WO2012142927A1 - 一种纯化二氢吡啶类钙通道阻滞剂并制备其纳米的方法 - Google Patents

一种纯化二氢吡啶类钙通道阻滞剂并制备其纳米的方法 Download PDF

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WO2012142927A1
WO2012142927A1 PCT/CN2012/074045 CN2012074045W WO2012142927A1 WO 2012142927 A1 WO2012142927 A1 WO 2012142927A1 CN 2012074045 W CN2012074045 W CN 2012074045W WO 2012142927 A1 WO2012142927 A1 WO 2012142927A1
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ultrasonic
calcium channel
crystallization
pharmaceutically acceptable
amount
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PCT/CN2012/074045
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English (en)
French (fr)
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陈琼
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合肥贝霓医药科技有限公司
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Priority claimed from CN201110096853.6A external-priority patent/CN102746217B/zh
Application filed by 合肥贝霓医药科技有限公司 filed Critical 合肥贝霓医药科技有限公司
Priority to JP2014504151A priority Critical patent/JP2014511867A/ja
Priority to EP12773774.0A priority patent/EP2700632A4/en
Priority to US14/112,236 priority patent/US20140031557A1/en
Publication of WO2012142927A1 publication Critical patent/WO2012142927A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0081—Use of vibrations, e.g. ultrasound

Definitions

  • the invention relates to the technical field of medicine, and is a method for purifying a dihydropyridine calcium channel ion blocker drug and a pharmaceutically acceptable salt thereof and directly preparing the nanoparticle thereof by ultrasonic crystallization technology.
  • Dihydropyridine calcium channel blockers are an important class of cardiovascular drugs that have developed rapidly in the past 20 years after ⁇ -blockers. They are now widely used in the treatment of hypertension and angina pectoris. Some arrhythmias such as supraventricular tachycardia and hypertrophic cardiomyopathy, some drugs are also used to prevent cerebral ischemia and spasm and to reverse early atherosclerosis.
  • dihydropyridine calcium channel blockers especially cilnidipine, lercanidipine, amlodipine and benidipine in water
  • a sex drug or a pharmaceutically acceptable salt thereof is rapidly dissolved from a preparation, and it is often necessary to pulverize the drug to the nanoparticles.
  • 794993 provides a method of pulverizing benidipine hydrochloride to 1. 0 ⁇ 50. 0 4 111.
  • This patent pulverizes the crystals of large particles "from large to small” by mechanical grinding to a crystal of a suitable size. This method not only consumes a lot of energy and time, but also has a wide distribution of crystal diameters.
  • the invention purifies the dihydropyridine calcium channel blocker drug or its pharmaceutically acceptable salt (such as cilnidipine, lercanidipine, amlodipine) by ultrasonic crystallization technology, and directly obtains Nanoparticles of suitable crystal size.
  • the most notable feature of the present invention is that crystallization is obtained from “small to large", and since the solvent is rapidly and crystallization in solution, the crystal grain size distribution is concentrated; the required energy consumption is low, time and labor saving, and production is easy. Summary of the invention:
  • the invention purifies a dihydropyridine calcium channel ion blocker drug and a pharmaceutically acceptable salt thereof by a technique of ultrasonic crystallization, and can directly prepare a nanoparticle thereof.
  • the ordinary solution crystallization (crystallization) process is usually achieved by lowering the temperature, standing, etc., which is a long and slow process.
  • a saturated or supersaturated solution is first formed by changing the temperature, changing the polarity of the solvent, adding a poor solvent, and the like, and then obtaining a nano-sized granule having a suitable crystal size by ultrasonication.
  • Solution ultrasonic crystallization (crystallization) is in one A process of rapid balancing.
  • the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof such as cilnidipine, lercanidipine, and ammonia chloride
  • a solvent such as methanol
  • a saturated or supersaturated solution is formed by changing the temperature, changing the polarity of the solvent, adding a poor solvent, etc., and promoting the crystallization of the solution by ultrasonic strengthening.
  • high-purity drug nanoparticles are directly obtained by conventional operations such as filtration (straining), washing, and drying.
  • the good solvent and inferior solvent for dissolving and/or forming the drug nanoparticles are generally lower ketone, lower alcohol, lower ether, lower ester, acetonitrile, dichloromethane, chloroform, acetic anhydride and common small molecule solvent, and the preferred solvent is methanol.
  • a single common solvent such as ethanol, acetone, N, N-dimethylformamide (DMF), acetonitrile, diethyl ether, methylene chloride, dimethyl sulfoxide (DMS0) and water, or two, or three and three
  • the combination of the above solvents, a single solvent is preferably methanol and acetonitrile, and the combined solvent mainly selects a solvent combination of mutually soluble, preferably methanol-acetone, methanol-water, methanol-ethanol, acetonitrile-water, acetonitrile-acetone, DMF-water, DMF-acetone, DMS0-water, DMS0-ethanol, nine kinds of two solvents combination, but not limited to this.
  • the ratio of methanol to acetone is 0 ⁇ 100%: 100 ⁇ 0%, the ratio of methanol to water is 0 ⁇ 100%, the ratio of methanol to ethanol is 0 ⁇ 100%, and the ratio of acetonitrile to water is 100 ⁇ 0%: 0 ⁇ 100%, the ratio of acetonitrile to acetone is 100 ⁇ 0%: 0 ⁇ 100%, the ratio of DMF to water is 0 ⁇ 100%: 100 ⁇ 0%, the ratio of DMF to acetone is 0 ⁇ 100%: 100 ⁇ 0%; DMS0-water ratio is 0 ⁇ 100%: 100 ⁇ 0%; DMS0-ethanol ratio is 0 ⁇ 100%: 100 ⁇ 0%.
  • the ultrasonic crystallization frequency is from 20 kHz to 500 kHz, preferably from 20 kHz to 100 kHz.
  • the ultrasonic power is lmW to 5000W, preferably 1W to 500W.
  • the ultrasonic intensity is 0. lmW/cm2 ⁇ 500W cm2, preferably 0. lW/cm2 ⁇ 50W/cm2 o
  • the ultrasonic time is lmin ⁇ 24hour, preferably 3min ⁇ 120min.
  • the ultrasonic crystallization temperature is _78 °C to 100 °C, and the preferred temperature is -5 °C to 30 °C.
  • the obtained nanoparticles of the dihydropyridine calcium channel ion blocker drug have a particle size of 20 nm to 2000 nm, and the median size of the particle size is 200 nm to 1500 nm.
  • the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof may be added in an amount of 0.1 to 40 times lower alcohol, heated to reflux to dissolve, lower in temperature, and ultrasonically assisted in crystallization.
  • the amount of ethanol is 0. 01 ⁇ 100 times the amount of ethanol.
  • the amount of ethanol is 0. 1 ⁇ 40 times the amount of ethanol. , lowering the temperature, ultrasonic assisted crystallization.
  • the amount of water is 0. 01 ⁇ 100 times the amount of water.
  • the amount of the water is 0. 01 ⁇ 100 times the amount of water. , lowering the temperature, ultrasonic assisted crystallization.
  • the amount of the primary crystal of the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof is added, 0.1 to 40 times lower alcohol, heated to reflux to dissolve, adding 1/100 amount of water, while Ultrasonic drips into the water.
  • an amount of the primary crystallization of the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof 0. 1 to 40 times lower alcohol, dissolved under heating, adding 1/10 amount of acetone, ultrasonic Add acetone to the start of crystallization, stop adding acetone, and continue ultrasound (not more than 60 minutes).
  • the first crystallization of the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof 0. 1 ⁇ 15 times N, N-dimethylformamide (DMF), heated to reflux , adding 0. 1 ⁇ 100 times the amount of water, lowering the temperature, and ultrasonic assisted crystallization.
  • DMF N, N-dimethylformamide
  • the amount of primary crystals of the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof is added, 0.1 to 15 times of DMF, dissolved under heating, and added with 1/100 amount of water while ultrasonically Drip a JT ⁇
  • the amount of ethanol is 0. 1 ⁇ 100 times the amount of ethanol.
  • the amount of the ethanol is 0. 1 ⁇ 100 times the amount of ethanol. , lower the temperature, ultrasonic crystallization.
  • the amount of primary crystals of the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof is added, 0.1 to 15 times of DMF, dissolved under heating, and added with 1/10 amount of ethanol. Add acetone to the start of crystallization, stop adding acetone, and continue the ultrasound (not more than 60 minutes).
  • the primary crystal of the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof is added in an amount of 0.1 to 40 times acetonitrile, heated to reflux to dissolve, the temperature is lowered, and ultrasonic assisted crystallization.
  • the amount of water is 0. 01 ⁇ 100 times the amount of water, the amount of water is 0. 01 ⁇ 100 times the amount of water, Reduce the temperature and assist the crystallization.
  • the amount of primary crystals of the dihydropyridine calcium channel ion blocker drug or a pharmaceutically acceptable salt thereof is added, 0.1 to 40 times of acetonitrile is added, and the reflux angle is heated to add 1/100 amount of water while ultrasonically Drip crystallization.
  • the amount of ethanol is 0. 1 ⁇ 10 times the amount of ethanol.
  • the amount of ethanol is 0. 1 ⁇ 10 times the amount of ethanol. , lower the temperature, ultrasonic crystallization.
  • the amount of acetone is 0. 1 ⁇ 10 times the amount of acetone.
  • the acetone is added in an amount of 0. 1 ⁇ 10 times the amount of acetone. , lower the temperature, ultrasonic crystallization.
  • the amount of acetone is 0. 1 ⁇ 10 times the amount of acetone.
  • the acetone is added in an amount of 0. 1 ⁇ 10 times the amount of acetone. Add acetone to the crystallization after the ultrasonication, stop adding the acetone, and continue the ultrasound (not more than 60 minutes).
  • the amount of ethanol is 0. 1 ⁇ 10 times the amount of ethanol.
  • the amount of ethanol is 0. 1 ⁇ 10 times the amount of ethanol.
  • Ultrasonic drops are added to the ethanol to start crystallization, stop adding acetone, continue ultrasound (not more than 5 minutes).
  • the amount of the ethanol is 0. 1 ⁇ 100 times the amount of ethanol.
  • the amount of the ethanol is 0. 1 ⁇ 100 times the amount of ethanol. , lower the temperature, ultrasonic crystallization.
  • Amlodipine mesylate primary crystal 10g adding 10mL of methanol, heated to reflux and dissolved, cooled in ice bath, 150W ultrasonic lOmin crystallization, suction filtration, collected white crystal, crystal size see Figure 1.
  • the primary crystal of lercanidipine hydrochloride was 10g, added with 10mL of methanol, dissolved under heating and refluxed, added with water 20mL, cooled in ice bath, 150W ultrasonic, and after crystallization, continue to ultrasonic lOmin to obtain pale yellow crystal.
  • the primary crystal of lercanidipine hydrochloride was 10 g, and 10 mL of methanol was added thereto, and the mixture was heated to reflux to dissolve. Water (3 mL) was added thereto, and 100 W of ultrasonic was applied thereto while adding water to the crystallization.
  • Amlodipine mesylate primary crystal 10g add 10mL of DMF, heated to reflux, add water 3mL, 150W ultrasonic, dripping to complete crystallization.
  • the primary crystal of lercanidipine hydrochloride was 10 g, and 10 mL of methanol was added thereto, and the mixture was heated to reflux to dissolve, and acetone (10 mL) was added thereto, and the mixture was cooled in an ice bath, and 200 W was subjected to ultrasonic crystallization.
  • Example 10 The primary crystal of lercanidipine hydrochloride was 10g, 10mL of methanol was added, dissolved under heating and refluxed, acetone was added 3mL, 200W ultrasonic, acetone was added dropwise to start crystallization, and ultrasonication was continued for 3 min.
  • the primary crystal of cilnidipine was 10g, and 10 mL of DMF was added, and the mixture was heated to reflux to dissolve, and 20 mL of ethanol was added thereto, and the mixture was cooled in an ice bath, and 200 W ultrasonic crystallization was performed.
  • the primary crystal of amlodipine mesylate was 10 g, and 10 mL of acetonitrile was added, and the mixture was heated to reflux to dissolve, cooled in an ice bath, and subjected to ultrasonic crystallization at 150 W.
  • Amlodipine mesylate drug primary crystal 10 g add 10 mL of acetonitrile, dissolved under reflux, add water 10 mL, cool in ice bath, 150 W ultrasonic crystallization.
  • Amlodipine mesylate primary crystal 10g add 10mL of acetonitrile, heated to reflux and dissolve, add water 3mL, 150W ultrasonic, dripping to complete crystallization.
  • the primary crystal of lercanidipine hydrochloride was 10g, added with 10mL of DMSO, dissolved under heating and refluxed, added with water 30mL, cooled in an ice bath, and ultrasonically crystallized by 150W.
  • the primary crystal of lercanidipine hydrochloride was 10g, added with 10mL of DMSO, dissolved under heating and refluxed, added with 20mL of ethanol, cooled in an ice bath, and ultrasonically crystallized by 150W.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种通过超声结晶技术对二氢吡啶类钙通道离子阻滞剂类药物及其可药用盐进行纯化并直接制备其纳米粒的方法。

Description

一种纯化二氢吡啶类钙通道阻滞剂并制备其纳米的方法 技术领域：
本发明涉及医药技术领域， 是通过超声结晶的技术， 对二氢吡啶类钙通道 离子阻滞剂类药物及其可药用的盐进行纯化并直接制备其纳米粒的方法。 背景技术：
二氢吡啶类钙通道阻滞剂类药物是继 β -受体阻滞剂之后， 近 20多年迅速 发展的一类重要的心血管药物， 现在临床上已经广泛的用于治疗高血压、 心 绞痛、 室上性心动过速等心律失常以及肥厚型心肌病等， 有些药物还用于防 治脑缺血和痉挛以及逆转早期动脉粥样硬化。
由于二氢吡啶类钙通道阻滞剂类药物， 尤其是西尼地平、 乐卡地平、 氨 氯地平、 贝尼地平等在水中的溶解度非常低， 为了使二氢吡啶类钙通道离子 阻滞剂性类药物或其可药用盐从制剂中迅速溶出， 往往须将药物粉碎至纳米 颗粒。 例如： 794993 提供了一种将盐酸贝尼地平粉碎至1. 0〜50. 0 4 111的 方法。 该专利是通过机械研磨的方法， "从大至小"将大颗粒的结晶粉碎至适 宜尺寸的晶体。 此法不仅需耗费巨大的能量和时间， 而且晶体颗径分布面宽。
本发明通过超声结晶技术， 意想不到地对二氢吡啶类钙通道阻滞剂类药 物或其可药用盐 （如西尼地平、 乐卡地平、 氨氯地平等） 进行了纯化， 并直 接获得了晶体大小尺寸适宜的纳米粒。 本发明最显著的特点是： "从小到大" 地获得结晶， 而且由于溶剂在溶液中迅速平衡地结晶， 晶体粒径分布比较集 中； 所需能耗低、 省时省力， 易于生产制备。 发明内容：
本发明通过超声结晶的技术， 对二氢吡啶类钙通道离子阻滞剂类药物及 其可药用盐进行了纯化， 并可直接制备其纳米粒的方法。
普通溶液析晶 （结晶） 过程通常是通过降低温度、 静置等手段达到， 是 一个长时间缓慢的过程。 而在本发明所提供的超声结晶方法， 是首先通过改 变温度、 改变溶剂极性、 加入劣溶剂等方法， 形成饱和或过饱和溶液， 然后 通过超声获得晶体大小尺寸适宜的纳米粒体。 溶液超声析晶 （结晶） 是在一 个迅速平衡的过程中进行。 由于析晶 （结晶） 溶剂的不同、 析晶 （结晶） 方 式的不同、 以及晶体生长速度的不同， 分子与分子间的结合方式必然不同， 因此必然导致分子晶型和晶体尺寸的不同。
为获取本专利所述的药物纳米粒， 可先将二氢吡啶类钙通道离子阻滞剂 性类药物或其可药用盐，如西尼地平、乐卡地平、氨氯地平等溶于良溶剂（如： 甲醇等） 中， 然后通过改变温度、 改变溶剂极性、 加入劣溶剂等方法， 形成 饱和或过饱和溶液， 通过超声强化， 促使溶液析晶。然后， 通过过滤（抽滤）、 洗涤、 干燥等常规操作， 直接获得高纯度的药物纳米粒。
溶解并 /或形成药物纳米粒的良溶剂、 劣溶剂通常为低级酮、 低级醇、 低 级醚、 低级酯、 乙腈、 二氯甲垸、 氯仿、 醋酐及常用小分子溶剂， 优选溶媒 为甲醇、 乙醇、 丙酮、 N、 N-二甲基甲酰胺 （DMF)、 乙腈、 乙醚、 二氯甲垸、 二甲亚砜 （DMS0 ) 和水等单一常用溶剂， 或两种、 或三种及三种以上溶剂的 组合， 单一溶剂优选甲醇和乙腈， 联合溶剂主要选择互溶的溶剂组合， 优选 甲醇-丙酮、 甲醇 -水、 甲醇-乙醇、 乙腈 -水、 乙腈-丙酮、 DMF-水、 DMF-丙酮、 DMS0-水、 DMS0-乙醇九种两两溶剂组合， 但不仅限于此。 其中甲醇与丙酮的 比例为 0〜100%： 100〜0%， 甲醇与水的比例为 0〜100%， 甲醇与乙醇的比例为 0〜100%， 乙腈与水的比例为 100〜0%： 0〜100%， 乙腈与丙酮的比例为 100〜 0%： 0〜100%， DMF与水的比例为 0〜100%： 100〜0%， DMF与丙酮的比例为 0〜 100%： 100〜0%； DMS0-水的比例为 0〜100%： 100〜0%； DMS0-乙醇的比例为 0〜 100%： 100〜0%。
超声结晶频率为 20kHz〜500kHz， 优选 20kHz〜100kHz。 超声功率为 lmW〜 5000W, 优选 1W〜500W。 超声声强为 0. lmW/cm2〜500W cm2， 优选 0. lW/cm2〜 50W/cm2 o超声时间为 lmin〜24hour，优选 3min〜120min。超声结晶温度为 _78 °C~100°C，优选温度为 -5 °C ~30 °C。 所获得的二氢吡啶类钙通道离子阻滞剂性 类药物的纳米粒， 其粒径大小为 20 nm~2000nm， 粒径大小的中值为 200nm~1500nm。
具体操作为：
可将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的低级醇， 加热回流溶解， 降低温度， 超声辅助析晶。 或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的甲醇， 加热回流溶解， 加入 0. 01〜100倍量的乙醇， 降 低温度， 超声辅助析晶。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的甲醇， 加热回流溶解， 加入 0. 01〜100倍量的水， 降低 温度， 超声辅助析晶。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的低级醇， 加热回流溶解， 加入 1/100量的水， 边超声边 滴水析晶。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的低级醇， 加热回流溶解， 加入 0. 1〜100倍量的丙酮， 降 低温度， 超声析晶。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的低级醇， 加热回流溶解， 加入 1/10量的丙酮， 超声时滴 加丙酮至开始析晶止， 停止滴加丙酮， 继续超声 （不超过 60分钟）。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜15倍的 N， N-二甲基甲酰胺 （DMF) , 加热回流溶解， 加入 0. 1〜 100倍量的水， 降低温度， 超声辅助析晶。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜15倍的 DMF, 加热回流溶解， 加入 1/100量的水， 边超声边滴水 个 JT曰
曰曰
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜15倍的 DMF, 加热回流溶解， 加入 0. 1〜100倍量的乙醇， 降低 温度， 超声析晶。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜15倍的 DMF, 加热回流溶解， 加入 1/10量的乙醇， 超声时滴加 丙酮至开始析晶止， 停止滴加丙酮， 继续超声 （不超过 60分钟）。
或将二氢吡啶类钙通道离子阻滞剂性类药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈， 加热回流溶解， 降低温度， 超声辅助析晶。 或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈， 加热回流溶角 加入 0. 01〜100倍量的水， 降低 温度， 超声辅助析晶。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈， 加热回流溶角 加入 1/100量的水， 边超声边滴 水析晶。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈， 加热回流溶角 ， 加入 0. 1〜10倍量的乙醇， 降低 温度， 超声析晶。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈， 加热回流溶角 ， 加入 0. 1〜10倍量的丙酮， 降低 温度， 超声析晶。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈， 加热回流溶角 ， 加入 0. 1〜10倍量的丙酮， 超声 时滴加丙酮至开始析晶止， 停止滴加丙酮， 继续超声 （不超过 60分钟）。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈， 加热回流溶角 ， 加入 0. 1〜10倍量的乙醇， 超声 时滴加乙醇至开始析晶止， 停止滴加丙酮， 继续超声 （不超过 5分钟）。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜40倍的乙腈加热回流溶解， ]口入 0. 1〜100倍量的乙醇， 即缓缓 加入 0. 1〜1000倍量的水， 超声 l〜60min。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜20倍的 DMS0加热回流溶解， ]口入 0. 1〜100倍量的乙醇， 降低温 度， 超声析晶。
或将二氢吡啶类钙通道离子阻滞剂性 药物或其可药用盐的初级结晶适 量， 加入 0. 1〜20倍的 DMS0加热回流溶解， 加入 0. 1〜1000倍量的水， 超声析 曰
曰曰 具体实施方式: 以下结合实施例对本发明作详细描述。
实施例 1
甲磺酸氨氯地平初级结晶 10g， 加入 lOmL的甲醇， 加热回流溶解， 冰浴降 温， 150W超声 lOmin析晶， 抽滤， 收集得白色结晶， 晶型尺寸见附图 1。
实施例 2
西尼地平初级结晶 10g，加入 lOmL的甲醇，加热回流溶解，冰浴降温， 150W 超声 lOmin析晶， 抽滤， 得淡黄色结晶。
实施例 3
西尼地平初级结晶 10g， 加入 lOmL的甲醇， 加热回流溶解， 加水 12mL， 冰 浴降温， 150W超声， 析晶后继续超声 2min。
实施例 4
西尼地平初级结晶 10g， 加入 lOmL的甲醇， 加热回流溶解， 加乙醇 20mL， 冰浴降温， 150W超声， 析晶后继续超声 5min。
实施例 5
盐酸乐卡地平初级结晶 10g， 加入 lOmL的甲醇， 加热回流溶解， 加水 20mL， 冰浴降温， 150W超声， 析晶后继续超声 lOmin, 得淡黄色结晶。
实施例 6
盐酸乐卡地平初级结晶 10g， 加入 lOmL的甲醇， 加热回流溶解， 加水 3mL， 100W超声， 边超声边滴加水至析晶完全。
实施例 7
甲磺酸氨氯地平初级结晶 10g， 加入 lOmL的 DMF, 加热回流溶解， 加水 3mL， 150W超声， 滴水至析晶完全。
实施例 8
甲磺酸氨氯地平初级结晶 10. lg， 加入 l lmL的 DMF， 加热回流溶解， 加丙 酮 15mL， 冰浴降温， 200W超声析晶。
实施例 9
盐酸乐卡地平初级结晶 10g， 加入 lOmL的甲醇， 加热回流溶解， 加丙酮 lOmL, 冰浴降温， 200W超声析晶。
实施例 10 盐酸乐卡地平初级结晶 10g，加入 lOmL的甲醇，加热回流溶解，加丙酮 3mL， 200W超声， 滴加丙酮至开始析晶止， 继续再超声 3min。
实施例 11
西尼地平初级结晶 10g， 加入 lOmL的甲醇， 加热回流溶解， 加丙酮 3mL， 200W超声， 滴加丙酮至开始析晶止， 继续再超声 3min。
实施例 12
西尼地平初级结晶 10g， 加入 lOmL的 DMF, 加热回流溶解， 加水 15mL， 200W 超声析晶。
实施例 13
西尼地平初级结晶 10g， 加入 lOmL的 DMF, 加热回流溶解， 加水 5mL， 150W 超声， 滴水至析晶完全。
实施例 14
西尼地平初级结晶 10g， 加入 lOmL的 DMF, 加热回流溶解， 加乙醇 20mL， 冰浴降温， 200W超声析晶。
实施例 15
西尼地平初级结晶 10g，加入 lOmL的 DMF,加热回流溶解，加丙酮 3mL， 200W 超声， 滴加丙酮至开始析晶， 继续再超声 10min。
实施例 16
甲磺酸氨氯地平初级结晶 10g， 加入 lOmL的乙腈， 加热回流溶解， 冰浴降 温， 150W超声析晶。
实施例 17
甲磺酸氨氯地平药物初级结晶 10 g， 加入 lOmL的乙腈， 加热回流溶解， 加水 10mL， 冰浴降温， 150W超声析晶。
实施例 18
甲磺酸氨氯地平初级结晶 10g，加入 lOmL的乙腈，加热回流溶解，加水 3mL， 150W超声， 滴水至析晶完全。
实施例 19
西尼地平初级结晶 10g， 加入 lOmL的乙腈， 加热回流溶解， 加乙醇 10mL， 冰浴降温， 200W超声析晶。 实施例 20
西尼地平初级结晶 10g， 加入 10mL的乙腈， 加热回流溶解， 加丙酮 3mL， 200W超声， 滴加丙酮至开始析晶止， 继续再超声 15min。
实施例 21
西尼地平初级结晶 10. lg， 加入 10mL的乙腈， 加热回流溶解， 加丙酮 3mL， 200W超声， 滴加水至析晶完全。
实施例 22
盐酸乐卡地平初级结晶 10g， 加入 10mL的 DMSO, 加热回流溶解，加水 30mL， 冰浴降温， 150W超声析晶。
实施例 23
盐酸乐卡地平初级结晶 10g， 加入 10mL的 DMSO , 加热回流溶解， 加乙醇 20mL， 冰浴降温， 150W超声析晶。

Claims

权利要求书
1. 一种通过超声结晶技术对二氢吡啶类钙通道离子阻滞剂类药物及其 可药用的盐进行纯化并直接制备其纳米粒的方法。
2. 权利要求 1所述的超声结晶的方法是首先通过改变温度、 改变溶剂 极性、加入劣溶剂等方法， 形成二氢吡啶类钙通道离子阻滞剂性类药物及其 可药用的盐的饱和或过饱和溶液，然后通过超声获得晶体大小尺寸适宜的纳 米粒。
3.按权利要求 1和权利要求 2所述的二氢吡啶类钙通道离子阻滞剂性类 药物及其可药用盐的纳米粒， 其粒径大小为 20nm~2000nm,粒径大小的中值 为 200匪〜 1500匪。
4. 按权利要求 1和权利要求 2所述的超声制备二氢吡啶类钙通道离子 阻滞剂性类药物及其可药用盐纳米粒的温度为 -78°C ~100°C ,优选温度为 -5 °C ~30°C。
5.按权利要求 1和权利要求 2所述的超声制备二氢吡啶类钙通道离子 阻滞剂性类药物及其可药用盐纳米粒的溶媒为低级酮、 低级醇、 低级醚、 低 级酸、低级酯、二氯曱烷、 氯仿、 醋酐及常用小分子溶剂， 优选溶媒为丙酮、 乙醇、 曱醇、 N、 N-二曱基曱酰胺（DMF ) 、 乙腈、 乙醚、 二氯曱烷、 二曱 亚砜（DMSO )和水等单一常用溶剂， 或两种、 或三种及三种以上溶剂的组 合。
6. 按权利要求 1和权利要求 2所述的超声频率为 20kHz ~ 500kHz, 优 选 20kHz ~ 100kHzo
7. 按权利要求 1和权利要求 2所述的超声功率为 lmW ~ 5000W,优选 1W ~ 500W。
8. 按权利要求 1和权利要求 2所述的超声强度为 0.1mW/cm2 ~
500W/cm2, 优选 0.1W/cm2 ~ 50W/cm2。
8. 按权利要求 1和权利要求 2所述的超声时间为 lmin ~ 24hour, 优选 3min ~ 120min。
9. 权利要求 1所述的通过权利要求 2 ~ 8的方法制得的二氢吡啶类钙通 道离子阻滞剂性类药物及其可药用盐的纳米粒。
1
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