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CN-122011081-A - Preparation method of budesonide new crystal form and budesonide new crystal form

CN122011081ACN 122011081 ACN122011081 ACN 122011081ACN-122011081-A

Abstract

The invention discloses a preparation method of a budesonide new crystal form and the budesonide new crystal form, which adopts the technical scheme that in a solvent crystallization system of budesonide, gradient cooling is adopted in the crystallization process, and the budesonide new crystal form is finally produced through freeze drying.

Inventors

  • XU KAILIN
  • LIANG LIYIN
  • LIU XINYU
  • Liao Shujin
  • ZHAO SUQING

Assignees

  • 广东工业大学

Dates

Publication Date
20260512
Application Date
20251227

Claims (8)

  1. 1. The preparation method of the budesonide new crystal form is characterized in that the budesonide new crystal form is produced by gradient cooling in the dissolution and crystallization process of budesonide and is obtained by freeze drying.
  2. 2. The method for preparing a novel crystalline form of budesonide according to claim 1, wherein the gradient cooling is performed by storing at-20 ℃ for 25-68 hours and then at-80 ℃ for 26-96 hours.
  3. 3. The process for preparing a crystalline form of budesonide according to claim 1, wherein the freeze-drying is at-40 ℃, freeze-drying of 7 d.
  4. 4. The process for preparing a novel crystalline form of budesonide according to claim 1, wherein the dissolution of budesonide is by dissolving budesonide in methanol followed by the addition of water.
  5. 5. The method for preparing the novel budesonide crystal according to claim 1, wherein the ratio of budesonide, methanol and water is 100 mg:5 mL:5 mL.
  6. 6. The method for preparing a novel crystalline form of budesonide according to any one of claims 1 to 5, comprising the following steps in order: 1) Dissolving 100 mg budesonide in 5 mL methanol, and performing ultrasonic vibration until the budesonide is completely dissolved to obtain a methanol solution of the budesonide for later use; 2) Preparing 5 mL of purified water for later use; 3) Then using a pipette to quickly drop the budesonide solution prepared in the step 1) into the step 2), and performing the whole process at room temperature; 4) Sealing with fresh-keeping film after adding, and punching several small holes at the sealing place, and storing at-20deg.C for 25-68 hr; 5) Transferring the solution in 4) to a refrigerator at-80 ℃ for 26-96 h 6) The solution in 5) was transferred to a freeze dryer with a freeze dryer cold trap temperature set at-40 ℃ and stored at 7 d.
  7. 7. The novel budesonide crystal form is characterized by being prepared by adopting the preparation method of the novel budesonide crystal form in any one of claims 1-6.
  8. 8. The novel crystalline form of budesonide according to claim 7, wherein the novel crystalline form of budesonide has an X-ray powder diffraction pattern 2-theta value of 6.13 ° ± 0.2 °, 12.19 ° ± 0.2 °, 18.25 ° ± 0.2 °, 24.59 ° ± 0.2 °, 30.87 ° ± 0.2 °, 37.29 ° ± 0.2 °.

Description

Preparation method of budesonide new crystal form and budesonide new crystal form Technical Field The invention belongs to the technical field of medicine preparation, and particularly relates to a method for inducing a budesonide medicine crystal form by using low-temperature control. Background The development and accurate regulation of new crystal forms of medicaments are important components of pharmaceutical crystallography research, and directly determine whether dominant crystal forms with excellent physicochemical properties, outstanding curative effect and high safety index can be screened out, so that the development of the crystal forms has immeasurable academic value and real components. Different crystal forms of the same medicine often have distinct characteristics in curative effect, safety, stability and even preparation technology. The essence of crystallization is molecular self-assembly, hydrophobic accumulation, hydrogen bond network, van der Waals attraction, electrostatic coupling and other intermolecular acting forces, strength and orientation, molecular arrangement operation, and finally locking of the crystal appearance and skeleton. At low temperature, the nucleation rate is inhibited under low supersaturation, the system is easier to fall into a metastable zone, the high-energy polymorphism or solvate appears preferentially, the original conformation of flexible drug molecules is frozen at low temperature, the directional interactions of intermolecular hydrogen bonds, halogen bonds and the like are changed, and a hydrogen bond network which cannot be obtained at normal temperature is generated, so that new crystal cells are assembled, laminar or needle-shaped growth is caused by slow diffusion, a large amount of dislocation and microstrain are introduced into the crystal cells, and conditions are provided for subsequent crystal growth or crystal transformation. The patent selects the gradient cooling induced budesonide based on freeze drying as an experimental method for research, and discusses the formation of a new crystal form of the gradient cooling induced budesonide based on freeze drying and a method thereof. Budesonide (Budesonide, BUD for short), chemical name of 16 alpha, 17 alpha-22R, S-propylmethylenedioxy-pregna-1, 4-diene-11 beta, 21-dihydroxy-3, 20-dione, chemical formula C 25H34O6, and structural formula shown below. The medicine is developed and marketed by Astra AB (AstraZeneca) which is one of precursor companies of Asparagus (AstraZeneca) in Sweden, is an inhaled glucocorticoid, has strong local anti-inflammatory and immunosuppressive effects, can remarkably inhibit the generation and release of airway inflammatory mediators, is widely used for the long-term control of bronchial asthma and Chronic Obstructive Pulmonary Disease (COPD) in clinic, and can also be used for the treatment of allergic rhinitis and inflammatory bowel disease. As known, BUD has only one crystal form, and Chinese patent CN116650449A (title of the invention: an inhalation type ultrafine crystal method of budesonide with adjustable particle size) discloses a method for micronizing ultrafine crystals of budesonide, wherein the 2 theta value of the X-ray powder diffraction pattern of the ultrafine crystals of budesonide is 6.06°±0.2°、10.10°±0.2°、11.36°±0.2°、12.07°±0.2°、14.43°±0.2°、15.42°±0.2°、16.04°±0.2°、10.10°±0.2°、16.88°±0.2°、10.10°±0.2°、18.43°±0.2°、19.56°±0.2°、21.34°±0.2°、22.76°±0.2°. Chinese patent CN119390750a discloses a method of ultra-fine crystals of budesonide whose X-ray powder diffraction pattern 2 theta values are consistent with CN116650449 a. The preparation of budesonide porous microspheres by a high pressure homogenization technique in combination with a spray drying method illustrates a method for preparing budesonide porous microspheres by a high pressure homogenization technique in combination with a spray drying method, wherein the budesonide porous microspheres obtained by the high pressure homogenization method in combination with the spray drying are amorphous particles. Disclosure of Invention The invention aims to provide a gradient cooling auxiliary regulation and control method based on freeze drying, and a new crystal form of budesonide is obtained. A second object provided by the present invention is to provide a new crystalline form of budesonide. Therefore, the technical scheme provided by the invention is as follows: for this purpose, the first technical solution provided by the present invention is as follows: The preparation process of budesonide crystal form includes gradient cooling to induce budesonide crystal form to produce during the dissolution and crystallization of budesonide, and freeze drying to obtain budesonide crystal form. Further, the preparation method of the budesonide new crystal form comprises the steps of firstly preserving at-20 ℃ for 25-68 hours and then preserving at-80 ℃ for 26-96 hours. Further, the preparation method of the budeso