Process for making drug crystals of desired size distribution and morphology

Abstract

To provide a process for forming drug crystals of narrow size distribution and desire dimensions and morphology.SOLUTION: The present invention relates to a process for providing corticosteroid crystals of desired size distribution and morphology, the process comprising the steps of: providing recrystallized ultra-large columnar crystals having aspect ratios of more than 1 and less than 20, the aspect ratio of a given columnar crystal being the ratio of a longest dimension along a lengthwise axis relative to a shortest dimension of a transverse plane perpendicular to the lengthwise axis; and sizing the recrystallized ultra-large columnar crystals to provide a collection of sized crystals having target dimensions, wherein the sizing includes segmenting at least a part of the recrystallized ultra-large columnar crystals along the respective lengthwise axes while retaining the dimensions of the transverse plane perpendicular to the lengthwise axis.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to certain particles that are particularly suitable for being coated to provide sustained release formulations. The present invention relates to a process for producing drug crystals of a desired particle size distribution and morphology. [Background technology]

[0002] The drug crystals are completely coated or encapsulated in a thin polymer membrane and are continuously dispersed. The '100 patent can be injected into a joint or other body part, thereby Fluticasone propionate is released locally over a long period of time, but with low total Polyvinyl alcohol exposure does not produce clinically significant HPA axis suppression Crystalline fluticasone propionate is disclosed.

[0003] Fluid bed reactors are used to coat or encapsulate individual solid particles containing drug crystals. Such devices are commonly used in the form of differential airflow. The coating is atomized from a nozzle while suspending solid particles using a flow rate (r flow). The material (eg, droplets of a polymer solution) is sprayed to coat the individual solid particles.

[0004] Fluid bed equipment produces a controlled, reproducible and uniform particle size distribution of the drug crystals to be coated. It works best when the fabric has a non-uniform distribution of particle sizes. For example, the coating parameters affect the optimization process of small particles. When the parameter is optimized to move, the large particles remain stationary. When the filter is optimized for large particles, small particles impact the sidewall with a large impact. may break down and / or agglomerate with uneven coating coverage. Fine particles ("fine particles"), e.g., particles less than 15% of the mean diameter, may be trapped in the filter of the device. may cause further problems by clogging the printer and / or Agglomeration can change the quality of the coating. Particle shape also affects the This affects buoyancy and floating ability and therefore affects the quality of the coating.

[0005] Thus, there exists a need in the art for formulations of drug particles having desirable and controllable particle size distributions and morphologies. There is a need to reproducibly provide crystals. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US9,987,233 Summary of the Invention

[0007] In the present invention, the desired particle size, shape and composition suitable for uniform coating by the fluidized bed method are obtained. A plurality or population of drug crystals having a particle size distribution is provided. Also disclosed are methods for their preparation. As shown.

[0008] In certain embodiments, the drug crystals have a cube-like morphology (i.e., all dimensions are equal). Fluticasone propionate with a narrow particle size distribution in the range of 50 to 250 μm It is a phosphate ester (FP) crystal.

[0009] The methods and processes described herein are directed to administering fluticasone, such as fluticasone propionate. It should be noted that the present invention is not limited to ruticasone esters. Rather, one or more embodiments may include Therefore, other drug substances, especially poorly soluble drugs that prefer longitudinal crystal growth (corticosteroids) This allows for recrystallization and particle size changes of the powders. [Brief description of the drawings]

[0010] [Figure 1] 1 shows a flow chart of a process for preparing a population of size-controlled drug crystals, according to one embodiment.

[0011] [Figure 2A-C] FIG. 1 shows raw as-received drug material or active pharmaceutical ingredient (API) that has been recrystallized into thick, elongated, prismatic crystals prior to particle size adjustment to produce drug crystals of target dimensions.

[0012] [Diagram 3] 1 shows monoclinic Form I of fluticasone propionate (FP).

[0013] [Figure 4] 1 shows a schematic of a crystal growth mechanism for producing thick, elongated crystals.

[0014] [Diagram 5] SEM (scanning electron microscope) images of recrystallized FP crystals obtained under isothermal conditions are shown in small and large scale, respectively. [Figure 6] SEM (scanning electron microscope) images of recrystallized FP crystals obtained under isothermal conditions are shown in small and large scale, respectively.

[0015] [Figure 7] Small- and large-scale SEM images of recrystallized FP crystals obtained under different isothermal conditions are shown, respectively. [Figure 8] Small- and large-scale SEM images of recrystallized FP crystals obtained under different isothermal conditions are shown, respectively.

[0016] [Figure 9]1 shows the X-ray diffraction patterns of raw drug material (commercial source) and recrystallized FP crystals according to one embodiment.

[0017] [Figure 10] 1 shows a benchtop rotor / stator homogenizer.

[0018] [Figure 11] 1 shows an SEM image of size-controlled (milled and then sieved) drug crystals.

[0019] [Figure 12] 1 shows the particle size distribution of size-controlled drug crystals, according to one embodiment.

[0020] [Figure 13] 1 shows a side-by-side comparison of commercially available source FP crystals and size-controlled drug crystals obtained according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Described herein are methods for providing bulk crystals having a particular targeted particle size distribution and morphology. A process is described which comprises: (1) forming a crystalline silicon substrate having an aspect ratio of greater than 1 and less than 20; providing a recrystallized columnar crystal having a predetermined aspect ratio of the columnar crystal; is the ratio of the longest dimension along the longitudinal axis to the shortest dimension of the cross section perpendicular to the longitudinal axis. (2) adjusting the grain size of the recrystallized columnar crystals to have a specific target size. providing a population of crystals having a controlled particle size, the step of controlling the particle size comprising: , reconnected along their respective longitudinal axes while retaining the dimensions of the cross sections perpendicular to the longitudinal axes. A step including segmenting (dividing) at least a portion of the crystallized columnar crystals; , including.

[0022] The process is applicable to any crystals, but is particularly suited to bulk drug crystals, i.e., monodisperse To produce a population of drug crystals with controlled particle size, shape and mass distribution. It is particularly suitable to coat these crystals with a fluidized bed type coating device. This makes it particularly suitable for

[0023] FIG. 1 shows a schematic of a process according to one embodiment of the present disclosure. Process (100) comprises: Raw drug substances, such as APIs, are available from commercial sources (110), which are typically microparticulate. The resulting crystals are then crystallized (e.g., less than 5 microns). The as-obtained API (11 0) is recrystallized (120) to obtain columnar crystals having an aspect ratio in the range of more than 1 and less than 20. wherein the aspect ratio of a given crystal is the shortest dimension of a cross section perpendicular to the longitudinal axis. The ratio of the longest dimension along the longitudinal axis to the diameter of the recrystallized columnar crystals is then The particle size is adjusted (130) to provide bulk drug crystals of a target size. The step is characterized in that at least some of the recrystallized columnar crystals are preferentially segmented along their longitudinal axes. The present invention includes milling that is mented, i.e., where the cross-sectional dimensions perpendicular to the longitudinal axis are retained. The segmented crystals are sieved to recover crystals that meet a particular target size. The bulk drug crystals (140) are sized to have a narrow particle size distribution as defined herein. In particular, bulk drug crystals include a collection of crystals that are substantially uniform in shape, particle size and mass. It has a distribution and is suitable for fluidized bed coating.

[0024] In certain embodiments, the sized crystals are shorter than the recrystallized columnar crystals. However, the dimensions of the cross sections perpendicular to the longitudinal axis of the recrystallized columnar crystals are maintained. In an embodiment, the crystals with a controlled particle size have an aspect ratio in the range of 1 to 3. In one specific embodiment, the size-controlled drug crystals are cubic in shape and have an aspect ratio of about 1. As used herein, the term "substantially uniform" means a ratio of 25% or less, Or preferably it refers to a difference of 15% or less, or preferably 5% or less.

[0025] 2A-2C show raw drug material (e.g., commercially available crystalline fluticasone shown in FIG. 2A). propionate ester) was first recrystallized into large cylindrical crystals (Figure 2B), followed by As defined in the Specification, size-controlled crystals with a narrow size distribution (e.g. For example, the recrystallized columnar crystals are shortened and sieved (FIG. 2C). .

[0026] In order to effectively carry out the particle size adjustment process, the recrystallized crystalline It is important that the columnar crystals first meet a specific target dimension. The target dimensions of the recrystallized columnar drug crystals meet one or more of the following criteria: (i) 90% of the total mass is 1200 microns or less (D 90 );(ii)Total mass 50% of the particles are less than 350±180 microns (D 50 );(iii) 10 of the total mass % or less is less than 50 microns (D 10 (iv) 75% or more of the total volume of the drug crystals The top has an aspect ratio of 1 to 5.

[0027] In other more specific embodiments, the recrystallized columnar crystals have a minimum dimension of at least The diameter is also 10 to 500 microns.

[0028] As used herein, laser diffraction refers to the process of measuring the intensity of a sample or collection of particles (e.g., The particle size and particle size distribution of the crystallized columnar crystals and the crystals with adjusted particle size were measured. More specifically, D 10 The value is the sample It refers to the diameter at which 10% of the mass is made up of particles with diameters less than this value. 50 The value is the value at which 50% of the sample masses are less than this value and 50% of the sample masses are greater than this value. The diameter of the particle is larger than the particle diameter.

[0029] In the histogram, D 10 , D 50 and D. 90 is the cumulative mass per particle diameter. are the intercepts for 0%, 50% and 90% since the density is the same for all particles. However, mass and volume have a linear relationship, so the percentages above remain the same. The method also gives the cumulative distribution of the volume.

[0030] In an even more specific embodiment, the particle size adjustment step is carried out using a rotor / stator type homogenizer. The process involves crushing the columnar crystals in a homogenizer, typically a rotor / stator type homogenizer. The rotor comprises a rotating inner rotor, a fixed outer sheath, a carrier liquid medium, and a fixed and a solid medium (e.g., recrystallized columnar crystals).

[0031] In an even more specific embodiment, the particle size adjustment step comprises sieving the drug crystals. The present invention further includes a

[0032] In certain embodiments, the resulting size-controlled crystals meet one or more of the following criteria: (i) 90% of the total mass (D 90 ) is 190 microns or less; (ii) 50% of the total mass (D 50 (iii) the total particle size is less than 90 ± 20 microns; 10% of mass (D 10 (iv) the bulk of the drug crystals is less than 30 microns; Or, 75% or more of the total volume of the aggregate has an aspect ratio of 1 to 3.

[0033] The process disclosed herein is a process for coating a polymeric material by a fluidized bed method. It is particularly suitable for recrystallization and particle size control of crystals of PI (ie, drug crystals).

[0034] Thus, a further embodiment is a composite of components each coated with a thin film of polymer. Suitable polymers include polyvinyl alcohol, polyvinyl chloride ... Alcohol, polylactic acid (PLA), polylactic-co-glycolic acid (PLGA) , polycaprolactone (PCL), and poly(trimethylene carbonate) (pTMC The preferred polymer for the coating is poly(ethylene glycol). It is vinyl alcohol. The film thickness is about 1 to 10 microns.

[0035] Specific features are described in further detail below.

[0036] recrystallization Recrystallization may be further carried out to provide size-controlled crystals of a target size. This is an essential step by first producing large, supersized crystals that can be grown (e.g., shortened) over time. Suitably, the supersized crystals have a columnar crystal shape (also called "columnar crystals") due to preferential crystal growth along their length. As used herein, "columnar crystals" refers broadly to a crystal shape that resembles a column, i.e., the crystals have a preferential axis and a cross-section along (e.g., perpendicular to) the preferential axis that is of approximately the same shape and size.

[0037] As disclosed herein, the majority (at least 90%) of the columnar crystals are between 50 and 25 0 microns in thickness (i.e., the shortest dimension of the cross section perpendicular to the longitudinal axis), as well as The columnar crystals have aspect ratios ranging from 0.1 to 1.0 mm. These columnar crystals are called ultra-large crystals because they reassemble into a cubic target morphology with target dimensions in the range of 50 to 250 microns. This is because the particle size can vary in both thickness and length.

[0038] Conventional recrystallization does not easily yield extra-large crystals due to stagnation of crystal growth. Figure 3 shows monoclinic form I of fluticasone propionate (FP). The crystal structure shows preferential crystal growth along the c-axis (longitudinal direction) compared to the ab-plane (transverse plane). However, this preferential growth tends to stagnate before the ab-plane can grow wider than 10-15 microns. In fact, typical known recrystallization methods, such as co-solvents, anti-solvents (direct and inverse methods), surface / interface modifiers during nucleation and growth, slow and fast cooling, are only capable of producing thin, needle-like crystals with at least one dimension not meeting the target dimension.

[0039] In contrast to conventional recrystallization, according to embodiments of the present disclosure, commercially available FP crystals are produced without methanol. It is possible to recrystallize the granules into very large crystals. The recrystallization time and conditions (e.g. By controlling the crystal growth rate (e.g., temperature), it is possible to grow the crystal to the ab plane even after the c-axis growth has slowed down. The growth mechanism is shown in FIG. The ultra-large crystals (200) have a longest dimension (L) along their longitudinal axis and a shortest dimension (D) in their cross-section. The aspect ratio is L / D. Suitably, the shortest dimension (D) may be approximately the same as at least one target dimension of the sized drug crystals, thereby facilitating sizing by breaking the ultra-large crystals primarily along their length.

[0040] In certain embodiments, the target dimensions of the recrystallized pillared drug crystals are determined by one of the following criteria: (i) 90% of the total mass is 1200 microns or less (D 90 ) and (ii) 50% of the total mass is less than 350 ± 180 microns (D 50 ) ;(i ii) 10% or less of the total mass is less than 50 microns (D 10 (iv) drug crystals; At least 75% of the total volume has an aspect ratio of 1 to 5.

[0041] Particle size adjustment To obtain the target size, the extra large crystals are appropriately sized by milling in a rotor / stator homogenizer, optionally with further steps of sieving and rinsing.

[0042] Conventionally, large crystals are sized using a jet mill or pin mill. However, they tend to produce heterogeneous crystals with a large amount of fine grains. Crystals with taxial growth (e.g. FP crystals) are very fragile and are difficult to grow using conventional jet or pinhole crystals. Milling by powder grinding inevitably produces very fine powders that do not meet the target size.

[0043] According to one embodiment, a rotor / stator homogenizer is utilized to reduce the amount of conventional particles. Addresses the technical limitations of the diameter change process. Rotor / stator type homogenizers are typically The rotor comprises a rotating inner rotor, a fixed outer sheath, a carrier liquid medium, and a fixed This type of homogenizer is used to produce microparticles or emulsions. It has traditionally been used in

[0044] Surprisingly, by controlling the operating parameters, the crystallization step can be We have found that ultra-large crystals can be uniformly broken along their length axis (e.g., c-axis) while their shortest dimension (width) remains largely unchanged. In particular, by optimizing the rotating head configuration (any combination of fine, medium, or coarse), rotation speed (ranging from 3000 to 26000 rpm), solids content (5-50% w / v recrystallized columnar crystals), type of carrier fluid, and number of rotor / stator passes (1-10), thick, elongated crystals can be gently broken (shortened) primarily along their c-axis, with minimal loss due to the formation of very fine particles.

[0045] The carrier fluid may be water, one or more polar organic solvents (e.g., acetone), one or more protons, Aromatic solvents (e.g., methanol, ethanol, or isopropanol), or combinations thereof Optionally, a surfactant may be present in the carrier fluid. Suitable surfactants include non-ionic surfactants such as polysorbates. In a specific embodiment, it is polysorbate 80 (eg, 0.1-0.5% w / v).

[0046] If necessary, particle size adjustment may be performed by sieving the milled (e.g., shortened) crystals to obtain a particle size distribution. This may further include narrowing the size distribution. In various embodiments, the crushed crystals is sieved through one or more sieves to remove any fine particles or remaining large crystals. Typically, two separate sieving steps allow for narrow separations on a reproducible scale. A particle size distribution can be produced.

[0047] Additionally, the sieved crystals can be rinsed to further remove fines. The sieved crystals were mixed with a surfactant, water, and optionally methanol, ethanol, or isotonic acid. Rinse one or more times with a rinse solution containing one or more water-miscible solvents, such as isopropanol. Suitable surfactants include polysorbates such as polysorbate 80. In this embodiment, the surfactant is present in the rinse solution in an amount of 0.05 to 1.0%. For example, the rinse solution can be a 0.5% polysorbate 80 solution.

[0048] In certain embodiments, the particle size controlled granules obtained by the processes disclosed herein are A drug crystal is a collection of drug crystals that meets one or more of the following statistical criteria: i) 90% of the total mass (D 90 (ii) 50% of the total mass is 190 microns or less; %(D 50 (iii) 10% of the total mass (D 10 ) less than 30 microns; (iv) less than 7% of the total volume of the bulk or aggregate of drug crystals; At least 5% have an aspect ratio of 1 to 3. EXAMPLES

[0049] Example 1 Recrystallization of fluticasone propionate Slow evaporation at 45°C Fluticasone propionate was administered in methanol at concentrations ranging from 10 to 15 mg / ml. , recrystallization on both small and large scales. During evaporation, the temperature was kept constant at 45°C. Small scale studies were carried out with 20 ml to 2 L of solution. On the other hand, the large-scale experiment was carried out at 20 to 100 L. Figure 5 shows the recrystallized particles in the small-scale experiment. 5 shows an SEM image of the small scale, while FIG. 6 shows an image at a larger scale. Both small and large scale crystals produced thick, elongated crystals suitable for further particle size modification. It was.

[0050] Example 2 Recrystallization of fluticasone propionate Slow evaporation at 25°C Fluticasone propionate is administered in small scale doses of 20 mL to 2 L and in doses of 20 to 10 Recrystallization was performed from concentrations of 10-15mg / ml in methanol in both 0L and large scale systems. The temperature was kept constant at 25°C during slow evaporation for 20 hours. Figure 7 shows an SEM image of the particles generated on a small scale, and Figure 8 shows an SEM image on a large scale. Shows.

[0051] Different large-scale batches were run to test the reproducibility of the recrystallization method. Four large-scale The results of particle size analysis by laser diffraction on the batch are shown below:

[0052] TIFF2024174908000001.tif43135

[0053] Laser diffraction assumes equivalent spheres when calculating results. The aspect ratio ranges from 3 to 50, but most of the aspect ratios are between 5 and 20. is in the range.

[0054] Recrystallized fluticasone propionate meets USP specifications and is It has been confirmed that catecholamine propionate is in the Form I polymorphic crystalline form, which is the same as the original commercial form. FIG. 9 shows the X-ray diffraction patterns of as-obtained (Form I) and recrystallized FP crystals. As shown, the polymorphism of Form I did not change after recrystallization. Ta.

[0055] Example 3 Particle size modification of recrystallized fluticasone propionate. Recrystallized fluticasone propionate crystals prepared according to Examples 1 or 2 The mixture was milled using a rotor / stator homogenizer. The figure shows a rotor / stator type homogenizer.

[0056] An exemplary set of operating parameters is as follows: 5~10% solid medium Carrier fluid: 0.1% to 0.5% Polysorbate 80 (surfactant) in USP water Rotor speed: 15,000-20,000 rpm (grinding is in the range of 3,000-26,000 rpm) (operable within 100 Hz) Rotor configuration: Coarse, medium, or fine, or a combination of two or more rotors Number of times this cycle will run: Maximum 5 times

[0057] The crushed crystals are then sieved through two separate sieves to remove fines or remaining large crystals. The crystals were removed. Figure 11 shows the size-altered (milling and subsequent sieving) drug crystals. SEM images of the above are shown.

[0058] FIG. 12 shows the overall particle size distribution using a Malvern particle size analyzer. As can be seen, the resulting drug crystals have a relatively narrow distribution, minimal amounts of fine material, and very little crystallinity. There is no fine material present (no particles smaller than 9 μm).

[0059] FIG. 13 shows a comparison of commercially available sources of FP crystals with highly variable particle sizes and one embodiment of the present disclosure. FIG. 11 is a side-by-side comparison of FP drug crystals having target sizes formed according to the method of the present invention.

[0060] Example 4 Drug release behavior The narrow particle size distribution of the drug crystals is essential for the coating process and therefore for the encapsulated drug. The release profile of the drug was improved by removing particulates from the drug crystals prior to coating. By this, both the quality and efficiency of the coating were improved. In vivo testing requires narrow particle size distributions (e.g., D 50 Coating thickness is within the range of 50 to 250 microns. The release from coated particles was compared to that from coated particles with a broad particle size distribution. and showed that it is slower and more stable.

[0061] The various embodiments described above can be combined to provide further embodiments. U.S. patents referenced herein and / or listed in the Application Data Sheet, U.S. Patent Publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications ([insert list] , all of which are incorporated herein by reference in their entirety. Aspects of the embodiments are disclosed in various patents, publications, and other publications to provide further embodiments, as appropriate. The concepts of the applications and publications can be modified to be used.

[0062] These and other changes can be made to the embodiments in light of the above detailed description. Generally, the terms used in the following claims are intended to clarify the scope of the claims. The specification and claims should not be construed as being limited to the specific embodiments disclosed. rather, all possible implementations are to be considered as equivalents to the full scope of rights that such claims are entitled to. Accordingly, the claims should be construed to include the present disclosure. Not done.

[0063] This application is a continuation of U.S. Provisional Application No. 62 / 832,179, filed April 10, 2019. The benefit of prior art is claimed, and is incorporated herein by reference in its entirety.

Claims

1. 1. A process for providing crystals of a desired particle size distribution and morphology, comprising: A step of providing recrystallized columnar crystals having an aspect ratio of greater than 1 and less than 20. The aspect ratio of the predetermined columnar crystals is determined based on the shortest dimension of a cross section perpendicular to the longitudinal axis. a ratio of the longest dimension along the longitudinal axis to the step; The recrystallized columnar crystals are subjected to particle size adjustment to obtain a particle size-adjusted crystal having a target dimension. providing a mass of crystals, the particle size adjustment being performed by a front surface perpendicular to the longitudinal axis; While maintaining the cross-sectional dimensions, the recrystallized segmenting at least a portion of the columnar crystals; A process including.

2. The recrystallized columnar crystals meet the following criteria: (i) 90% by mass of the recrystallized columnar crystals are 1,200 microns or less. ； (ii) 50% by weight of the recrystallized columnar crystals are less than 350±180 microns. Something; (iii) 10% by weight or less of the recrystallized columnar crystals are less than 50 microns. and (iv) 75% or more of the total volume of the recrystallized columnar crystals has an aspect ratio of 1 to 5. having The process of claim 1 further comprising one or more of the following:

3. The recrystallized columnar crystals meet the following criteria: (i) 50% by mass of the recrystallized columnar crystals are in the range of 80 to 600 microns. Something; (ii) 75% by mass of the recrystallized columnar crystals are in the range of 50 to 800 microns. and (ii) 90% by mass of the recrystallized columnar crystals are in the range of 20 to 1100 microns. Being in The process of claim 1 further comprising one or more of the following:

4. The population of sized crystals has a target size of: (i) 90% by mass of the particle size-adjusted crystals are 190 microns or less; (ii) 50% by mass of the particle size-adjusted crystals are less than 90±20 microns. and; (iii) 10% by weight or less of the particle size-adjusted crystals are less than 30 microns. and; (iv) 75% or more of the total volume of the particle size-adjusted crystals has an aspect ratio of 1 to 3. Having The process of claim 1 , wherein one or more of the following are satisfied:

5. The population of sized crystals has a target size of: (i) 50% by mass of the particle size-adjusted crystals are in the range of 35 to 130 microns. thing; (ii) 75% by weight of the particle size-adjusted crystals are in the range of 30 to 145 microns. and (ii) 90% by mass of the particle size-adjusted crystals are in the range of 25 to 170 microns. To do so, The process of claim 1 , wherein one or more of the following are satisfied:

6. The particle size adjustment is performed by homogenizing the recrystallized columnar particles in a rotor / stator type homogenizer.

2. The method of claim 1, further comprising shortening the longitudinal axis of the crystal to provide a shortened crystal.

6. The process according to any one of claims 5 to 5.

7. The particle size adjustment may include sieving the shortened crystals to provide sieved crystals. The process of claim 6, further comprising:

8. The sieved crystals are mixed with a surfactant, water, methanol, ethanol and isopropanol. and rinsing the surface with a rinsing solution containing at least one solvent selected from the group consisting of alcohol and ethanol. The process of claim 7 .

9. 9. The method according to claim 8, wherein the rinse solution contains 0.05 to 1% (w / w) polysorbate 80. The process described.

10. 10. Any one of claims 1 to 9, wherein the crystal is a crystal of a pharmaceutical active ingredient (API). The process described in

11. 10. The method according to claim 1, wherein the crystal is a crystal of fluticasone propionate. The process according to any one of claims 1 to 5.

12. The particle size-controlled crystals are then coated with a polymer film by a fluidized bed coating device. The process according to any one of claims 1 to 11, wherein the particles are coated one by one.

13. The polymer membrane may be polyvinyl alcohol, polylactic acid (PLA), polylactic acid-glycol Poly(trimethylene carbonate) copolymer (PLGA), polycaprolactone (PCL), poly(trimethylene carbonate) 13. The process according to claim 12, wherein the polymer is formed from a polysaccharide, a polysaccharide copolymer ... Process.

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