WO2017000270A1 - 枸橼酸舍曲林的2种晶型及其制备方法 - Google Patents

枸橼酸舍曲林的2种晶型及其制备方法 Download PDF

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WO2017000270A1
WO2017000270A1 PCT/CN2015/083017 CN2015083017W WO2017000270A1 WO 2017000270 A1 WO2017000270 A1 WO 2017000270A1 CN 2015083017 W CN2015083017 W CN 2015083017W WO 2017000270 A1 WO2017000270 A1 WO 2017000270A1
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sertraline
crystal form
citrate
sertraline citrate
powder diffraction
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PCT/CN2015/083017
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French (fr)
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徐静
张艳红
徐光昳
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徐静
哈尔滨健迪医药科技开发有限公司
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Priority to PCT/CN2015/083017 priority Critical patent/WO2017000270A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid

Definitions

  • the invention belongs to the field of medicinal chemical polymorphs, and particularly relates to the preparation of sertraline citrate crystal form by different crystallization methods and a synthesis process thereof.
  • the polymorphism phenomenon refers to a phenomenon in which solid materials are arranged in two or more different spatial arrangements to form solid states having different physicochemical properties.
  • polymorphs also include multi-component crystal forms such as organic solvates, hydrates and the like.
  • Drug polymorphism is widespread in drug development and is an inherent property of organic small molecule compounds. Theoretically, small molecule drugs can have an infinite number of crystal packing methods - polymorphs. Studies have shown that the number of drug polymorphs found is directly proportional to the time and resources of the research they are investigating.
  • Polymorphism is not only controlled by the internal structure of the molecule itself, functional group properties, intramolecular and intermolecular interactions, but also by drug synthesis process design, crystallization and purification conditions, formulation excipient selection, formulation process Route and granulation methods, as well as storage conditions, packaging materials and other factors. Different crystal forms have different colors, melting points, solubility, dissolution properties, chemical stability, reactivity, mechanical stability, etc. These physical and chemical properties or processability sometimes directly affect the safe and effective performance of the drug. Therefore, crystal research and control has become an important research content in the drug development process.
  • the actual blood level of the drug can be advantageously influenced by selecting polymorphs having different solubilities and/or inherent dissolution rates.
  • Sertraline citrate chemical name (1S, 4S)–4–(3,4–dichlorophenyl)–1,2,3,4–tetrahydro–N–methyl–1–naphthylamine ⁇ Citrate monohydrate.
  • Sertraline citrate is a selective serotonin reuptake inhibitor. Its mechanism of action is related to its inhibition of serotonin reuptake in central neurons. At clinical doses, sertraline blocks the uptake of serotonin by human platelets. Studies have shown that sertraline is a potent and selective neuronal serotonin reuptake inhibitor with only a modest effect on norepinephrine and dopamine.
  • Sertraline is used to treat symptoms associated with depression, including depression with or without history of mania. After satisfactory results, continued use of sertraline can effectively prevent recurrence and recurrence of depression. Sertraline is also used to treat obsessive-compulsive disorder. After satisfactory results, continued use of sertraline can effectively prevent the recurrence of the initial symptoms of obsessive-compulsive disorder.
  • Sertraline citrate is a selective 5-HT reuptake inhibitor, and its mechanism of action is to increase the local content of 5-HT by selectively inhibiting the central nervous system presynaptic membrane, thereby strengthening the brain. It is the inhibitory ejaculation effect of 5-HT in the anterior hypothalamus, so it can significantly prolong the ejaculation latency, improve the quality of sexual life, and effectively treat premature ejaculation.
  • sertraline is still in the clinical research stage at home and abroad and has not been approved for marketing.
  • a large number of clinical studies have shown that sertraline can significantly prolong the ejaculation latency, improve the quality of sexual life, the treatment of premature ejaculation is effective, the side effects are small, and the tolerance is good.
  • sertraline 100 mg or placebo respectively.
  • the intravaginal ejaculation latency of the placebo group and the experimental group were treated by pre-treatment.
  • Sertraline citrate is the first variety of our company.
  • the crystal form of the raw material of sertraline citrate used in the CN1091096 patent is not mentioned.
  • One aspect of the invention provides two crystal forms of sertraline citrate.
  • the first crystal form of sertraline citrate provided by the present invention is named as crystal form A.
  • the 2 ⁇ angle of the X-ray powder diffraction pattern of the crystal has distinct characteristic absorption peaks at about 8.49, 10.76, 11.77, 13.05, 14.59, 16.20, 20.25, 20.83, 22.60, 23.35, and 26.54.
  • the specific X powder diffraction pattern is shown in Figure 1.
  • the infrared spectrum of the crystal is shown in Figure 2.
  • the second crystal form of sertraline citrate provided by the present invention is named as crystal form B.
  • the 2 ⁇ angle of the X-ray powder diffraction pattern of the crystal has distinct characteristic absorption peaks at about 14.20, 14.86, 15.65, 16.62, 17.23, 18.22, 19.98, 21.14, 24.69, 27.32, 28.64, 29.69, and 30.83.
  • the specific X powder diffraction pattern is shown in Figure 3.
  • the infrared spectrum of the crystal is shown in Figure 4.
  • Another aspect of the invention provides a process for the preparation of these two crystal forms of sertraline citrate. Specifically:
  • Method 1 Take 50.0 g of sertraline citrate, add 250 ml of 95% ethanol, heat to 60-70 ° C to dissolve until clarification, keep for 10 minutes, stop heating and add 7500 ml of water, drop to room temperature, keep stirring for 24 h, The crystal form of sertraline citrate obtained by filtration and dried under reduced pressure at room temperature for 12 hours.
  • the ratio of the solvent to sertraline citrate is 4 ml to 10 ml: 1 g.
  • the ratio of ethanol to water is 1:20-30.
  • the incubation time is 10 minutes.
  • Method 2 Take 50.0 g of sertraline citrate, add 300 ml of 95% ethanol, heat to 60-70 ° C to dissolve until clarification, keep for 10 minutes, stop heating to room temperature, keep stirring for 24 h, filter, dry at room temperature under reduced pressure. The crystal form of sertraline citrate obtained in 12 hours.
  • the ratio of the solvent to sertraline citrate is 4 ml to 10 ml: 1 g.
  • the incubation time is 10 minutes.
  • An advantage of the present invention is that the crystalline form A and the crystalline form B of sertraline citrate according to the present invention have good performance and high bioavailability; or/and have good properties in terms of stability, satisfying pharmaceutical preparations.
  • the requirement is favorable for storage, thereby meeting the requirements of drug stability; the preparation method is simple in operation, less in steps, small in environmental protection pressure, and suitable for industrial production.
  • the crystal form A of the invention has been clinically phased, clinically phase 2, and bioequivalence tested by the GMP workshop, and the clinical curative effect is obvious, and the adverse reactions are few.
  • the crystalline form A and the crystalline form B of sertraline citrate according to the present invention and a pharmaceutically acceptable excipient are prepared into tablets or dragees suitable for oral administration, injection by the digestive tract or intranasal administration, Granules, sublingual tablets, capsules, suppositories, emulsions, ointments, skin-coating gels, injection preparations, oral solutions.
  • the excipients include conventional fillers, disintegrants, binders, and the like.
  • the filler is a commonly used filler such as starch, lactose, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate, and the like.
  • the disintegrating agent such as carboxymethyl cellulose and a salt thereof, croscarmellose and a salt thereof, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, etc. .
  • the binder is a commonly used binder such as povidone, hydroxypropylmethylcellulose, starch slurry or the like.
  • the lubricant is, for example, magnesium stearate, calcium stearate or the like.
  • the above-mentioned polymorphic form of sertraline citrate provided by the present invention is useful for preparing a medicament for treating symptoms associated with depression and premature ejaculation.
  • Figure 1 X-ray powder diffraction pattern of Form A of sertraline citrate in Example 1 of the present invention.
  • Figure 2 Infrared spectrum of Form A of sertraline citrate in Example 1 of the present invention.
  • Figure 4 Infrared spectrum of Form 2 of succinic acid citrate in Example 2 of the present invention.
  • the specific crystal form of the diffraction spectrum obtained from the crystalline compound is often characteristic, and the relative intensity of the band (especially at low angles) may be due to crystallization conditions.
  • the dominant orientation effect due to the difference in particle size, relative content of the mixture, and other test conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystals that are targeted, and it is more important to note the position of the peaks rather than their relative intensities when determining whether they are the same as the known crystal forms.
  • Table 1 X-ray powder diffraction data of Form A of sertraline citrate in Example 1 of the present invention
  • the obtained sample was subjected to solubility measurement, and as a result, the sertraline citrate crystal form A sample was easily soluble in ethanol (11%, g/ml) and slightly soluble in 0.1 mol/L hydrochloric acid solution (0.2%, g/ml). ), very slightly soluble in water (0.01%, g / ml).
  • Table 2 X-ray powder diffraction data of Form 2 of sertraline citrate in Example 2 of the present invention
  • the obtained sample was subjected to solubility measurement, and as a result, the sample of sertraline citrate crystal form B was dissolved in ethanol (1%, g/ml), and slightly dissolved in a 0.1 mol/L hydrochloric acid solution (0.01%, g/ml). ), almost insoluble in water (less than 0.01%, g / ml).
  • Table 3 X-ray powder diffraction data of Form A of sertraline citrate in Example 3 of the present invention
  • the obtained sample was subjected to infrared test, and the obtained infrared spectrum was identical to that of FIG.
  • Table 4 X-ray powder diffraction data of Example 4 of the present invention, Sertraline citrate Form B
  • the obtained sample was subjected to infrared test, and the obtained infrared spectrum was as shown in Fig. 4.
  • Example 5 Stability test of sertraline citrate of Form A and Form B
  • the samples of Form A and Form B of sertraline citrate were tested for influencing factors, and samples were taken at 0, 5, 10, and 30 days. Influencing factors
  • the test conditions are as follows: (1) high temperature test: 60 ° C, the opening of the weighing bottle; (2) high humidity test: 25 ° C, RH 92.5%, placed in the opening of the weighing bottle. (3) Light test: 4500Lx ⁇ 500Lx, placed in the opening of the weighing bottle.
  • RESULTS During the period from 0 to 30 days, the sample was tested at a high temperature of 60 ° C for 30 days. The total amount of impurities in Form A was increased from 0.00% to 0.09% compared with the initial result of 0 days. The total amount of impurities of type A is increased from 0.00 to 0.02%. The sample was placed in a constant temperature and humidity incubator at 25 ° C and a relative humidity of 92.5%. After being placed for 30 days, the test results of the relevant substances of the sample did not differ from the initial results of 0 days. After 30 days of illumination, the results of the relevant substances in the samples did not differ from the initial results of 0 days.
  • the enantiomers at various time points were not detected at a high temperature of 60 ° C, high humidity, and light.
  • Example 6 Dissolution test of sertraline citrate in Form A and Form B
  • the crystal form A and the crystal form B serotonin were separately prepared by the same prescription and process to prepare the sericillin citrate tablets and the dissolution properties were determined by dissolution measurement to evaluate the two crystal forms of citric acid.
  • the dissolution characteristics of sertraline The results are as follows.
  • the crystal form A has a fast dissolution rate of sertraline, and the dissolution peak has been reached at 10 minutes, while the dissolution rate of the crystal form B is slightly slower than that of the crystal form A, and the peak of dissolution is reached at 20 minutes. Therefore, it is more preferred that the crystalline form A of sertraline citrate is subjected to the next clinical trial.
  • the sertraline citrate tablets prepared by the crystal form A sericillin and the sertraline hydrochloride tablets prepared by the same prescription and process were separated by dissolution in two different dissolution media to distinguish the solubility properties.
  • the dissolution characteristics of the two sertraline were evaluated. The results are as follows.
  • sertraline citrate is superior to sertraline hydrochloride in both solubility and dissolution.
  • 1 g of sertraline citrate can be dissolved in 13 ml of ethanol and 4.5 ml of chloroform
  • 1 g of sertraline hydrochloride can be dissolved in 70 ml of ethanol and 9 ml of chloroform.
  • the dissolution rate of sertraline citrate tablets was up to 97% in 15 minutes, while the dissolution of sertraline hydrochloride tablets was only 90% in 15 minutes.
  • Example 7 Phase 2 clinical trial data of crystal form A of sertraline citrate
  • the median ejaculation latency was 1.20 and 1.17 minutes before treatment with sertraline and placebo, respectively.
  • the median ejaculation latency was 3.79 and 1.79 minutes at the end of treatment (6 weeks), and the median ejaculation latency was prolonged. 2.56, 0.86 minutes.
  • the patient's spouse sexual life satisfaction results were basically consistent with the patient's sexual life satisfaction results.
  • the T max of sertraline in plasma was determined to be 7.1 ⁇ 2.3 (mean ⁇ standard deviation, the same below) and 7.6 ⁇ 2.2. h, C max were 12.07 ⁇ 6.53 and 10.76 ⁇ 3.21ng/ml, respectively, t 1/2 was 30.66 ⁇ 10.86 and 31.92 ⁇ 7.56h, respectively, calculated by the trapezoidal method, AUC 0-t was 393.4 ⁇ 195.4 and 396.7 ⁇ 148.5 respectively. Ng ⁇ h/ml, AUC 0- ⁇ is 453.0 ⁇ 230.1 and 459.6 ⁇ 188.5 ng ⁇ h/ml, respectively.
  • the relative bioavailability of sertraline citrate tablets was 97.7 ⁇ 15.9% on average calculated by AUC 0-t.
  • the main pharmacokinetic parameters obtained were logarithmically transformed and analyzed for variance, and the bioequivalence evaluation was further carried out by double unilateral t test and (1-2 ⁇ ) confidence interval method.
  • the results showed that both the AUC 0-t and C max of the two formulations rejected the bioequivalence hypothesis.
  • the 90% confidence limit of the test preparation AUC 0-t was 87.9% ⁇ 105.8% of the corresponding parameters of the reference preparation; the 90% confidence limit of Cmax was 97.6% ⁇ 117.6% of the corresponding parameters of the reference preparation. Both formulations are considered to be bioequivalent.

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Abstract

本发明涉及枸橼酸舍曲林的晶型A和晶型B及其制备方法。枸橼酸舍曲林的晶型A和晶型B溶解性好，溶出度高，稳定性高，利于储存。

Description

枸橼酸舍曲林的2种晶型及其制备方法 技术领域
本发明属于药物化学多晶型研究领域，具体涉及利用不同结晶方法制备枸橼酸舍曲林晶型体及其合成工艺研究。
背景技术
多晶型现象是指固体物质以两种或两种以上的不同空间排列方式，形成的具有不同物理化学性质的固体状态的现象。在药物研究领域，多晶型还包括了有机溶剂化物、水合物等多组分晶体形式。药物多晶现象在药物开发过程中广泛存在，是有机小分子化合物固有的特性。理论上小分子药物可以有无限多的晶体堆积方式-多晶型，研究表明，药物多晶型的发现数量与其投入的研究的时间和资源成正比例。多晶型现象不光受到分子本身的空间结构和官能基团性能，分子内和分子间的相互作用等内在因素的控制，它还受药物合成工艺设计、结晶和纯化条件、制剂辅料选择、制剂工艺路线和制粒方法、以及储存条件、包装材料等诸方面因素的影响。不同晶型具有不同的颜色、熔点、溶解度、溶出性能、化学稳定性、反应性、机械稳定性等，这些物理化学性能或可加工性能有时直接影响到药物的安全、有效性能。因此晶型研究和控制成为药物研发过程中的重要研究内容。通过选择具有不同溶解度和/或固有的溶出速率的多晶型就可以有利地影响药物的实际血液水平。
枸橼酸舍曲林，化学名为(1S,4S)–4–(3,4–二氯苯基)–1,2,3,4–四氢–N–甲基–1–萘胺枸橼酸盐一水合物。枸橼酸舍曲林是一种选择性的5-羟色胺再摄取抑制剂。其作用机制与其对中枢神经元5-羟色胺再摄取的抑制有关。在临床剂量下，舍曲林阻断人血小板对5-羟色胺的摄取。研究提示舍曲林是一种强效和选择性的神经元5-羟色胺再摄取抑制剂，对去甲肾上腺素和多巴胺仅有微弱影响。舍曲林用于治疗抑郁症的相关症状，包括伴随焦虑、有或无躁狂史的抑郁症。疗效满意后，继续服用舍曲林可有效地防止抑郁症的复发和再发。舍曲林也用于治疗强迫症。疗效满意后，继续服用舍曲林可有效地防止强迫症初始症状的复发。
我公司于2002年申请了舍曲林及其盐和它们用于治疗哺乳动物早泄的用途，授权公告号CN1091096。枸橼酸舍曲林为选择性的5-HT再摄取抑制剂，其作用机制为通过选择性抑制中枢神经突触前膜对5-HT再摄取，使其局部含量增加，进而加强脑内尤其是下丘脑前部5-HT的抑制射精作用，因此可明显延长射精潜伏期、改善性生活质量，有效治疗早泄。
目前，舍曲林治疗早泄在国内外尚处于临床研究阶段，尚未获准上市。大量临床研究表明，舍曲林可显著延长射精潜伏期，改善性生活质量，治疗早泄疗效确切、副作用小、耐受性好。据文献报道，36例阴茎插入阴道内不到2分钟即射精的早泄患者分别口服舍曲林100mg或安慰剂，连续治疗4周后，安慰剂组和试验组阴道内射精潜伏期分别由治疗前的46±41秒增加至2.27±3.78分钟和4.27±5.68分钟，性生活质量满意率分别为19.4％和41.7％，两组相比均有显著差异。治疗组的不良反应发生率与安慰剂组相比无显著差异。
枸橼酸舍曲林为我公司首创品种，CN1091096专利中未涉及到所用枸橼酸舍曲林原料的晶型。
在剑桥晶体数据库(Cambridge Crystallographic Data Centre，CCDC)中无关于枸橼酸舍曲 林的晶型数据。
发明内容
本发明一方面提供了枸橼酸舍曲林的2种晶型。
本发明提供的枸橼酸舍曲林第一种晶型，该晶型命名为A晶型。该晶体的X-射线粉末衍射图的2θ角在约为8.49、10.76、11.77、13.05、14.59、16.20、20.25、20.83、22.60、23.35和26.54等处有明显的特征吸收峰。具体X粉末衍射图见图1。该晶体的红外光谱如图2所示。
本发明提供的枸橼酸舍曲林第二种晶型，该晶型命名为B晶型。该晶体的X-射线粉末衍射图的2θ角在约为14.20、14.86、15.65、16.62、17.23、18.22、19.98、21.14、24.69、27.32、28.64、29.69和30.83等处有明显的特征吸收峰。具体X粉末衍射图见图3。该晶体的红外光谱如图4所示。
本发明另一方面提供了这两种枸橼酸舍曲林晶型的制备方法。具体为：
方法1：取枸橼酸舍曲林50.0g，加入250ml的95％乙醇，加热到60-70℃溶解至澄清，保持10分钟，停止加热并滴加7500ml水，降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到的枸橼酸舍曲林A晶型。
优选的，所述溶剂用量与枸橼酸舍曲林的比例为4ml～10ml∶1g。
优选的，所述的乙醇和水的比例为1：20～30。
优选的，保温搅拌时间为10分钟。
方法2：取枸橼酸舍曲林50.0g，加入300ml的95％乙醇，加热到60-70℃溶解至澄清，保持10分钟，停止加热降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到的枸橼酸舍曲林B晶型。
优选的，所述溶剂用量与枸橼酸舍曲林的比例为4ml～10ml∶1g。
优选的，保温搅拌时间为10分钟。
本发明的优点是，本发明所述的枸橼酸舍曲林晶型A和晶型B具有良好的性能，生物利用度高；或/和在稳定性方面具有良好的性能，满足药用制剂要求，有利于储存，从而符合药物稳定性的要求；所述的制备方法操作简便，步骤较少，环保压力小，适合工业化生产。
本发明的晶型A经GMP车间生产的产品已经临床1期、临床2期、生物等效性试验验证，临床疗效明显，不良反应少。
本发明所述的枸橼酸舍曲林晶型A和晶型B以及药学上可接受的赋形剂制成适合口服、不经消化道注射或通过鼻内给药的片剂或糖衣片、颗粒、舌下片、胶囊、栓剂、乳剂、软膏、涂肤胶、注射制剂、口服液。所述赋形剂包括常规的填充剂、崩解剂、粘合剂等。所述填充剂如淀粉、乳糖、微晶纤维素、糊精、甘露醇、氧化镁、硫酸钙等常用填充剂。所述崩解剂如羧甲基纤维素及其盐、交联羧甲基纤维素及其盐、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素等常用崩解剂。所述粘合剂如聚维酮、羟丙基甲基纤维素、淀粉浆等常用粘合剂。所述润滑剂如硬脂酸镁、硬脂酸钙等。
本发明提供的上述枸橼酸舍曲林多晶型体在制备治疗抑郁症的相关症状和早泄症的药物中的用途。
附图说明
图1：本发明实施例1枸橼酸舍曲林晶型A的X-射线粉末衍射谱图。
图2：本发明实施例1枸橼酸舍曲林晶型A的红外光谱图。
图3：本发明实施例2枸橼酸舍曲林晶型B的X-射线粉末衍射谱图
图4：本发明实施例2枸橼酸舍曲林晶型B的红外光谱图。
具体实施方式
为了更详细的介绍本发明，给出下述制备实例。但本发明的范围不局限于此。
实验条件：
需要说明的是，在粉末样品X射线衍射图谱中，由晶体化合物得到的衍射谱图特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径、混合物的相对含量和其它测试条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶体并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的位置而不是它们的相对强度。另外，判断晶型是否一样时应注意保持整体观念，因为并不是一条衍射线代表一个物相，而是一套特定的“d-I/I1”数据才代表某一物相。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的晶体是特征性的。
实施例1：枸橼酸舍曲林晶型A的制备：
取枸橼酸舍曲林50.0g，加入200ml的95％乙醇，加热到60-70℃溶解至澄清，保持10min，停止加热并滴加6000ml水，降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到的枸橼酸舍曲林结晶性粉末。经X-射线粉末衍射测定，显示得到的晶型为晶型A。具体峰位如下表1所示。
表1：本发明实施例1枸橼酸舍曲林晶型A的X-射线粉末衍射数据
d-value 2Theta
10.40774 8.489
8.21686 10.758
7.51086 11.773
6.77915 13.049
6.06333 14.597
5.46866 16.195
5.19552 17.052
4.93935 17.944
4.38118 20.253
4.26198 20.825
4.09394 21.69
3.93128 22.599
3.806 23.354
3.3561 26.538
3.20684 27.797
3.11644 28.621
2.91816 30.611
2.75289 32.498
2.21907 40.623
对得到的样品进行其他测试，得到的红外光谱如图2所示。
对得到的样品进行溶解度测定，结果为：枸橼酸舍曲林晶型A样品易溶于乙醇(11％，g/ml)、微溶于0.1mol/L盐酸溶液(0.2％，g/ml)，极微溶于水(0.01％，g/ml)。
实施例2：枸橼酸舍曲林晶型B的制备：
取枸橼酸舍曲林50.0g，加入500ml的95％乙醇，加热到60-70℃溶解至澄清，保持10min，停止加热降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到的枸橼酸舍曲林结晶性粉末。经X-射线粉末衍射测定，显示得到的晶型为晶型B。具体峰位如下表2所示。
表2：本发明实施例2枸橼酸舍曲林晶型B的X-射线粉末衍射数据
d-value 2Theta
6.87119 12.873
6.2533 14.152
5.95815 14.857
5.67372 15.606
5.35544 16.54
5.15702 17.181
4.87193 18.194
4.43993 19.982
4.21121 21.079
3.9882 22.273
3.60758 24.658
3.2666 27.279
3.11787 28.607
3.01326 29.623
2.90445 30.759
2.82738 31.619
2.67865 33.425
2.53958 35.314
对得到的样品进行其他测试，得到的红外光谱如图4所示。
对得到的样品进行溶解度测定，结果为：枸橼酸舍曲林晶型B样品溶解于乙醇(1％，g/ml)、极微溶解于0.1mol/L盐酸溶液(0.01％，g/ml)，几乎不溶于水(小于0.01％，g/ml)。
实施例3：枸橼酸舍曲林晶型A的制备：
取枸橼酸舍曲林50.0g，加入500ml的95％乙醇，加热到60-70℃溶解至澄清，保持10min，停止加热并滴加10000ml水，降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到的枸橼酸舍曲林结晶性粉末。经X-射线粉末衍射测定，显示得到的晶型与实施例1的晶型一致。具体峰位如下表1所示。
表3：本发明实施例3枸橼酸舍曲林晶型A的X-射线粉末衍射数据
d-value 2Theta
10.29621 8.581
8.18349 10.802
7.47345 11.832
6.77695 13.053
6.03419 14.668
5.44748 16.258
5.16764 17.145
4.91592 18.03
4.63469 19.134
4.36799 20.315
4.25045 20.883
3.92196 22.654
3.80046 23.388
3.44557 25.837
3.34967 26.59
3.19261 27.924
3.11042 28.677
3.01153 29.64
2.90955 20.704
2.74956 32.539
2.42382 37.06
2.21913 40.622
对得到的样品进行红外测试，得到的红外光谱与图2一致。
实施例4：枸橼酸舍曲林晶型B的制备：
取枸橼酸舍曲林50.0g，加入200ml的95％乙醇，加热到60-70℃溶解至澄清，保持10min，停止加热降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到的枸橼酸舍曲林结晶性粉末。经X-射线粉末衍射测定，显示得到的晶型与实施例2的晶型一致。具体峰位如下表2所示。
表4：本发明实施例4枸橼酸舍曲林晶型B的X-射线粉末衍射数据
d-value 2Theta
9.65441 9.153
8.35948 10.574
6.85922 12.896
6.23324 14.197
5.95556 14.863
5.65804 15.649
5.33053 16.617
5.14247 17.23
4.86577 18.218
4.65475 19.051
4.44042 19.98
4.19827 21.145
3.97964 22.321
3.77309 23.56
6.60265 24.692
3.26231 27.315
3.11429 28.641
3.0071 29.685
2.89828 30.826
2.82384 31.66
2.67111 33.522
2.53806 35.336
对得到的样品进行红外测试，得到的红外光谱如图4一致。
显然本文公开的本发明经充分考虑以实现上述目标，但应了解所属领域技术人员可以提出许多改进和实施方案，因此，所附权利要求覆盖所有这些落入本发明的主旨和范围的改进和实施方案。
实施例5：晶型A、晶型B的枸橼酸舍曲林的稳定性试验
1、影响因素试验：
取枸橼酸舍曲林的晶型A和晶型B样品，分别进行影响因素试验，分别于0天、5天、10天、30天取样检验。影响因素试验条件如下：(1)高温试验：60℃，称量瓶中开口放置；(2)高湿试验：25℃，RH92.5％，称量瓶中开口放置。(3)光照试验：4500Lx±500Lx，称量瓶中开口放置。
结果：在0至30天考察期间，样品在高温60℃，放置30天后样品的有关物质的检测结果与0天初始结果相比，晶型A的杂质总量由0.00％增加到0.09％，晶型A的杂质总量由0.00增加到0.02％。样品置于25℃，相对湿度92.5％的恒温恒湿培养箱中，放置30天后，样品的有关物质检测结果与0天初始结果相比无差别。光照30天，样品的有关物质检测结果与0天初始结果相比无差别。
在0至30天考察期间，高温60℃、高湿、光照条件下，各时间点的对映异构体未检出。
在0至30天考察期间，高湿、光照条件下外观颜色未发生改变，高温条件下药物颜色由白色逐渐变为浅黄色。
由上述的结果看出，高温60℃条件下，两种晶型样品不太稳定，有关物质稍有增加。而在光照、高湿条件下，两种晶型质量很稳定，未发生变化。
2、加速稳定性试验
取三批中试规模的晶型A的枸橼酸舍曲林样品，置RH75％(NaCl饱和溶液)中，并放置于室温为40℃的恒温培养箱中。于1月、2月、3月、6月取样按稳定性重点考察项目进行测定。
结果：本品三批样品市售包装，在40℃、相对湿度75％RH条件下考察6个月，各项考察指标无明显变化，其中有关物质变化范围为0.72％(最低)～0.91％(最高)。含量的变化范围为98.8％(最低)～99.2％(最高)，未显示明显的下降趋势。表明晶型A的枸橼酸舍曲林在加速稳定性6个月中稳定性良好。
3、长期稳定性试验
取三批中试规模的晶型A的枸橼酸舍曲林样品，置RH 64％(NaCO2饱和溶液)中，并放置于室温为25℃的恒温培养箱中。于3月、6月、9月、12月、18月、24月、36月取样按稳定性重点考察项目进行测定。
结果：本品三批样品市售包装，在25℃、相对湿度64％RH条件下考察36个月，各项考 察指标无明显变化，其中有关物质变化范围为0.72％(最低)～0.81％(最高)。含量的变化范围为99.32％(最低)～100.02％(最高)，未显示明显的下降趋势。表明晶型A的枸橼酸舍曲林在36个月中稳定性良好。
实施例6：晶型A、晶型B的枸橼酸舍曲林的溶出度试验
分别取晶型A、晶型B枸橼酸舍曲林采取相同处方、工艺制备枸橼酸舍曲林片与通过溶出度测定区分其溶解性能的不同，以评价两种晶型的枸橼酸舍曲林的溶出特性。结果如下表。
表5两种晶型的枸橼酸舍曲林片溶出度测定对比结果表
Figure PCTCN2015083017-appb-000001
由此可见，晶型A的枸橼酸舍曲林溶解速度快，10分钟时已达到溶出峰值，而晶型B的溶解速度比晶型A稍慢，于20分钟时达到溶出的峰值。因此，更优选晶型A的枸橼酸舍曲林进行下一步的临床试验。
再取晶型A枸橼酸舍曲林制备的枸橼酸舍曲林片与相同处方、工艺制备的盐酸舍曲林片通过两种不同溶出介质中溶出度测定区分其溶解性能的不同，以评价两种舍曲林的溶出特性。结果如下表。
表6枸橼酸舍曲林片和盐酸舍曲林片溶出度测定对比结果表
Figure PCTCN2015083017-appb-000002
经试验证明，枸橼酸舍曲林在溶解性能和溶出度两个方面均优于盐酸舍曲林。1克枸橼酸舍曲林可溶解于13ml乙醇和4.5ml氯仿中，而1克盐酸舍曲林可溶解于70ml乙醇和9ml氯仿中。以0.1mol/L盐酸溶液为溶出液，枸橼酸舍曲林片15分钟溶出度可达97％，而盐酸舍曲林片15分钟溶出度仅达90％。
实施例7：晶型A的枸橼酸舍曲林的2期临床试验数据
2005年由北京大学第一医院牵头进行关于晶型A的枸橼酸舍曲林治疗早泄的有效性和安全性评价的临床试验，本试验按照剂量可调、随机双盲、安慰剂平行对照的多中心临床研究设计。计划有180名受试者进入本研究，被随机分配至试验组和安慰剂对照组。由6所医院共同完成(参加二期临床的另外五家医院为：北京大学人民医院、北京大学第三医院、解放军总医院、北京同仁医院、北京朝阳医院)。
本试验共入组患者178例，其中，枸橼酸舍曲林118例、安慰剂组60例；完成试验全部访视者169例，枸橼酸舍曲林115例、安慰剂组54例；全部患者均使用了研究药物并进行了至少一次安全性评价和疗效评价，进入安全性人群、ITT[愿意治疗(Intent To Treat))]人群，166例患者进入PP[符合方案(Per Protocol)]人群。
共9例患者提前终止研究，其中试验组(枸橼酸舍曲林)3例(2.54％)，对照组(安慰剂)6例(10％)。两组患者的人口学资料，基线病情等方面，无统计学差异，两组具有可比性。
通过本次为期6周的多中心、随机双盲、安慰剂平行对照评价枸橼酸舍曲林治疗早泄有效性和安全性临床研究，结果显示：枸橼酸舍曲林片连续给药2周后按需给药2-4周用于治疗早泄患者是有效和安全的。
射精潜伏时间(分钟)及延长时间效果明显：
枸橼酸舍曲林、安慰剂组治疗前中位射精潜伏时间分别为1.20、1.17分钟，治疗结束(6周)时中位射精潜伏时间分别为3.79、1.79分钟，中位射精潜伏时间分别延长2.56、0.86分钟。
患者性生活满意度明显提高：
枸橼酸舍曲林、安慰剂组患者治疗前除个别患者偶有满意外，绝大多数均无满意的性生活，治疗后性生活满意度平均值分别为45.76％、14.65％％，两组差异有统计学意义，枸橼酸舍曲林、安慰剂组患者分别有64.47％、17.02％患者有不同程度改善。
患者配偶性生活满意度结果与患者性生活满意度结果基本一致。
患者有无满意性生活的变化：
治疗前两组患者几乎均无满意性生活，治疗后枸橼酸舍曲林组有满意性生活的比率上升到41.53％，安慰剂对照组则为13.33％。
两组试验前后实验室检查、心电图检查及不良事件情况均相近，枸橼酸舍曲林组发生一例肝功异常。
结论：晶型A的枸橼酸舍曲林用于治疗早泄是安全和有效的。
实施例8：晶型A的枸橼酸舍曲林的生物等效性试验
2003年由国家药品临床研究基地辽宁省人民医院沈阳药科大学药物代谢与药物动力学实验室进行了枸橼酸舍曲林片人体生物利用度及生物等效性试验，本试验采用液相色谱-质谱-质谱联用法，测定了18名健康男性受试者口服由晶型A的枸橼酸舍曲林片(受试制剂，哈尔滨健迪医药科技开发有限公司和哈药集团三精制药有限公司研制)和佐洛复片(参比制剂， 大连辉瑞制药有限公司生产)后不同时刻血浆中舍曲林的浓度，绘制了血药浓度-时间曲线。根据血药浓度-时间数据，采用梯形法计算AUC值，以半对数作图法，由消除相末端的浓度点计算t 1/2，并求出主要药物动力学参数。
18名健康受试者口服含舍曲林50mg的受试制剂和参比制剂后，测得血浆中舍曲林的T max分别为7.1±2.3(均值±标准差，下同)和7.6±2.2h，C max分别为12.07±6.53和10.76±3.21ng/ml，t 1/2分别为30.66±10.86和31.92±7.56h，用梯形法计算，AUC 0-t分别为393.4±195.4和396.7±148.5ng·h/ml，AUC 0-∞分别为453.0±230.1和459.6±188.5ng·h/ml。以AUC 0-t计算，枸橼酸舍曲林片的相对生物利用度平均为97.7±15.9％。
将所得的主要药动学参数对数转换后进行方差分析，并进一步采用双单侧t检验和(1-2α)置信区间法进行生物等效性评价。结果表明：两种制剂的AUC 0-t和C max均拒绝生物不等效假设。受试制剂AUC 0-t的90％可信限为参比制剂相应参数的87.9％～105.8％；C max的90％可信限为参比制剂相应参数的97.6％～117.6％。可认为两种制剂具有生物等效性。
[根据细则26改正13.08.2015]　
[根据细则26改正13.08.2015]　

Claims (10)

  1. 一种枸橼酸舍曲林的晶型，所述枸橼酸舍曲林的晶型为晶型A、晶型B，所述枸橼酸舍曲林的晶型基本上是纯净的。
  2. 根据权利要求1所述枸橼酸舍曲林的晶型，所述晶型A，其X-射线粉末衍射图中大约在2θ为23.35位置有峰；或者其X-射线粉末衍射图中大约在2θ为8.49、10.76、11.77、13.05、14.59、16.20、20.25、20.83、22.60、23.35和26.54位置的一处或多处有峰；或者其X-射线粉末衍射图基本上如图1所示。
  3. 根据权利要求1所述的枸橼酸舍曲林的晶型，所述晶型B，其X-射线粉末衍射图中大约在2θ为21.14位置有峰；或者其X-射线粉末衍射图中大约在2θ为14.20、14.86、15.65、16.62、17.23、18.22、19.98、21.14、24.69、27.32、28.64、29.69和30.83位置的一处或多处有峰；或者其X-射线粉末衍射图基本上如图3所示。
  4. 根据权利要求2所述的枸橼酸舍曲林晶型A，其特征在于：所述晶型A具有基本上如图2所示的红外光谱。
  5. 根据权利要求3所述的枸橼酸舍曲林晶型B，其特征在于：所述晶型B具有基本上如图4所示的红外光谱。
  6. 根据权利要求2所述的枸橼酸舍曲林晶型A的制备方法，其具体为：取枸橼酸舍曲林50.0g，加入250ml的95％乙醇，加热到60～70℃溶解至澄清，保持10分钟，停止加热，并滴加7500ml水，降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到枸橼酸舍曲林晶体A晶型。
  7. 根据权利要求6所述的方法，其特征在于：所述95％乙醇用量与枸橼酸舍曲林的比例为4ml～10ml∶1g；所述的95％乙醇和水的体积比例为1：20～30。
  8. 根据权利要求3所述的枸橼酸舍曲林晶型B的制备方法，其具体为：取枸橼酸舍曲林50.0g，加入300ml的95％乙醇，加热到60-70℃溶解至澄清，保持10分钟，停止加热降至室温，保持搅拌24h，过滤，常温减压干燥12小时得到枸橼酸舍曲林晶体B晶型。
  9. 根据权利要求8所述的方法，其特征在于：所述95％乙醇用量与枸橼酸舍曲林的比例为 4ml～10ml∶1g。
  10. 根据权利要求1所述的枸橼酸舍曲林在制备治疗抑郁症的相关症状和早泄症的药物中的用途。
PCT/CN2015/083017 2015-07-01 2015-07-01 枸橼酸舍曲林的2种晶型及其制备方法 WO2017000270A1 (zh)

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CN111675610A (zh) * 2020-06-18 2020-09-18 湖南新绿方药业有限公司 一种制备高纯度、不结块细颗粒枸橼酸晶体的精制方法

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CN1285345A (zh) * 2000-09-15 2001-02-28 哈尔滨健迪医药科技开发有限公司 舍曲林及其盐和它们用于治疗哺乳动物早泄的用途
CN105061217A (zh) * 2015-06-30 2015-11-18 徐静 枸橼酸舍曲林的2种晶型及其制备方法

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CN1285345A (zh) * 2000-09-15 2001-02-28 哈尔滨健迪医药科技开发有限公司 舍曲林及其盐和它们用于治疗哺乳动物早泄的用途
CN105061217A (zh) * 2015-06-30 2015-11-18 徐静 枸橼酸舍曲林的2种晶型及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111675610A (zh) * 2020-06-18 2020-09-18 湖南新绿方药业有限公司 一种制备高纯度、不结块细颗粒枸橼酸晶体的精制方法
CN111675610B (zh) * 2020-06-18 2023-08-29 湖南新绿方药业有限公司 一种制备高纯度、不结块细颗粒枸橼酸晶体的精制方法

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