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CN-122006284-A - Continuous solution crystallization method, special device and application of bezafibrate crystals with controllable granularity

CN122006284ACN 122006284 ACN122006284 ACN 122006284ACN-122006284-A

Abstract

The invention belongs to the technical field of medicine crystallization, and discloses a continuous elution crystallization method, a special device and application of bezafibrate crystals with controllable granularity. The method is characterized in that a continuous solution crystallization technology of synergy of an ultrasonic field and a tubular crystallizer is adopted, a solution of bezafibrate in a good solvent and an antisolvent are continuously introduced into the tubular crystallizer, mixed crystallization is carried out under the controllable flow rate ratio and ultrasonic energy input, and the generation and crystal growth dynamics of supersaturation degree are precisely regulated, so that the beza Bei Texiao particle size crystal with the average particle size D50 of 2-21 mu m and uniform particle size distribution (C.V. < 70%) is directly obtained. The invention realizes the accurate, continuous and amplified regulation and control of the crystal granularity, the solubility of the obtained product is obviously improved, and the invention is applicable to pharmaceutical preparations with higher requirements on bioavailability.

Inventors

  • ZHU LIANG
  • LIU HAIYANG
  • ZHAO WENLI
  • WANG YANFEI

Assignees

  • 天津科技大学

Dates

Publication Date
20260512
Application Date
20260203

Claims (10)

  1. 1. A continuous solution crystallization method of bezafibrate crystals with controllable product granularity is characterized by comprising the following steps: (1) Continuously introducing the benzalkonium Bei Teliang solvent solution and the antisolvent into a tubular crystallizer at a controllable flow rate ratio, wherein the flow rate ratio of the antisolvent to the good solvent solution is 0.1-15; (2) Applying an ultrasonic field coupled with the tubular crystallizer to act on the mixed liquid flow in the tubular crystallizer to induce the bezafibrate crystals to separate out, wherein the crystallization temperature is 20-25 ℃; (3) Controlling the residence time of bezafibrate crystals in the tubular crystallizer, and regulating and controlling the nucleation and growth of crystals; (4) And collecting crystal slurry flowing out of the outlet of the tubular crystallizer, and carrying out solid-liquid separation and drying to obtain bezafibrate crystals with average particle size D50 less than or equal to 21 mu m.
  2. 2. The continuous dialysis crystallization method as claimed in claim 1, wherein the good solvent is at least one of ethanol, methanol, and acetone, and the anti-solvent is water.
  3. 3. The continuous solvency crystallization method according to claim 1, wherein the concentration of bezafibrate in the beza Bei Teliang solvent solution is 3g/L.
  4. 4. The continuous solvency crystallization method according to claim 1, wherein the flow rate ratio of the anti-solvent to the good solvent solution is in the range of 0.25 to 10.
  5. 5. The method of claim 1, wherein the ultrasound field has a frequency of 10 kHz-50 kHz and a power density of 1W/mL-10W/mL.
  6. 6. The continuous solvency crystallization method according to claim 1, wherein the residence time of the crystals in the tubular crystallizer is 1-60 seconds.
  7. 7. A continuous crystallization apparatus for carrying out the method of any one of claims 1-6, comprising: The liquid supply unit comprises a benzalkonium Bei Teliang solvent solution storage tank, an antisolvent storage tank, two jet pumps for stably conveying the benzalkonium Bei Teliang solvent solution and the antisolvent to the mixed crystallization unit, and a conveying pipeline; the mixed crystallization unit comprises a tubular crystallizer and an ultrasonic energy introduction device fixed below the tubular crystallizer, and output pipelines of the two jet pumps are respectively connected to a feed inlet of the tubular crystallizer; the control system regulates and controls the flow rate ratio of the two liquid flows and the output power of the ultrasonic energy leading-in device; And a product collection unit including a crystal collection tank for receiving and processing the magma from the mixed crystallization unit.
  8. 8. The device according to claim 7, wherein the tubular crystallizer is made of quartz, stainless steel or hastelloy, and the ultrasonic energy introduction device comprises an ultrasonic transducer and an ultrasonic generator, and the ultrasonic transducer adopts a clamping type ultrasonic transducer or an immersion type ultrasonic transducer.
  9. 9. A bezafibrate crystal prepared by the process of any one of claims 1 to 6, characterized in that the average particle size D50 of the crystal is 21 μm or less and the coefficient of variation of the particle size distribution is C.V <70%.
  10. 10. Use of bezafibrate crystals according to claim 9 for the preparation of hypolipidemic drugs for increasing dissolution rate and oral bioavailability.

Description

Continuous solution crystallization method, special device and application of bezafibrate crystals with controllable granularity Technical Field The invention belongs to the technical field of medicine crystallization, and particularly relates to a continuous elution crystallization method, a special device and application of bezafibrate crystals with controllable granularity. Background Bezafibrate (Bezafibrate) is used as a first fibrate lipid-lowering drug, can rapidly lower triglyceride and raise HDL by activating PPAR-alpha, and has irreplaceable clinical value in both acute and chronic hyperlipidemia intervention. However, the very low water solubility of BCS class II (only 3.43 μg·ml -1 at 37 ℃) determines the "dissolution rate = efficacy rate limiting step", which is directly governed by crystal particle size, and the acute phase requires ultra-fine particles of 10 μm or less to achieve "minutes" level fast onset of action, and the maintenance phase requires slow release particles of about 20-150 μm to avoid blood drug fluctuations. Therefore, the "same active molecule, two particle size specifications" has become the most urgent and unmet industrial demand for the high-end formulation market (fast disintegrating tablet+slow release capsule) of bezafibrate. The prior preparation process exploration of the bezafibrate is mainly focused on crystal form innovation, crystallization process optimization and superfine powder development, and partially relates to crystal form determination and particle size control. For example, european patent EP93107734A discloses a crystallization process of a bezafibrate beta-crystal form, a new stable crystal form is determined by characterization of FT-IR, XRD and the like, a specific mixed solvent is adopted for crystallization preparation, the bulk density, the filterability and the flowability of a product are better, the product is processed by a solid preparation, chinese patent CN105218370A discloses a preparation method of a bezafibrate Bei Techao micropowder, one-dimensional or two-dimensional superfine powder with the size less than or equal to 30 mu m is obtained by an ultrasonic auxiliary process, the bioavailability and the solubility of the drug can be improved, and the process is suitable for continuous production. However, in the traditional kettle-type crystallization process, the mass transfer and heat transfer efficiency of a bezafibrate crystallization system is easily influenced by the solvent ratio and the mixing effect, so that the control difficulty of crystal habit consistency is high, and the problem of crystal agglomeration is further aggravated due to the fact that local supersaturation is too high when mass transfer is intensified through stirring. To achieve "acute-ultrafine/chronic-coarse" one-touch switching on one production line, it is necessary to introduce a novel crystallization platform that can achieve conditions of overspray crystallization supersaturation in the pipeline with uniform mixing on the millisecond scale. Disclosure of Invention In order to overcome the limitation of the prior art, the invention provides a continuous solution crystallization method, a special device and application of bezafibrate crystals with controllable granularity. The method realizes the accurate regulation and control of the granularity of the product by strengthening the mixing through the tubular crystallizer and combining the ultrasonic cavitation effect and regulating the two-phase flow rate ratio. The invention aims at realizing the following technical scheme: the invention provides a continuous solution crystallization method of bezafibrate crystals with controllable product granularity, which comprises the following steps: (1) Continuously introducing the benzalkonium Bei Teliang solvent solution and the antisolvent into a tubular crystallizer at a controllable flow rate ratio, wherein the flow rate ratio of the antisolvent to the good solvent solution is 0.1-15; (2) Applying an ultrasonic field coupled with the tubular crystallizer to act on the mixed liquid flow in the tubular crystallizer to induce the bezafibrate crystals to separate out, wherein the crystallization temperature is 20-25 ℃; (3) Controlling the residence time of bezafibrate crystals in the tubular crystallizer, and regulating and controlling crystal nucleation and growth to obtain crystal slurry; (4) And collecting crystal slurry flowing out of the outlet of the tubular crystallizer, and carrying out solid-liquid separation and drying to obtain bezafibrate crystals with average particle size D50 less than or equal to 21 mu m. Preferably, the good solvent is at least one of ethanol, methanol and acetone. Preferably, the preparation method of the good solvent solution comprises the steps of dissolving bezafibrate raw material medicines in the good solvent to prepare a bezafibrate Bei Teliang solvent solution with saturated or nearly saturated concentration, preferably pr