Preparation method of new crystal form of budesonide and new crystal form of budesonide
A novel budesonide crystal form was prepared by using a gradient cooling induction method of freeze-drying, which solves the problem of preparing budesonide crystal forms with excellent physicochemical properties and safety in existing technologies. This method enables a simple and environmentally friendly preparation process and expands the scope of crystal form research.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GUANGDONG UNIV OF TECH
- Filing Date
- 2025-12-27
- Publication Date
- 2026-05-12
AI Technical Summary
Existing technologies make it difficult to prepare new budesonide crystal forms with excellent physicochemical properties and safety through simple methods.
A new budesonide crystal form was prepared by using a gradient cooling induction method during freeze-drying. This was achieved by controlling the freeze-drying conditions through gradient cooling during the solvent crystallization process of budesonide.
A new crystal form was successfully prepared, which broadened the scope of drug crystal form research, provided guidance for drug formulation production, and the preparation process is simple, environmentally friendly and safe.
Smart Images
Figure CN122011081A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug preparation technology, and in particular relates to a method for inducing budesonide drug crystal form using low temperature control. Background Technology
[0002] The discovery and precise control of novel drug crystal forms is a crucial component of pharmaceutical crystallography research. It directly determines whether advantageous crystal forms with superior physicochemical properties, outstanding efficacy, and high safety index can be screened out, thus possessing immeasurable academic value and practical significance for crystal form development. Different crystal forms of the same drug often exhibit drastically different characteristics in terms of efficacy, safety, stability, and even formulation processes.
[0003] Crystallization is essentially molecular self-assembly. The strength and orientation of intermolecular forces, such as hydrophobic stacking, hydrogen bond networks, van der Waals attraction, and electrostatic coupling, manipulate molecular arrangement, ultimately locking the crystal's morphology and framework. At low temperatures, it is possible to induce the nucleation of new crystal forms different from those at room temperature: the nucleation rate is suppressed at low supersaturation, the system is more likely to fall into the metastable region, allowing high-energy polymorphs or solvates to preferentially appear. Furthermore, low temperatures freeze the original conformation of flexible drug molecules, altering the directional interactions of intermolecular hydrogen bonds and halogen bonds, generating hydrogen bond networks unattainable at room temperature, thus assembling into entirely new unit cells. Slow diffusion leads to layered or needle-like growth, introducing numerous dislocations and micro-strains into the lattice, providing conditions for subsequent crystal growth or transformation. This patent selects freeze-drying-based gradient cooling-induced budesonide as the experimental method for research, exploring the formation and method of new budesonide crystal forms induced by freeze-drying gradient cooling.
[0004] Budesonide (BUD), chemically named 16α,17α-22R,S-propylmethylenedioxy-pregn-1,4-diene-11β,21-dihydroxy-3,20-dione, has the chemical formula C0. 25 H 34 O6, with the structural formula shown below. This drug was first developed and marketed by Astra AB, one of the predecessor companies of AstraZeneca in Sweden. It is an inhaled glucocorticoid with potent local anti-inflammatory and immunosuppressive effects. It can significantly inhibit the production and release of airway inflammatory mediators and is widely used clinically for the long-term control of bronchial asthma and chronic obstructive pulmonary disease (COPD). It can also be used to treat allergic rhinitis and inflammatory bowel disease.
[0005]
[0006] According to known reports, BUD currently only has one crystal form. For example, Chinese patent CN116650449A (invention title: A method for tunable particle size absorption-type budesonide ultrafine crystals) discloses a method for micronizing budesonide into ultrafine crystals. The X-ray powder diffraction pattern of this budesonide ultrafine crystal has 2θ values of 6.06°±0.2°, 10.10°±0.2°, and 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°.
[0007] Chinese patent CN119390750A discloses a method for preparing budesonide ultrafine crystals, the 2θ value of which is consistent with that of CN116650449A in its X-ray powder diffraction pattern. The paper also describes a method for preparing budesonide porous microspheres using high-pressure homogenization combined with spray drying, wherein the budesonide porous microspheres obtained by this method are amorphous particles. Summary of the Invention
[0008] The purpose of this invention is to provide a gradient cooling-assisted control method based on freeze-drying to obtain a new crystal form of budesonide.
[0009] The second objective of this invention is to provide a new crystal form of budesonide.
[0010] Therefore, the technical solution provided by this invention is as follows:
[0011] Therefore, the first technical solution provided by this invention is as follows:
[0012] A method for preparing a new budesonide crystal form involves inducing the formation of a new budesonide crystal form by gradient cooling during the dissolution and crystallization process of budesonide, and obtaining the new budesonide crystal form by freeze-drying.
[0013] Furthermore, in the above-mentioned method for preparing the new budesonide crystal form, the gradient cooling involves first storing at -20 ℃ for 25-68 h; then storing at -80 ℃ for 26-96 h.
[0014] Furthermore, in the above-mentioned method for preparing the new budesonide crystal form, the freeze-drying is carried out at -40°C for 7 days.
[0015] Furthermore, in the above-mentioned method for preparing the new budesonide crystal form, the dissolution of budesonide involves first dissolving budesonide in methanol and then adding water.
[0016] Furthermore, in the above-mentioned method for preparing the new budesonide crystal form, the ratio of budesonide, methanol, and water is 100 mg: 5 mL: 5 mL.
[0017] Furthermore, the above-mentioned method for preparing the new budesonide crystal form includes the following steps in sequence:
[0018] 1) Dissolve 100 mg of budesonide in 5 mL of methanol and sonicate until the budesonide is completely dissolved to obtain a methanol solution of budesonide for later use;
[0019] 2) Prepare 5 mL of purified water for later use;
[0020] 3) Then, using a pipette, quickly add the solution from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature;
[0021] 4) After adding the ingredients, seal the container with plastic wrap and poke several small holes in the seal. Store at -20 ℃ for 25-68 hours.
[0022] 5) Transfer the solution from step 4) to a -80°C freezer and store for 26-96 hours.
[0023] 6) Transfer the solution from 5) to a freeze dryer, set the freeze dryer cold trap temperature to -40 ℃, and store for 7 days.
[0024] The present invention also provides a new budesonide crystal form, which is prepared by the method for preparing the new budesonide crystal form described in the first technical solution.
[0025] Furthermore, the 2θ values of the X-ray powder diffraction patterns of the aforementioned new budesonide crystal form are 6.13°±0.2°, 12.19°±0.2°, 18.25°±0.2°, 24.59°±0.2°, 30.87°±0.2°, and 37.29°±0.2°.
[0026] Compared with the prior art, the technical solution provided by the present invention has the following technical advantages:
[0027] 1. The technical solution provided by this invention is to introduce a gradient cooling process in the crystallization system of budesonide solvent, without involving complicated intermediate control steps, so as to obtain a new crystal form of budesonide and a method thereof.
[0028] 2. The gradient cooling step in the technical solution provided by this invention is simple and controllable, which not only prepares a new crystal form of budesonide, but also makes the preparation process precise, environmentally friendly and safe, in line with the national concept of green production.
[0029] 3. The technical solution provided by this invention is based on gradient cooling assisted by freeze-drying, which has yielded a new crystal form, broadened the research on drug crystal forms, and provided certain guidance for the subsequent production of drug formulations.
[0030] In summary, the technical solution provided by this invention, through gradient cooling control, successfully prepared a new crystal form of budesonide without using a large amount of organic solvents and complex process control. Attached Figure Description
[0031] Figure 1 The X-ray powder diffraction patterns of the new budesonide crystal form induced by gradient cooling assisted by freeze-drying and the original budesonide crystal form are compared.
[0032] Figure 2 This is the complete X-ray powder diffraction pattern of the new crystal form prepared in Example 1;
[0033] Figure 3 This is the complete X-ray powder diffraction pattern of the new crystal form prepared in Example 2;
[0034] Figure 4 The X-ray powder diffraction pattern provided in Comparative Example 1;
[0035] Figure 5 The X-ray powder diffraction pattern provided in Comparative Example 2;
[0036] Figure 6 The X-ray powder diffraction pattern provided in Comparative Example 3;
[0037] Figure 7 The X-ray powder diffraction pattern provided in Comparative Example 4;
[0038] Figure 8 The X-ray powder diffraction pattern provided in Comparative Example 5;
[0039] Figure 9 This is a comparison of the DSC images of the new crystal form prepared in Example 1 with the DSC images of the active pharmaceutical ingredient;
[0040] Figure 10 This is a comparison of the DSC images of the new crystal form prepared in Example 2 with the DSC images of the active pharmaceutical ingredient;
[0041] Figure 11 The infrared spectra of the new crystal form prepared in Example 1 and budesonide active pharmaceutical ingredient are shown.
[0042] Figure 12This is the infrared spectrum of the new crystal form prepared in Example 2 and the budesonide active pharmaceutical ingredient;
[0043] Figure 13 This is a comparison chart of the solubility of the new crystal form and the original crystal form in solutions with different pH values;
[0044] Figure 14 This is the three-month stability XRD pattern of Example 1;
[0045] Figure 15 This is the three-month stability XRD pattern of Example 2;
[0046] Figure 16 This is a SEM image of the active pharmaceutical ingredient ①;
[0047] Figure 17 This is the SEM image of the active pharmaceutical ingredient (API) ②;
[0048] Figure 18 This is a SEM image of the new crystal form ①;
[0049] Figure 19 This is the SEM image of the new crystal form ②.
[0050] Figure 20 X-ray powder diffraction comparison spectra of budesonide crystal form and active pharmaceutical ingredient crystal form prepared by freeze-drying under different induction conditions. Detailed Implementation
[0051] The following describes the new crystal forms of budesonide induced by gradient cooling in solvent systems and their methods, in conjunction with specific implementation methods and the content of the invention. However, these methods are not limited to these specific forms, and all those related to this patent are protected.
[0052] Example 1
[0053] 1) Accurately weigh 100 mg of budesonide and add it to a 15 mL centrifuge tube. Then slowly add 5 mL of methanol to the centrifuge tube to dissolve the budesonide. Sonicate the solution until it is completely transparent and set aside for later use.
[0054] 2) Take 5 mL of purified water into another centrifuge tube and keep it for later use.
[0055] 3) Use a 5 mL pipette to quickly add the purified water from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature.
[0056] 4) After adding the ingredients, seal the container with plastic wrap and poke 10-15 holes in the seal. Place it in a -20°C refrigerator for 68 hours.
[0057] 5) Transfer the centrifuge tubes from 4) to a -80 ℃ freezer and store for 4 days.
[0058] 6) Transfer the centrifuge tubes from 5) to a freeze dryer. Set the freeze dryer cold trap temperature to -40 °C and freeze dry for 7 days. Send a portion of the resulting crystals to XPRD for testing.
[0059] The X-ray powder diffraction pattern of crystalline budesonide was recorded under the following conditions: indoor temperature 25 ℃, relative humidity <60%; XPert PRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); Cu Kα radiation (λ=1.5406Å); tube voltage 40 kV; tube current 40 mA; 2θ scan range 4~50°; step size 0.01313°; counting time 30 ms / step. The detection results are as follows: Figure 1 (In the comparison diagram, black represents the crystal form of the active pharmaceutical ingredient, and red represents the crystal form obtained in Example 1.) Figure 2 (See the full crystal form diagram in Example 1). The 2θ values of the new crystal form are 6.13°±0.2°, 12.19°±0.2°, 18.25°±0.2°, 24.59°±0.2°, 30.87°±0.2°, and 37.29°±0.2°. The differences compared to existing crystal forms confirm that it is a new crystal form.
[0060] Example 2
[0061] 1) Accurately weigh 100 mg of budesonide and add it to a 15 mL centrifuge tube. Then slowly add 5 mL of methanol to the centrifuge tube to dissolve the budesonide. Sonicate the solution until it is completely transparent and set aside for later use.
[0062] 2) Take 5 mL of purified water into another centrifuge tube and keep it for later use.
[0063] 3) Use a 5 mL pipette to quickly add the purified water from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature.
[0064] 4) After adding the ingredients, seal the container with plastic wrap and poke 10-15 holes in the seal. Place it in a -20°C refrigerator for 25 hours.
[0065] 5) Transfer the centrifuge tubes from 4) to a -80 ℃ freezer and store for 26 h.
[0066] 6) Transfer the centrifuge tubes from 5) to a freeze dryer. Set the freeze dryer cold trap temperature to -40 °C and freeze dry for 7 days. Send a portion of the resulting crystals to XPRD for testing.
[0067] Record the X-ray powder diffraction pattern of crystalline budesonide under the following conditions: indoor temperature 25℃, relative humidity <60%; XPert PRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); Cu Kα radiation (λ=1.5406Å); tube voltage 40 kV; tube current 40 mA; 2θ scan range 4~50°; step size 0.01313°; counting time 30 ms / step. The detection results are as follows: Figure 3 (See the full crystal form diagram in Example 2). The 2θ values of the new crystal form are 6.28°±0.2°, 12.36°±0.2°, 18.24°±0.2°, 24.46°±0.2°, 30.76°±0.2°, and 37.17°±0.2°. The differences compared to existing crystal forms confirm that it is a new crystal form.
[0068] The following comparative cases are all failure cases, as the target crystal form could not be obtained under the conditions of our laboratory. Because the target crystal form was not obtained in the following cases, only XRD analysis was performed, and no other tests were conducted.
[0069] Comparative Example 1
[0070] 1) Accurately weigh 100 mg of budesonide and add it to a 15 mL centrifuge tube. Then slowly add 5 mL of ethanol solvent to the centrifuge tube to dissolve the budesonide. Sonicate the solution until it is completely transparent and set aside for later use.
[0071] 2) Take 5 mL of purified water into another centrifuge tube and keep it for later use.
[0072] 3) Use a 5 mL pipette to quickly add the purified water from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature.
[0073] 4) After adding the ingredients, seal the container with plastic wrap and poke 10-15 holes in the seal. Place it in a -20°C refrigerator for 48 hours.
[0074] 5) Transfer the centrifuge tubes from 4) to a -80 ℃ freezer and store for 6 days.
[0075] 6) Transfer the centrifuge tubes from 5) to a freeze dryer. Set the freeze dryer cold trap temperature to -40 °C and freeze dry for 7 days. Send a portion of the resulting crystals to XPRD for testing.
[0076] The X-ray powder diffraction pattern of crystalline budesonide was recorded under the following conditions: indoor temperature 25 ℃, relative humidity <60%; XPert PRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); Cu Kα radiation (λ=1.5406Å); tube voltage 40 kV; tube current 40 mA; 2θ scan range 4~50°; step size 0.01313°; counting time 30 ms / step. The detection results are as follows: Figure 4 The image shown (black represents the crystal form of the active pharmaceutical ingredient, green represents the crystal form obtained in Comparative Example 1, and red represents the target crystal form) is not the target crystal form.
[0077] Comparative Example 2
[0078] 1) Accurately weigh 100 mg of budesonide and add it to a 15 mL centrifuge tube. Then slowly add 5 mL of methanol solvent to the centrifuge tube to dissolve the budesonide. Sonicate the solution until it is completely transparent and set aside for use.
[0079] 2) Take 5 mL of purified water into another centrifuge tube and keep it for later use.
[0080] 3) Use a 5 mL pipette to quickly add the purified water from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature.
[0081] 4) Transfer the centrifuge tubes from 3) to a -80 ℃ freezer and store for 8 days.
[0082] 5) Transfer the centrifuge tubes from 4) to a freeze dryer. Set the freeze dryer cold trap temperature to -40 °C and freeze-dry for 7 days. Send a portion of the resulting crystals to XPRD for testing.
[0083] Record the X-ray powder diffraction pattern of crystalline budesonide under the following conditions: indoor temperature 25℃, relative humidity <60%; XPert PRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); Cu Kα radiation (λ=1.5406Å); tube voltage 40 kV; tube current 40 mA; 2θ scan range 4~50°; step size 0.01313°; counting time 30 ms / step. The detection results are as follows: Figure 5 The image shown (black represents the crystal form of the active pharmaceutical ingredient, green represents the crystal form obtained in Comparative Example 2, and red represents the target crystal form) is not the target crystal form.
[0084] Comparative Example 3
[0085] 1) Accurately weigh 100 mg of budesonide and add it to a 15 mL centrifuge tube. Then slowly add 5 mL of ethanol solvent to the centrifuge tube to dissolve the budesonide. Sonicate the solution until it is completely transparent and set aside for later use.
[0086] 2) Take 5 mL of purified water into another centrifuge tube and keep it for later use.
[0087] 3) Use a 5 mL pipette to quickly add the purified water from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature.
[0088] 4) Transfer the centrifuge tubes from 3) to a -80 ℃ freezer and store for 8 days.
[0089] 5) Transfer the centrifuge tubes from 4) to a freeze dryer. Set the freeze dryer cold trap temperature to -40 °C and freeze-dry for 7 days. Send a portion of the resulting crystals to XPRD for testing.
[0090] Record the X-ray powder diffraction pattern of crystalline budesonide under the following conditions: indoor temperature 25℃, relative humidity <60%; XPert PRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); Cu Kα radiation (λ=1.5406Å); tube voltage 40 kV; tube current 40 mA; 2θ scan range 4~50°; step size 0.01313°; counting time 30 ms / step. The detection results are as follows: Figure 6 The image shown (black represents the crystal form of the active pharmaceutical ingredient, green represents the crystal form obtained in Comparative Example 3, and red represents the target crystal form) is not the target crystal form.
[0091] Comparative Example 4
[0092] 1) Accurately weigh 100 mg of budesonide and add it to a 15 mL centrifuge tube. Then slowly add 5 mL of isopropanol solvent to the centrifuge tube to dissolve the budesonide. Sonicate the solution until it is completely transparent and set aside for use.
[0093] 2) Take 5 mL of purified water into another centrifuge tube and keep it for later use.
[0094] 3) Use a 5 mL pipette to quickly add the purified water from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature.
[0095] 4) After adding the ingredients, seal the container with plastic wrap and poke 10-15 holes in the seal. Place it in a refrigerator at 2-8 ℃ for 30 hours.
[0096] 5) Transfer the centrifuge tubes from 4) to a -80 ℃ freezer and store for 6 days.
[0097] 6) Transfer the centrifuge tubes from 5) to a freeze dryer. Set the freeze dryer cold trap temperature to -40 °C and freeze dry for 7 days. Send a portion of the resulting crystals to XPRD for testing.
[0098] The X-ray powder diffraction pattern of crystalline budesonide was recorded under the following conditions: indoor temperature 25 ℃, relative humidity <60%; XPert PRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); Cu Kα radiation (λ=1.5406Å); tube voltage 40 kV; tube current 40 mA; 2θ scan range 4~50°; step size 0.01313°; counting time 30 ms / step. The detection results are as follows: Figure 7 The image shown (black represents the crystal form of the active pharmaceutical ingredient, green represents the crystal form obtained in Comparative Example 4, and red represents the target crystal form) is not the target crystal form.
[0099] Comparative Example 5
[0100] 1) Accurately weigh 100 mg of budesonide and add it to a 15 mL centrifuge tube. Then slowly add 5 mL of isopropanol solvent to the centrifuge tube to dissolve the budesonide. Sonicate the solution until it is completely transparent and set aside for use.
[0101] 2) Take 5 mL of purified water into another centrifuge tube and keep it for later use.
[0102] 3) Use a 5 mL pipette to quickly add the purified water from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature.
[0103] 4) After adding the ingredients, seal the container with plastic wrap and poke 10-15 holes in the seal. Place it in a -20°C refrigerator for 30 hours.
[0104] 5) Transfer the centrifuge tubes from 4) to a -80 ℃ freezer and store for 6 days.
[0105] 6) Transfer the centrifuge tubes from 5) to a freeze dryer. Set the freeze dryer cold trap temperature to -40 °C and freeze dry for 7 days. Send a portion of the resulting crystals to XPRD for testing.
[0106] The X-ray powder diffraction pattern of crystalline budesonide was recorded under the following conditions: indoor temperature 25 ℃, relative humidity <60%; XPert PRO polycrystalline X-ray diffractometer (PANalytical, Netherlands); Cu Kα radiation (λ=1.5406Å); tube voltage 40 kV; tube current 40 mA; 2θ scan range 4~50°; step size 0.01313°; counting time 30 ms / step. The detection results are as follows: Figure 8 The image shown (black represents the crystal form of the active pharmaceutical ingredient, green represents the crystal form obtained in Comparative Example 5, and red represents the target crystal form) is not the target crystal form.
[0107] To investigate the properties of the new budesonide crystal form provided in this application, the DSC of this new crystal form and the original crystal form were measured below.
[0108] The specific conditions are as follows: heating in a sealed aluminum pot at a heating rate of 10 ℃ / min, a heating temperature range of 25 to 350 ℃, a nitrogen atmosphere, and a flow rate of 20 mL / min.
[0109] Comparison of DSC images (red) and DSC images (black) of the raw drug substance prepared in Example 1 (see attached image). Figure 9 For a comparison of the DSC pattern (blue) of the new crystal form prepared in Example 2 and the DSC pattern (black) of the active pharmaceutical ingredient, please refer to the image. Figure 10 ,from Figure 9-10 It can be clearly seen that the DSC spectra of the new budesonide crystal forms prepared in Examples 1 and 2 are significantly different from those of the active pharmaceutical ingredient. The position of the melting endothermic peak of the new crystal form is different from that of the active pharmaceutical ingredient, and the peak shape is also different, indicating that the new crystal form differs from the active pharmaceutical ingredient in thermodynamic properties.
[0110] Meanwhile, in order to further explore the characteristics of the new budesonide crystal form provided in this application, the infrared spectra of the new crystal form and the original crystal form were measured below.
[0111] Specific conditions were as follows: FT-IR spectroscopy was performed using a Nicolet-6700 FT-IR spectrometer (Thermo Scientific, USA). Each sample was mixed with KBr at a ratio of 1:100, pressed into a pellet, and then measured in transmission mode (spectral range 4000–400 cm⁻¹). -1 The resolution is 4 cm. -1 (64 interferograms were acquired for each spectrum). Infrared spectra of the new crystalline form (red) and budesonide API (black) prepared in Example 1 are shown in the attached image. Figure 11 Example 2: Infrared spectra of the new crystal form (blue) and budesonide active pharmaceutical ingredient (black) are shown in the attached image. Figure 12 .from Figure 11 and Figure 12 It can be seen that the infrared spectra obtained in Examples 1 and 2 are consistent with those of the active pharmaceutical ingredient, indicating that no change occurred in the types of functional groups and chemical bonds of the active pharmaceutical ingredient in Examples 1 and 2.
[0112] To demonstrate the effectiveness of the new budesonide crystal form provided in this application, the solubility of this new crystal form and the original crystal form in hydrochloric acid solution at pH 1.2, aqueous solution at pH 7, and PBS solutions at pH 6.8 and pH 7.4 were determined below.
[0113] The specific procedure is as follows: After the new and original crystal forms have reached dissolution equilibrium, samples are taken and filtered through a 0.22 μm filter membrane. An appropriate amount of the filtrate is taken, and the absorbance value is measured at a wavelength of 247 nm according to the ultraviolet-visible spectrophotometric method (Chinese Pharmacopoeia 2020 edition). The absorbance is then substituted into the standard curve to obtain the solubility of the new and original crystal forms, as shown in Table 1. Figure 13 As shown.
[0114] Table 1 Solubility Table
[0115]
[0116] Through Table 1 and Figure 13 It can be seen that in hydrochloric acid solution (pH=1.2) and deionized water (pH=7.0), although the new crystal form is not as good as the original crystal form, its solubility is slightly higher in sodium phosphate buffer solution (pH=7.4), and its solubility is much higher in sodium phosphate buffer solution (pH=6.8). The human respiratory tract generally exhibits a "slightly acidic to near-neutral" gradient, with a slightly acidic pH in the bronchi and alveoli. The jejunum has a pH close to 6.8, while the stomach has a pH of approximately 1.0–2.0. Considering the characteristics of the new crystal form, it is possible to reduce budesonide release in the stomach and increase absorption in the upper small intestine, as well as reduce absorption in the upper respiratory tract and increase absorption in the lower respiratory tract, providing a new approach for targeted drug therapy research.
[0117] To verify the stability of the prepared new budesonide crystal form, a three-month stability test was conducted.
[0118] Example 1: XRD pattern of the stability of a new budesonide crystal form after three months (black represents the active pharmaceutical ingredient crystal form, red represents the crystal form of Example 1, and green represents the crystal form obtained after three months of storage in a -20 °C refrigerator). (See attached image.) Figure 14 See the XRD pattern of stability after three months for Example 2 (black represents the crystal form of the active pharmaceutical ingredient, blue represents the crystal form of Example 2, and green represents the crystal form obtained after three months of storage in a -20°C refrigerator). Figure 15 The results showed that the stability of the crystal was as expected, and the 2θ values of the main peaks in the XRD pattern remained consistent, with only some weak peaks changing.
[0119] To observe the surface morphology of the active pharmaceutical ingredient and the new crystal form, a SEM examination was performed using a Hitachi SU8220 field emission scanning electron microscope. (See attached document.) Figure 16-19 The results showed that the surface morphology of the active pharmaceutical ingredient crystal form was not significantly different from that of the new crystal form, both being irregular lumps.
[0120] from Figure 20As can be seen from the comparison of the active pharmaceutical ingredient (API) crystal forms, a new crystal form of budesonide can be obtained by using gradient temperature induction combined with freeze-drying technology, with methanol as the good solvent and water as the antisolvent; a transitional crystal form of budesonide is obtained by using gradient temperature induction combined with freeze-drying technology, with ethanol as the good solvent and water as the antisolvent, which is not a new crystal form; without gradient temperature induction, only freeze-drying technology is used, with methanol as the good solvent and water as the antisolvent, and the budesonide API crystal form is obtained.
[0121] To visually compare the differences in budesonide crystal forms prepared by different methods, refer to the X-ray powder diffraction comparison patterns of the new budesonide crystal forms induced by gradient cooling under different freeze-drying conditions and the original budesonide crystal form. Figure 15 ,pass Figure 15 It can be seen that the budesonide crystal forms prepared by different methods show obvious differences in X-ray powder diffraction patterns.
[0122] The above description is only a specific embodiment of the present invention and not all embodiments. Any equivalent modifications made by other people skilled in the art based on the present invention specification are covered by the claims of the present invention and are also protected by the present invention.
Claims
1. A method for preparing a new budesonide crystal form, characterized in that, During the dissolution and crystallization process of budesonide, a gradient cooling method was used to induce the formation of a new budesonide crystal form, which was then obtained by freeze-drying.
2. The method for preparing the new budesonide crystal form according to claim 1, characterized in that, The gradient cooling process involves first storing the product at -20 ℃ for 25-68 hours, and then storing it at -80 ℃ for 26-96 hours.
3. The method for preparing the new budesonide crystal form according to claim 1, characterized in that, The freeze-drying process was carried out at -40°C for 7 days.
4. The method for preparing the new budesonide crystal form according to claim 1, characterized in that, The dissolution of budesonide involves first dissolving budesonide in methanol, and then adding water.
5. The method for preparing the new budesonide crystal form according to claim 1, characterized in that, The ratio of budesonide, methanol, and water is 100 mg: 5 mL: 5 mL.
6. The method for preparing the new budesonide crystal form according to any one of claims 1-5, characterized in that, The steps are as follows: 1) Dissolve 100 mg of budesonide in 5 mL of methanol and sonicate until the budesonide is completely dissolved to obtain a methanol solution of budesonide for later use; 2) Prepare 5 mL of purified water for later use; 3) Then, using a pipette, quickly add the solution from step 2) into the budesonide solution prepared in step 1), and perform the entire process at room temperature; 4) After adding the ingredients, seal the container with plastic wrap and poke several small holes in the seal. Store at -20 ℃ for 25-68 hours. 5) Transfer the solution from step 4) to a -80°C freezer and store for 26-96 hours. 6) Transfer the solution from 5) to a freeze dryer, set the freeze dryer cold trap temperature to -40 ℃, and store for 7 days.
7. A novel budesonide crystal form, characterized in that, It was prepared using the method for preparing the new budesonide crystal form according to any one of claims 1-6.
8. The new budesonide crystal form according to claim 7, characterized in that, The X-ray powder diffraction patterns of the new budesonide crystal form have 2θ values of 6.13°±0.2°, 12.19°±0.2°, 18.25°±0.2°, 24.59°±0.2°, 30.87°±0.2°, and 37.29°±0.2°.