Treatment method for improving physical stability of raw material medicine

Abstract

The invention discloses a treatment method for improving physical stability of a raw material medicine, and relates to the technical field of medicine solid chemistry and preparations, the treatment method comprises the following steps: contacting the raw material medicine in an amorphous state with an ethanol medium, dispersing, and inducing the amorphous state to be converted into a crystal form; and standing, separating the solid, and drying the solid product to obtain a final product with stable crystal form and stable particle size. The preparation method has the advantages that the defects of slow and uncontrollable amorphous state conversion of raw material medicines in the prior art are overcome, the metastable amorphous state can be actively and quickly converted into a thermodynamically stable target crystal form, the long-term stability of the particle size of the product is synchronously realized in the process, and the influence of particle size change on the preparation product is reduced; the added ethanol medium is not only a poor solvent, but also an efficient crystal crystallization inducer, and can permeate into a molecular grid of the amorphous drug, so that the energy barrier of molecular rearrangement is reduced, and the original spontaneous and slow solid phase change is converted into a rapid and directional technological process.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical solid-state chemistry and formulation technology, and specifically to a method for improving the physical stability of active pharmaceutical ingredients. Background Technology

[0002] Inhaled medications are special drug formulations administered through the respiratory tract (mouth or nose). They transform the drug into tiny particles (aerosols, dry powder, or nebulized solutions) that are directly inhaled into the lungs, achieving precise delivery and rapid onset of action (often within minutes). This avoids the first-pass effect of oral medications and the systemic exposure associated with injections. Their core advantages lie in high local drug concentrations, small required doses, and fewer systemic side effects. They are the preferred treatment for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The main types include metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulized inhalers.

[0003] Particle size is a core factor in the efficacy of inhaled formulations, directly affecting drug deposition sites and bioavailability in the respiratory tract. It is crucial for the onset of action and therapeutic effect of drugs such as salbutamol sulfate. Ideally, the aerodynamics of inhaled drug particles should be controlled within the range of 1–5 micrometers. Particles with a diameter greater than 5 μm tend to deposit in the respiratory tract (oropharynx), are easily swallowed or cleared, reducing drug delivery to the lungs and potentially causing local irritation or systemic side effects. Particles with a diameter less than 1 μm are easily exhaled and difficult to deposit effectively in the airways. For emergency drugs like salbutamol sulfate, which require rapid action on bronchial smooth muscle, precise particle size control ensures a sufficient proportion of the drug can deeply deposit in the lower respiratory tract and small airway targets, achieving rapid bronchodilatory effects within 5–15 minutes. Therefore, particle size design is a key technical challenge in the development of inhaled formulations, directly determining whether the drug can efficiently and safely exert its local therapeutic advantages and avoiding the risks associated with increased dosing frequency or dosage due to ineffective deposition.

[0004] Currently, various technical approaches have been developed for adjusting the particle size of active pharmaceutical ingredients (APIs), which can be mainly divided into "top-down" pulverization technology and "bottom-up" crystallization control technology.

[0005] Top-down pulverization techniques use mechanical force to break large-sized active pharmaceutical ingredient (API) particles down to the target particle size range. Air jet milling is one of the most commonly used methods for preparing micron- and submicron-sized drug particles. Its principle is to use a high-speed airflow (such as compressed air or superheated steam) to carry particles through collisions, friction, and impacts against the chamber walls, thereby achieving pulverization. For salbutamol sulfate, air jet milling can effectively produce fine particles with a particle size distribution in the 1-5 micron range suitable for dry powder inhalers. The advantages of this method are fine particle size, narrow particle size distribution, and low pollution. The disadvantages are high energy consumption and the potential for drug crystal transformation or increased surface energy leading to agglomeration.

[0006] Ball milling involves placing salbutamol sulfate and grinding media (such as ceramic or stainless steel balls) into a milling jar. The rotation or vibration of the jar causes the grinding media to impact and grind the drug. By controlling the grinding time, ball-to-particle ratio, and rotation speed, the final particle size can be controlled to some extent. While ball milling is simple to operate, it can lead to contamination from media abrasion, and prolonged mechanical energy input may cause partial or complete amorphization of the drug, affecting its physical stability.

[0007] The "bottom-up" crystallization control technique involves controlling crystallization conditions during the drug's precipitation from solution to directly obtain particles of the target size.

[0008] The cooling crystallization method utilizes the difference in solubility of salbutamol sulfate at different temperatures. By programming the cooling process to achieve supersaturation of the solution, crystallization is induced. The cooling rate, final temperature, and stirring conditions are key parameters affecting particle size. Slow cooling generally favors the formation of larger, more uniformly distributed crystals, while rapid cooling tends to yield finer particles. This method is relatively mild, but it requires high precision in initial concentration and temperature control.

[0009] Spray drying involves atomizing a salbutamol sulfate solution, suspension, or emulsion into a hot drying gas using an atomizer. The solvent in the droplets evaporates instantly, forming dry solid particles. By controlling atomization parameters (such as atomization pressure and pore size), feed concentration, and drying temperature, microspheres with controllable particle size can be directly produced. This method completes the conversion from solution to micropowder in one step, making it suitable for continuous production. However, spray drying equipment requires high investment, has low thermal efficiency, consumes a lot of energy, involves complex dust recovery, and carries a certain risk of generating amorphous substances.

[0010] While amorphous active pharmaceutical ingredients (APIs) in inhalation formulations can enhance drug dissolution and pulmonary absorption through high solubility, their poor stability and tendency to crystallize significantly limit formulation performance. Due to their high free energy, amorphous APIs readily transform into crystalline forms during storage or processing, leading to a sharp drop in solubility and reduced efficacy. Furthermore, their strong affinity for water and high hygroscopicity can accelerate crystal transformation or trigger chemical degradation. In addition, the poor flowability and low bulk density of amorphous APIs can affect the uniform delivery of dry powder inhalers, necessitating the use of carriers (such as lactose) to optimize the process. Large-scale production further complicates process parameter control. Quality control requires strict monitoring of crystal form changes (e.g., XRD, DSC analysis) and assessment of the risk of peak blood drug concentrations due to rapid dissolution.

[0011] Currently, industrial processes typically employ "aging" or "annealing," where substances are allowed to slowly transform into a crystalline state under specific temperature and humidity conditions. This process can take several days to weeks, depending on the characteristics of the active pharmaceutical ingredient, and the endpoint (crystal form) and progress of the transformation are difficult to control precisely, severely impacting production efficiency and product quality reliability. Furthermore, traditional aging processes are extremely sensitive to temperature and humidity conditions; environmental fluctuations can easily lead to incomplete crystal form transformation or the formation of mixed crystal forms, further increasing the complexity of quality control.

[0012] In summary, the core disadvantages of amorphous active pharmaceutical ingredients (APIs) in inhalation formulations lie in their insufficient stability, complex processes, and stringent quality control. These disadvantages require control through excipient stabilization and process optimization, further increasing the difficulty of developing inhalation formulations. Summary of the Invention

[0013] Based on the problem of slow and uncontrollable amorphous transformation of active pharmaceutical ingredients in the prior art, the purpose of this invention is to provide a method for improving the physical stability of active pharmaceutical ingredients. This method can actively and rapidly transform metastable amorphous forms into thermodynamically stable target crystal forms, and simultaneously achieve long-term stability of product particle size in the process, reducing the impact of particle size changes on the formulation product.

[0014] This invention is achieved through the following technical solution:

[0015] This application provides a method for improving the physical stability of a drug substance, comprising the following steps:

[0016] The amorphous active pharmaceutical ingredient is dispersed after contact with an ethanol medium, which induces the amorphous form to transform into a crystalline form.

[0017] After standing, the solids are separated and dried to obtain a final product with stable crystal form and particle size.

[0018] Due to the characteristics of inhaled formulations, the synthetic production routes of active pharmaceutical ingredients (APIs) vary, and they may contain a certain amount of amorphous matter, and the particle size may not meet the requirements. They may need to be reprocessed, which will also generate a certain amount of amorphous matter. During long-term storage, this part of the API will slowly transform into a crystalline form, but it will bring about a certain change in particle size.

[0019] The processing method of this invention overcomes the shortcomings of slow and uncontrollable amorphous transformation of active pharmaceutical ingredients in existing technologies. It can actively and rapidly transform metastable amorphous states into thermodynamically stable target crystal forms, while simultaneously achieving long-term stability of product particle size and reducing the impact of particle size variations on the formulation. The added ethanol medium is not only a poor solvent but also a highly efficient "crystallization inducer." It can penetrate into the molecular network of amorphous drugs, lowering the energy barrier for molecular rearrangement, thereby transforming the originally spontaneous and slow solid-state phase transition into a rapid and directional process.

[0020] The product obtained by the processing method of the present invention is a fully crystalline stable system whose physical properties (such as particle size and crystal form) do not change with storage time. Since the obtained crystals are more thermodynamically stable and the ethanol medium can effectively remove the water and impurities adsorbed on the crystal surface, the product exhibits lower hygroscopicity and higher physical stability. Under accelerated test conditions, it is not easy to undergo crystal form transformation or particle size growth when stored for a long time.

[0021] The treatment method of the present invention does not delay or reduce the problem of amorphous substances in the active pharmaceutical ingredient, but rather eliminates the source of the problem at its root through crystal transformation.

[0022] The ethanol medium used in this invention is a low-toxicity and safe solvent that is easy to recycle and reuse, which significantly reduces safety risks, environmental pressures and raw material costs in the production process.

[0023] In one specific embodiment, the active pharmaceutical ingredient includes any one of salbutamol sulfate, budesonide, fluticasone propionate, beclomethasone propionate, fluticasone furoate, and glycopyrronium bromide.

[0024] In addition to using ethanol as a solvent, water, chloroform, isopropanol, etc. can also be used.

[0025] In one specific embodiment, the volume average particle size D50 of the active pharmaceutical ingredient is 1 μm to 5 μm.

[0026] In one specific embodiment, the temperature is controlled at 20°C to 40°C when dispersing the amorphous active pharmaceutical ingredient with the ethanol medium.

[0027] In one specific embodiment, the amorphous active pharmaceutical ingredient is dispersed in the ethanol medium for 0.5 to 24 hours.

[0028] In one specific embodiment, the amorphous active pharmaceutical ingredient is dispersed in an ethanol medium and then allowed to stand at a temperature of 20°C to 40°C.

[0029] In one specific embodiment, the standing time after dispersing the amorphous active pharmaceutical ingredient with ethanol medium is 1 to 7 days.

[0030] In one specific embodiment, the temperature for drying the separated solid is 20°C to 40°C.

[0031] In one specific embodiment, the ethanol medium is anhydrous ethanol.

[0032] In one specific embodiment, 4-50 mL of anhydrous ethanol is added per 1 g of active pharmaceutical ingredient.

[0033] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0034] (1) The processing method of the present invention overcomes the defects of slow and uncontrollable amorphous transformation of raw materials in the prior art. It can actively and rapidly transform metastable amorphous forms into thermodynamically stable target crystal forms, and simultaneously achieve long-term stability of product particle size, reducing the impact of particle size changes on the formulation product. Among them, the added ethanol medium is not only a poor solvent, but also a highly efficient "crystal crystallization inducer". It can penetrate into the molecular grid of amorphous drugs, reduce the energy barrier of molecular rearrangement, and thus transform the originally spontaneous and slow solid phase transition into a rapid and directional process.

[0035] (2) The product obtained by the processing method of the present invention is a completely crystalline stable system whose physical properties (such as particle size and crystal form) do not change with storage time. Since the obtained crystal is more thermodynamically stable and the ethanol medium can effectively remove the water and impurities adsorbed on the crystal surface, the product exhibits lower hygroscopicity and higher physical stability. Under accelerated test conditions, it is not easy to undergo crystal form transformation or particle size growth when stored for a long time.

[0036] (3) The treatment method of the present invention does not delay or reduce the problem of amorphous substances in the active pharmaceutical ingredient, but fundamentally eliminates the source of the problem through crystal transformation.

[0037] (4) The ethanol medium used in this invention is a low-toxicity and safe solvent that is easy to recycle and reuse, which significantly reduces the safety risks, environmental pressure and raw material costs in the production process. Attached Figure Description

[0038] To more clearly illustrate the technical solutions in this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0039] Figure 1 This is the PXRD image of the micronized salbutamol sulfate in Example 1 of the present invention before treatment with anhydrous ethanol;

[0040] Figure 2 This is a SEM image of the micronized salbutamol sulfate in Example 1 of the present invention before treatment with anhydrous ethanol;

[0041] Figure 3 This is the PXRD pattern of the micronized salbutamol sulfate in Example 1 of the present invention after treatment with anhydrous ethanol;

[0042] Figure 4This is a SEM image of the micronized salbutamol sulfate in Example 1 of the present invention after treatment with anhydrous ethanol;

[0043] Figure 5 This is the PXRD pattern of the micronized salbutamol sulfate after treatment with anhydrous ethanol in Example 2 of the present invention;

[0044] Figure 6 This is a SEM image of the micronized salbutamol sulfate after treatment with anhydrous ethanol in Example 2 of the present invention.

[0045] Figure 7 This is the PXRD pattern of the micronized salbutamol sulfate in Example 3 of the present invention after treatment with anhydrous ethanol;

[0046] Figure 8 This is a SEM image of the micronized salbutamol sulfate after treatment with anhydrous ethanol in Example 3 of the present invention.

[0047] Figure 9 This is the PXRD pattern of the micronized salbutamol sulfate in Example 4 of the present invention after treatment with anhydrous ethanol;

[0048] Figure 10 This is a SEM image of the micronized salbutamol sulfate after treatment with anhydrous ethanol in Example 4 of the present invention.

[0049] Figure 11 The image shows the PXRD pattern of micronized salbutamol sulfate after conventional aging in Comparative Example 1.

[0050] Figure 12 The image shows a SEM image of the micronized salbutamol sulfate after conventional aging in Comparative Example 1. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of this invention are only used to explain this invention and are not intended to limit this invention.

[0052] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that these specific details are not necessary to practice the invention. In other embodiments, well-known materials or methods have not been specifically described in order to avoid obscuring the invention.

[0053] Throughout this specification, references to "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with that embodiment or example is included in at least one embodiment of the invention. Therefore, the phrases "an embodiment," "an example," "an example," or "an example" appearing in various places throughout the specification do not necessarily refer to the same embodiment or example. Furthermore, specific features, structures, or characteristics can be combined in one or more embodiments or examples in any suitable combination and / or sub-combination. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described herein, as well as the features of those different embodiments or examples.

[0054] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0055] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the method may also include step (c), indicating that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0056] Example 1

[0057] This embodiment provides a method for improving the physical stability of a raw material drug, the specific method being:

[0058] S1. Take 20g of micronized salbutamol sulfate and analyze its particle size distribution (PSD) using a laser particle size analyzer, as shown in Table 1; analyze its crystal form using powder X-ray diffraction (PXRD), as shown in Table 1. Figure 1 As shown; the crystal morphology was examined by scanning electron microscopy (SEM), as follows: Figure 2 As shown in Table 2, the specific surface area was measured by the BET specific surface area analyzer.

[0059] S2. Take 5g of the sample from step S1, add 20mL of anhydrous ethanol, and disperse it evenly using a cell disruptor at 30℃ (90% power ratio) for 30min. Let it stand at room temperature in the dark for 1 day. Separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 1 for particle size analysis. Let it stand at room temperature in the dark for 3 days, then separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 2 for particle size analysis. Let it stand at room temperature in the dark for 5 days, then separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 3 for particle size, crystal form, crystal clusters, and specific surface area analysis.

[0060] like Figure 3 The image shows the PXRD pattern of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, compared with the untreated one, the characteristic peaks are higher, the half-peak width is narrower, and the peak shape is sharper and symmetrical, indicating that the diffraction intensity of the corresponding crystal plane is stronger, the crystallinity is higher, and the integrity is better.

[0061] like Figure 4 The image shown is an SEM image of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, the edges are more rounded, there are fewer burrs, and the shape is more uniform compared to the untreated product.

[0062] Example 2

[0063] This embodiment provides a method for improving the physical stability of a raw material drug. Unlike Embodiment 1, the dispersion temperature in this embodiment is controlled at 20°C. Other processes are the same as in Embodiment 1.

[0064] The specific method is as follows:

[0065] S1. Take 20g of micronized salbutamol sulfate and analyze its particle size distribution (PSD) using a laser particle size analyzer, as shown in Table 1; analyze its crystal form using powder X-ray diffraction (PXRD), as shown in Table 1. Figure 1As shown; the crystal morphology was examined by scanning electron microscopy (SEM), as follows: Figure 2 As shown in Table 2, the specific surface area was measured by the BET specific surface area analyzer.

[0066] S2. Take 5g of the sample from step S1, add 20mL of anhydrous ethanol, and disperse it evenly using a cell disruptor at 20℃ (90% power ratio) for 30min. Let it stand at room temperature in the dark for 1 day. Separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 1 for particle size analysis. Let it stand at room temperature in the dark for 3 days, then separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 2 for particle size analysis. Let it stand at room temperature in the dark for 5 days, then separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 3 for particle size, crystal form, crystal clusters, and specific surface area analysis.

[0067] like Figure 5 The image shows the PXRD pattern of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, compared with the untreated one, the characteristic peaks are higher, the half-peak width is narrower, and the peak shape is sharper and symmetrical, indicating that the diffraction intensity of the corresponding crystal plane is stronger, the crystallinity is higher, and the integrity is better.

[0068] like Figure 6 The image shown is an SEM image of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, the edges are more rounded, there are fewer burrs, and the shape is more uniform compared to the untreated product.

[0069] Example 3

[0070] This embodiment provides a method for improving the physical stability of a raw material drug. Unlike Embodiment 1, the dispersion temperature in this embodiment is controlled at 40°C. Other processes are the same as in Embodiment 1.

[0071] The specific method is as follows:

[0072] S1. Take 20g of micronized salbutamol sulfate and analyze its particle size distribution (PSD) using a laser particle size analyzer, as shown in Table 1; analyze its crystal form using powder X-ray diffraction (PXRD), as shown in Table 1. Figure 1 As shown; the crystal morphology was examined by scanning electron microscopy (SEM), as follows: Figure 2 As shown in Table 2, the specific surface area was measured by the BET specific surface area analyzer.

[0073] S2. Take 5g of the sample from step S1, add 20mL of anhydrous ethanol, and disperse it evenly using a cell disruptor at 40℃ (90% power ratio) for 30min. Incubate at room temperature in the dark for 1 day. Separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 1 for particle size analysis. Incubate at room temperature in the dark for 3 days, separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 2 for particle size analysis. Incubate at room temperature in the dark for 5 days, separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 3 for particle size, crystal form, crystal clusters, and specific surface area analysis.

[0074] like Figure 7 The image shows the PXRD pattern of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, compared with the untreated one, the characteristic peaks are higher, the half-peak width is narrower, and the peak shape is sharper and symmetrical, indicating that the diffraction intensity of the corresponding crystal plane is stronger, the crystallinity is higher, and the integrity is better.

[0075] like Figure 8 The image shown is an SEM image of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, the edges are more rounded, there are fewer burrs, and the shape is more uniform compared to the untreated product.

[0076] Example 4

[0077] This embodiment provides a method for improving the physical stability of the active pharmaceutical ingredient. The difference from Example 1 is that the amount of anhydrous ethanol used in this embodiment is 250 mL. Other processes are the same as in Example 1.

[0078] S1. Take 20g of micronized salbutamol sulfate and analyze its particle size distribution (PSD) using a laser particle size analyzer, as shown in Table 1; analyze its crystal form using powder X-ray diffraction (PXRD), as shown in Table 1. Figure 1 As shown; the crystal morphology was examined by scanning electron microscopy (SEM), as follows: Figure 2 As shown in Table 2, the specific surface area was measured by the BET specific surface area analyzer.

[0079] S2. Take 5g of the sample from step S1, add 250mL of anhydrous ethanol, and disperse it evenly using a cell disruptor at 30℃ (90% power ratio) for 30min. Let it stand at room temperature in the dark for 1 day. Separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 1 for particle size analysis. Let it stand at room temperature in the dark for 3 days, then separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 2 for particle size analysis. Let it stand at room temperature in the dark for 5 days, then separate salbutamol sulfate from the sample using a centrifuge, and then dry under reduced pressure at 30℃ / -0.095MPa to obtain sample 3 for particle size, crystal form, crystal clusters, and specific surface area analysis.

[0080] like Figure 9 The image shows the PXRD pattern of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, compared with the untreated one, the characteristic peaks are higher, the half-peak width is narrower, and the peak shape is sharper and symmetrical, indicating that the diffraction intensity of the corresponding crystal plane is stronger, the crystallinity is higher, and the integrity is better.

[0081] like Figure 10 The image shown is an SEM image of micronized salbutamol sulfate after treatment with anhydrous ethanol. As can be seen from the image, the edges are more rounded, there are fewer burrs, and the shape is more uniform compared to the untreated product.

[0082] Comparative Example 1

[0083] This comparative example provides a conventional processing method, specifically as follows:

[0084] S1. Take 20g of micronized salbutamol sulfate and analyze its particle size distribution (PSD) using a laser particle size analyzer, as shown in Table 1; analyze its crystal form using powder X-ray diffraction (PXRD), as shown in Table 1. Figure 1 As shown; the crystal morphology was examined by scanning electron microscopy (SEM), as follows: Figure 2 As shown in Table 2, the specific surface area was measured by the BET specific surface area analyzer.

[0085] S2. Take 5g of the sample from step S1, place it in a PE bag, and store it at room temperature away from light. Detect particle size after 18 days, and detect particle size, crystal form, crystal morphology, and specific surface area after 35 days.

[0086] like Figure 11 The image shows the PXRD pattern of micronized salbutamol sulfate after conventional aging. As can be seen from the image, the peak intensity is basically the same as that of the untreated sample, and other characteristic peaks also have relatively high peak intensities, indicating the presence of multiple crystal planes, general crystallinity, and poor integrity.

[0087] like Figure 12The image shown is a SEM image of micronized salbutamol sulfate after conventional aging. As can be seen from the image, compared with the untreated product, the edges are sharper, there are more burrs, and there is a tendency to harden.

[0088] Table 1. Particle Size Distribution (PSD) Detection Results

[0089]

[0090] Table 2. Surface Area Analyzer Test Results

[0091]

[0092] As shown in Table 1, the particle size of micronized salbutamol sulfate after ethanol crystallization remained basically unchanged and relatively stable compared to the untreated product; while the particle size of conventionally aged product increased significantly.

[0093] As shown in Table 2, the specific surface area of ​​micronized salbutamol sulfate after ethanol crystallization is lower than that of untreated salbutamol, indicating that the surface of the micronized particles is smoother after treatment, and the metastable amorphous morphology has undergone a crystalline transformation, transforming into a thermodynamically stable crystalline form; the specific surface area of ​​conventional aging did not change significantly.

[0094] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. A process for improving the physical stability of a drug substance, characterized in that, The method comprises the following steps: The amorphous raw material is dispersed in an ethanol medium to induce a crystal form transition from amorphous to crystal form. The solid is separated after standing, and the solid product is dried to obtain a final product with stable crystal form and particle size.

2. The process for improving the physical stability of a drug substance according to claim 1, wherein The raw material includes any one of salbutamol sulfate, budesonide, fluticasone propionate, beclometasone dipropionate, fluticasone propionate, and glycopyrronium bromide.

3. The process for improving the physical stability of a drug substance as claimed in claim 1, wherein, The volume average particle size D50 of the raw material is 1 μm to 5 μm.

4. The process for improving the physical stability of a drug substance according to claim 1, wherein The temperature during the dispersion of the amorphous raw material in the ethanol medium is controlled at 20°C to 40°C.

5. The method for improving the physical stability of a drug substance according to claim 1 or 4, wherein The time for the dispersion of the amorphous raw material in the ethanol medium is 0.5 to 24 hours.

6. The process for improving the physical stability of a drug substance according to claim 1, wherein After the dispersion of the amorphous raw material in the ethanol medium, standing is performed at a temperature of 20°C to 40°C.

7. The method for improving the physical stability of a drug substance according to claim 1 or 6, wherein The standing time after the dispersion of the amorphous raw material in the ethanol medium is 1 to 7 days.

8. The process for improving the physical stability of a drug substance according to claim 1, wherein The temperature for the drying of the separated solid is 20°C to 40°C.

9. The process for improving the physical stability of a drug substance as claimed in claim 1, wherein, The ethanol medium is anhydrous ethanol.

10. The process for improving the physical stability of a drug substance as claimed in claim 1, wherein, 4 to 50 mL of anhydrous ethanol is added per 1 g of raw material.

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