天后产品晶型、纯度和外观均没有发生改变，这说明新晶型M产品具有更优良的热稳定性。新晶型产品外观为短粗的棒状，具有更高的堆密度和流动性。该晶型产品由于稳定性、流动性和堆密度的提高而特别在泮托拉唑钠片剂、粉针剂等剂型的制备等后续制剂过程中具有更大的优势。同时，该产品在过滤、洗涤、干燥、包装和储存过程中也由于上述性质的提高而具有更佳的质量。同时，本发明的泮托拉唑钠化合物的新晶型的制备方法的操作条件简单易控，产品晶浆易过滤、洗涤和干燥，结晶过程的单程摩尔收率在90％以上，产品纯度在99％以上。
本发明获得的泮托拉唑钠新晶型化合物的毒性反应表明，其毒性比现有的泮托拉唑钠有所降低。
附图说明
图1：泮托拉唑钠化合物新晶型M的X-射线粉末衍射图；
图2：泮托拉唑钠化合物新晶型M的DSC分析图；
图3：泮托拉唑钠化合物新晶型M的显微镜照片。
具体实施方式
下面通过附图和实施例对本发明进一步详细说明。通过这些说明，本发明的特点和优点将变得更为清楚明确。
实施例1：
将干燥的泮托拉唑钠固体1g加入20mL等体积比的正丁醇和正戊醇中形成悬浮液，在搅拌下向悬浮液中加入0.005gBHA，将该悬浮液加热到15℃，使固体全部溶解，恒定温度，以0.12ml/min的速度向溶液中滴加60mL的环己烷得到悬浮液，同时施加频率为20KHz，功率为50W的超声波作用，然后以0.2℃/min速率降温至0℃，继续搅拌1h，真空抽滤晶浆，将产物在50℃、常压下干燥48h至恒重，得到M晶型泮托拉唑钠产品。 新晶型M产品的X-射线粉末衍射图谱如图1所示，其在衍射角2θ为5.62，11.62，12.16，13.80，17.18，18.80，21.72，23.44，25.16，26.88度处有特征峰。新晶型M的DSC分析图如图2所示，其在192.61℃有特征吸热峰，产品在60℃，90％相对湿度的条件下15天后产品晶型、纯度和外观均没有发生改变，常温、空气湿度条件下储存100天后，产品晶型、纯度、颜色均没有发生变化；新晶型M产品外观如图3所示，为短粗的棒状，具有更高的堆密度和流动性。该方法得到的新晶型产品纯度为99.5％，结晶过程单程摩尔收率高于91.2％。
实施例2：
将干燥的泮托拉唑钠固体2g加入30mL异戊醇中形成悬浮液，在搅拌下向悬浮液中加入等质量比的BHA和BHT共0.008g，将该悬浮液加热到20℃，使固体全部溶解，恒定温度，以1ml/min的速度向溶液中滴加100mL的正戊烷得到悬浮液，同时施加频率为40KHz，功率为60W的超声波作用，然后以0.5℃/min速率降温至2℃，继续搅拌2h，真空抽滤晶浆，将产物在50℃、常压下干燥40h至恒重，得到M晶型泮托拉唑钠产品。产品的X-射线粉末衍射图谱在衍射角2θ为5.64，11.42，12.18，13.80，17.16，18.82，21.68，23.02，25.18，26.98度处有特征峰。新晶型M的DSC分析图显示其在192.12℃有特征吸热峰，产品在60℃，90％相对湿度的条件下15天后产品晶型、纯度和外观均没有发生改变，常温、空气湿度条件下储存100天后，产品晶型、纯度、颜色均没有发生变化；新晶型M产品外观为短粗的棒状，具有更高的堆密度和流动性。该方法得到的新晶型产品纯度为99.3％，结晶过程单程摩尔收率为91.5％。
实施例3：
将干燥的泮托拉唑钠固体2.5g加入20mL正己醇中形成悬浮液，在搅拌下向悬浮液中加入0.01gPG，将该悬浮液加热到25℃，使固体全部溶解，恒定温度，以2ml/min的速度向溶液中滴加120mL的正辛烷得到悬浮液，同时施加频率为30KHz，功率为70W的超声波作用，然后以1℃/min速率降温至3℃，继续搅拌3h，真空抽滤晶浆，将产物在55℃、常压下干燥30h至恒重，得到M晶型泮托拉唑钠产品。产品的X-射线粉末衍射图谱在衍射角2θ为5.74，11.56，12.26，13.92，17.28，18.88，21.78，23.24，25.22，27.08度处有特征峰。新晶型M的DSC分析图显示其在192.80℃有特征吸热峰，产品在60℃，90％相对湿度的条件下15天后产品晶型、纯度和外观均没有发生改变，常温、空 气湿度条件下储存100天后，产品晶型、纯度、颜色均没有发生变化；新晶型M产品外观为短粗的棒状，具有更高的堆密度和流动性。该方法得到的新晶型产品纯度为99.6％，结晶过程单程摩尔收率为92.1％。
实施例4：
将干燥的泮托拉唑钠固体4g加入20mL异丁醇中形成悬浮液，在搅拌下向悬浮液中加入0.004gTBHQ，将该悬浮液加热到35℃，使固体全部溶解，恒定温度，以1ml/min的速度向溶液中滴加200mL等体积比的正己烷和正庚烷得到悬浮液，同时施加频率为50KHz，功率为100W的超声波作用，然后以2℃/min速率降温至5℃，继续搅拌4h，真空抽滤晶浆，将产物在60℃、常压下干燥24h至恒重，得到M晶型泮托拉唑钠产品。产品的X-射线粉末衍射图谱在衍射角2θ为5.62，11.42，12.14，13.80，17.12，18.70，21.64，23.40，25.20，26.84度处有特征峰。新晶型M的DSC分析图显示其在192.46℃有特征吸热峰，产品在60℃，90％相对湿度的条件下15天后产品晶型、纯度和外观均没有发生改变，常温、空气湿度条件下储存100天后，产品晶型、纯度、颜色均没有发生变化；新晶型M产品外观为短粗的棒状，具有更高的堆密度和流动性。该方法得到的新晶型产品纯度为99.7％，结晶过程单程摩尔收率为91.8％。
毒性反应实验：
对本发明获得的泮托拉唑钠新晶型化合物进行如下毒性反应实验(以实施例1获得的泮托拉唑钠化合物晶型为例)：
采用半数致死量法进行小鼠急性毒性实验。选择符合试验要求的ICR小鼠50只，按体重随机分5个剂量组，每组10只动物，雌雄各半。剂量设置为600、492、403.4、330.8、271.3mg/kg。泮托拉唑钠的浓度为30、24.6、20.2、16.5、13.6mg/mL，尾静脉注射给药。观察给药过程、给药后小鼠的毒性反应情况。结果，在给药过程中动物有挣扎、呼吸急促、给四肢瘫软、呼吸困难现象，重症出现死亡现象，LD50为391.52mg/kg。
对15只Beagle犬进行急性毒性试验，给予不同剂量的泮托拉唑钠44、67、100、150、225mg/kg。每个剂量组3只动物。观察给药后各组动物的毒性反应。结果，在剂量为150mg/kg时，表现为震颤、唾液分泌增加、瘫软、呕吐，然后20min后死亡，LD50为70mg/kg。将泮托拉唑钠按高、中、低剂量分为5、3、1g/kg组，试验周期为13wk，健康Wistar大鼠80只，雌雄各半，按体重随机分为4组，每天定时灌胃给药一次，于给药13wk及停药2wk，进行常规毒理学观察和指标检测。结果，中、低剂量组未见明显差异发生，高 剂量组给药结束，粒细胞(GR)明显降低，谷丙转氨醇(ALT)明显升高。病理组织学检查，一只动物肝细胞变性。停药结束，各剂量组各项指标均未见明显异常。泮托拉唑钠大鼠长期毒性试验无毒反应剂量为3g·kg-1。
本发明公开和提出的泮托拉唑钠晶型及其制备方法，本领域技术人员可通过借鉴本文内容，适当改变原料、工艺参数等环节实现。本发明的方法与产品已通过较佳实施例子进行了描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和产品进行改动或适当变更与组合，来实现本发明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，他们都被视为包括在本发明精神、范围和内容中。

Claims (10)

  1. 一种泮托拉唑钠晶体的晶型，其特征是X-射线粉末衍射图谱中，在衍射角2θ为5.62±0.2，11.62±0.2，12.16±0.2，13.80±0.2，17.18±0.2，18.80±0.2，21.72±0.2，23.44±0.2，25.16±0.2，26.88±0.2度处有特征峰。
  2. 如权利要求1所述的晶型，其特征是在192±2℃处有DSC吸热峰。
  3. 如权利要求1或2所述的泮托拉唑钠晶体的制备方法，其特征是：将泮托拉唑钠固体加入醇类溶剂中，配制成0.05～0.2g/mL的悬浮液，向悬浮液中加入抗氧化剂，在15～35℃使固体完全溶解；在施加超声波作用的条件下向溶液中滴加溶析剂，溶析剂用量是醇类溶剂体积的3～10倍；然后降温至0～5℃，继续搅拌1～3h；抽滤所形成的悬浮液，50～60℃干燥后得到泮托拉唑钠化合物新晶型晶体产品。
  4. 如权利要求3所述的制备方法，其特征是醇类溶剂选自正丁醇、异丁醇、正戊醇、异戊醇或正己醇中的一种或几种的混合溶剂。
  5. 如权利要求3所述的制备方法，其特征是所述抗氧化剂选自丁基羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯或特丁基对苯二酚中的一种或几种的混合物，抗氧化剂用量为加入的泮托拉唑钠质量的0.1％～0.5％。
  6. 如权利要求3所述的制备方法，其特征是溶析剂选自正庚烷、正己烷、正戊烷、环己烷、正辛烷中的一种或几种的混合溶剂，溶析剂的滴加速率是每分钟滴加溶析剂体积的0.2％～2％。
  7. 如权利要求3所述的制备方法，其特征是在结晶过程中引用了超声波，且超声波作用频率为20～50KHz，功率为50～100W。
  8. 如权利要求3所述的制备方法，其特征是所述的干燥条件是温度为50～60℃、常压的条件下进行24～48h。
  9. 如权利要求3所述的制备方法，悬浮液的降温速率是0.2～2℃/min。
  10. 泮托拉唑钠新晶型作为质子泵抑制剂适用于片剂和粉针剂的剂型。
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