Process for producing drug crystals with a desired particle 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] This disclosure relates to specific particles that are particularly suitable for coating to provide sustained-release formulations. This relates to a process for producing drug crystals with specific particle size distribution and morphology. [Background technology]

[0002] The drug crystals are completely coated or encapsulated in a thin polymer film, and are continuously absorbed. It can be released slowly. Patent Document 1 describes a substance that can be injected into a joint or other body part, thereby Fluticasone propionate is released locally over a long period of time, but the total Polyvinyl alcohol exposure does not cause clinically significant suppression of the HPA axis. Captive fluticasone propionate ester crystals are disclosed.

[0003] To coat or encapsulate individual solid particles containing drug crystals, a fluidized bed is used. The device is commonly used. Such a device uses differential airflow. Using r flow, solid particles are suspended while the coating is atomized from the nozzle. The material (e.g., droplets of a polymer solution) is sprayed onto the solid particles to coat them individually.

[0004] The fluidized bed system ensures that the drug crystals being coated are of a controlled, reproducible, and uniform particle size. It functions optimally when a cloth is present. The non-uniform distribution of particle size is a floating parameter. This affects the optimization process. For example, particles with small coating parameters are suspended. When optimized to do so, larger particles remain stationary. Conversely, when the parameters are large When optimized for large particles, small particles collide with the sidewalls with a large impact. This can lead to crushing and / or aggregation with uneven coating coverage. Fine particles ("microparticles"), such as microparticles with an average diameter of less than 15%, are filtered into the device. This could cause further problems by clogging the tap, and / or, Aggregation can alter the quality of the coating. The shape of the particles also affects the quality of the coating. This affects buoyancy and floating ability, thus impacting the quality of the coating.

[0005] Therefore, in the art, drug compounds having a desired controllable particle size distribution and morphology are required. There is a need to provide crystals in a reproducible manner. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] US9,987,233 [Overview of the project]

[0007] In this invention, suitable for uniform coating by the fluidized bed method, the desired particle size, shape and Multiple or a group of drug crystals having a particle size distribution are provided. A method for producing them is also provided. It will be shown.

[0008] In certain embodiments, the drug crystals are cubic in shape (i.e., all dimensions are equal) Fluticasone propio (particle size) and fluticasone propio (particle size) with a narrow particle size distribution in the range of 50-250 μm It is a fission product (FP) crystal.

[0009] The methods and processes described herein include fluticasone propionate and other f It should be noted that this is not limited to luticasone esters. Rather, one or more embodiments may include Therefore, recrystallization and particle size modification of other drug raw materials, particularly poorly soluble drugs (such as corticosteroids) that prioritize crystal growth in the length direction, become possible. is possible.

Brief Description of the Drawings

[0010] [Figure 1] A flowchart of a process for preparing a population of drug crystals with adjusted particle sizes according to one embodiment is shown.

[0011] [Figure 2A-C] Shows the as-obtained drug material or active pharmaceutical ingredient (API) of the raw material, which is recrystallized into thick and elongated columnar crystals before being particle size adjusted to drug crystals with the target dimensions.

[0012] [Figure 3] Shows the monoclinic form I of fluticasone propionate (FP).

[0013] [Figure 4] Schematically shows the crystal growth mechanism for producing thick and elongated crystals.

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

[0015] [Figure 7] SEM images of the recrystallized FP crystals obtained under another isothermal condition are shown at small and large scales respectively. [Figure 8] SEM images of the recrystallized FP crystals obtained under another isothermal condition are shown at small and large scales respectively.

[0016] [Figure 9]The X-ray diffraction patterns of raw drug materials (commercially available sources) and recrystallized FP crystals according to one embodiment are shown.

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

[0018] [Figure 11] The image shows SEM images of drug crystals with adjusted particle size (sieved after grinding).

[0019] [Figure 12] This shows the particle size distribution of drug crystals with adjusted particle size according to one embodiment.

[0020] [Figure 13] This shows a side-by-side comparison of commercially available FP crystals and particle-size-adjusted drug crystals obtained according to one embodiment of this disclosure. [Modes for carrying out the invention]

[0021] This specification provides for providing bulk crystals having a specific target particle size distribution and morphology. The process is described. This process has an aspect ratio greater than 1 and less than 20. A step of providing a recrystallized columnar crystal, wherein the aspect ratio of a predetermined columnar crystal However, it is the ratio of the longest dimension along the longitudinal axis to the shortest dimension of the cross-section perpendicular to the longitudinal axis. (1) The steps are to (2) adjust the particle size of the recrystallized columnar crystals to have a specific target size. A step of providing an aggregate of crystals with adjusted particle size, wherein the step of adjusting the particle size is , while maintaining the dimensions of the cross-section perpendicular to the longitudinal axis, reconnecting along each longitudinal axis A step comprising segmenting (dividing) at least a portion of the crystallized columnar crystals. , including.

[0022] This process is applicable to any crystal, but not to bulk drug crystals, i.e., monodisperse crystals. To generate particle-size-controlled drug crystal aggregates having particle size, shape, and mass distribution It is particularly suitable for coating these crystals using a fluidized bed coating apparatus. To make it particularly suitable for that purpose.

[0023] Figure 1 schematically shows a process according to one embodiment of the present disclosure. Process (100) is: The raw material drugs, such as APIs, derived from commercially available sources (110), are typically in fine particles. These are fossilized crystals (e.g., less than 5 microns). Next, the API (11) is obtained as is. Recrystallize (120) to obtain columnar crystals having an aspect ratio in the range of greater than 1 and less than 20. We provide this, but here, the aspect ratio of a given crystal is the shortest dimension of the cross-section perpendicular to the longitudinal axis. This is the ratio of the longest dimension along the longitudinal axis to the modulus. The recrystallized columnar crystals are then, The particle size is adjusted (130) to provide bulk drug crystals of the target size. The step is that at least a portion of the recrystallized columnar crystal preferentially segments along the longitudinal axis. This includes grinding, that is, grinding in which the dimensions of the cross-section perpendicular to the longitudinal axis are maintained. The segmented crystals are sieved, and crystals that meet specific target dimensions are collected. Bulk drug crystals (140) have particle size adjustments having a narrow particle size distribution as defined herein. It contains aggregates of crystals. In particular, the bulk drug crystals have a substantially uniform shape, particle size and mass. It has a distribution and is suitable for fluid bed coating.

[0024] In certain embodiments, the particle-size-adjusted crystals are shorter than the recrystallized columnar crystals. However, the dimensions of the cross-section perpendicular to the longitudinal axis of the recrystallized columnar crystal are retained. In the embodiment, the particle-size-adjusted crystals have an aspect ratio in the range of 1 to 3. In a typical embodiment, the particle-size-adjusted drug crystals are cubic in shape and have an aspect ratio of approximately 1 It has a ratio. In this specification, "approximately uniform" means "approximately the same" as 25% or less. Alternatively, it refers to a difference of 15% or less, or preferably 5% or less.

[0025] Figures 2A and 2C show the raw material drug (for example, commercially available crystalline fluticasone shown in Figure 2A). First, the propionic acid ester was recrystallized into large cylindrical crystals (Figure 2B), followed by Honmei As defined in the details, particle size adjustment is performed on a particle size-adjusted crystal with a narrow particle size distribution (example). For example, the recrystallized columnar crystals are shortened and sieved (Figure 2C). A specific embodiment is shown. .

[0026] In order to effectively carry out the particle size adjustment process, the recrystallized particles that are subject to particle size adjustment must be First, it is important that the columnar crystals satisfy specific target dimensions. In more specific embodiments... The target dimensions of the recrystallized columnar drug crystals must 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 them are less than 350 ± 180 microns (D 50 (iii) 10 of the total mass The percentage must be less than 50 microns (D 10 (iv) 75% or less of the total volume of drug crystals The top image must have an aspect ratio between 1 and 5.

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

[0028] When used herein, laser diffraction is used to analyze a sample or aggregate of particles (e.g., re- The particle size and particle size distribution of crystallized columnar crystals and particle size-adjusted crystals are measured. It is a methodology used for analysis. More specifically, D 10 The value is the sample This refers to the diameter composed of particles whose diameter is less than 10% of the mass. Similarly, D 50 The value is such that 50% of the sample mass is less than this value, and 50% of the sample mass is less than this value. It is the diameter of the particle, which is the largest.

[0029] In the histogram, D 10 , D 50 and D 90 1 of the cumulative mass at the particle size These are intercepts for 0%, 50%, and 90%. The density is the same for all particles. Mass and volume have a linear relationship, and therefore the percentages mentioned above remain the same. The method also shows the cumulative distribution of volume.

[0030] In a more specific embodiment, the particle size adjustment step is performed using a rotor / stator type homogenizer. This involves grinding columnar crystals in a homogenizer. Typically, this is done using a rotor / stator type homogenizer. It consists of a rotating inner rotor, a fixed outer sheath, a carrier liquid medium, and a solid It comprises a body medium (for example, recrystallized columnar crystals).

[0031] In a more specific embodiment, the particle size adjustment step is a step of sieving drug crystals. It also includes p.

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

[0033] The process disclosed herein is particularly suitable for the recrystallization and particle size adjustment of crystals of API (i.e., drug crystals) that can be coated by a fluid bed method. The process disclosed herein is particularly suitable for the recrystallization and particle size adjustment of crystals of API (i.e., drug crystals) that can be coated by a fluid bed method.

[0034] Thus, a further embodiment provides an aggregate of coated drug crystals, each coated with a thin film of a polymer. Suitable polymers include polyvinyl alcohol, as well as biodegradable polyesters such as polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and poly(trimethylene carbonate) (pTMC). A preferred polymer for coating is polyvinyl alcohol. The thickness of the thin film is about 1 to 10 microns. ーティングされた薬物結晶の集合体を提供する。適切なポリマーとしては、ポリビニルア ルコール、ならびにポリ乳酸(PLA)、ポリ乳酸-グリコール酸共重合体(PLGA) 、ポリカプロラクトン(PCL)、およびポリ(トリメチレンカーボネート)(pTMC )などの生分解性ポリエステルが挙げられる。コーティングに好ましいポリマーは、ポリ ビニルアルコールである。薄膜の厚さは約1~10ミクロンである。

[0035] Specific features will be described in more detail below.

[0036] Recrystallization Recrystallization is further particle size adjustment ( An essential step is to first generate large, supersized crystals (supersized crystals) that can be shortened, for example. Appropriately, supersized crystals have a columnar crystalline shape (also called “columnar crystals”) due to preferential crystal growth in the longitudinal direction. As used herein, “columnar crystal” broadly refers to a crystalline shape resembling a column, i.e., the crystal has a preferred axis and cross-sections of substantially the same shape and size along this preferred axis (e.g., perpendicular to the preferred axis).

[0037] As disclosed herein, the majority (at least 90%) of the columnar crystals are 50-25 Thickness in the range of 0 microns (i.e., the shortest dimension of the cross-section perpendicular to the longitudinal axis), and 1 It has aspect ratios in the range of greater than and less than 20. Columnar crystals are up to millimeters, and These can be up to a centimeter in length. These columnar crystals are called superlarge crystals because they can be reshaped into a cubic target form with target dimensions in the range of 50 to 250 microns. This is because it has both thickness and length that allow for changes in particle size.

[0038] Conventional recrystallization methods fail to readily produce very large crystals due to stagnation of crystal growth. Figure 3 shows monoclinic form I of fluticasone propionate (FP). The crystal structure exhibits preferential 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 to a width exceeding 10-15 microns. In fact, typical known recrystallization methods, such as cosolvents, poor solvents (direct and inverse methods), surface / interface modifiers during nucleation and growth, and slow and fast cooling, can only produce thin needle-shaped crystals where at least one dimension does not meet the target dimension.

[0039] In contrast to conventional recrystallization, according to embodiments of the present disclosure, commercially available FP crystals are metanitrate. From there, it can be recrystallized into a very large crystal. Recrystallization time and conditions (example) By controlling (for example, temperature), even after the c-axis growth has slowed down, the crystal can be grown on the ab-plane. It can be made to grow thicker along the way. Figure 4 schematically shows the growth mechanism. The extra-large crystal (200) has a longest dimension (L) along the longitudinal axis and a shortest dimension (D) in the cross-section. The aspect ratio is L / D. Preferably, the shortest dimension (D) may be approximately the same as at least one target dimension of the particle-size-adjusted drug crystal, thereby facilitating particle size modification by fracturing the extra-large crystal mainly along the longitudinal direction.

[0040] In certain embodiments, the target dimensions of the recrystallized columnar drug crystals are determined from the following criteria: One or more of the following conditions are met: (i) 90% of the total mass is 1200 microns or less (D 90 ) (ii) 50% of the total mass is less than 350 ± 180 microns (D 50 ) being; (i ii) Less than 10% 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 dimensions, extra-large crystals are appropriately particle-size-adjusted by grinding them in a rotor / stator homogenizer, which may involve further steps of sieving and rinsing.

[0042] Traditionally, large crystals are processed to adjust their particle size using a jet mill or pin mill. However, However, they tend to produce heterogeneous crystals with a large number of fine particles. c-axis epi Crystals with taxial growth (e.g., FP crystals) are very brittle, unlike conventional jet or pyrotechnic crystals. Grinding using a pulverizer inevitably produces extremely fine powder that does not meet the target dimensions.

[0043] According to one embodiment, by utilizing a rotor / stator type homogenizer, conventional particles Addressing the technical limitations of the diameter change process. Rotor / stator type homogenizers are typically It consists of a rotating inner rotor, a fixed outer sheath, a carrier liquid medium, and a solid It comprises a body medium. This type of homogenizer is used to produce particulate matter or emulsions. It has been used conventionally.

[0044] Surprisingly, by controlling the operating parameters, the recrystallization step can be obtained We found that extremely large crystals can be uniformly fractured along their longitudinal axis (e.g., the c-axis) while their minimum dimension (width) remains virtually unchanged. In particular, by optimizing the configuration of the rotating head (any combination of fine, medium, or coarse), the rotational speed (ranging from 3000 to 26000 rpm), the solid content (5-50% w / v recrystallized columnar crystals), the type of carrier fluid, and the number of times the crystal passes through the rotor / stator (1-10 times), thick, elongated crystals are gently fractured (shortened) mainly along the c-axis, minimizing losses due to the formation of very fine particles.

[0045] The carrier fluid is water, one or more polar organic solvents (e.g., acetone), one or more proto Non-stick solvents (e.g., methanol, ethanol, or isopropanol), or combinations thereof May include combinations. In some cases, surfactants may be present in the carrier fluid. Appropriate Examples of surfactants include nonionic surfactants such as polysorbates. In a specific embodiment, it is polysorbate 80 (e.g., 0.1-0.5% w / v).

[0046] If necessary, particle size adjustment is performed by sieving the crushed (e.g., shortened) crystals to separate the particles. This may further include narrowing the diameter distribution. In various embodiments, crushed crystals This involves sieving through one or more sieves to remove fine particles or remaining larger crystals. This can be done. Typically, two separate screening steps allow for narrowing the sieve to a reproducible scale. It is possible to generate a particle size distribution.

[0047] Furthermore, the sieved crystals can be rinsed to remove even more fine particles. Typically, The sieved crystals are mixed with a surfactant, water, and optionally methanol, ethanol, and Rinse once or twice with a rinse solution containing one or more water-miscible solvents, such as sopropanol. Examples of 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 could be a 0.5% polysorbate 80 solution.

[0048] In certain embodiments, the particle size adjustment obtained by the process disclosed herein is A drug crystal is an aggregate of drug crystals that satisfies one or more of the following statistical criteria: i) 90% of the total mass (D 90 (ii) that the diameter is 190 microns or less; (ii) 50 of the total mass %(D 50 (iii) The diameter is less than 90 ± 20 microns; (iii) 10% of the total mass (D 10 ) less than 30 microns; (iv) 7 of the total volume of the bulk or aggregate of drug crystals At least 5% of the image must have an aspect ratio of 1 to 3. [Examples]

[0049] Example 1 Recrystallization of fluticasone propionate Slow evaporation at an isothermal temperature of 45°C Fluticasone propionate is used in methanol at a concentration of 10-15 mg / ml. Recrystallization occurred on both small and large scales. For example, a slow process of 72 hours The temperature was kept constant at 45°C during evaporation. Small-scale tests were performed with 20 ml to 2 L of solution. On the other hand, large-scale experiments were conducted in 20-100 L volumes. Figure 5 shows recrystallized particles on a small scale. Figure 6 shows an SEM image of the small scale, while Figure 6 shows an image at a larger scale. As shown, the small scale Thick, elongated crystals suitable for further particle size modification are generated at both the kale and large scales. It was done.

[0050] Example 2 Recrystallization of fluticasone propionate Slow evaporation at an isothermal temperature of 25°C Fluticasone propionate is used in small-scale solutions of 20 mL to 2 L and 20 to 10 Recrystallization was performed in both large and small 0L scales, starting from a concentration of 10–15 mg / ml in methanol. For example, the temperature was kept constant at 25°C during a 20-hour slow evaporation process. (Figure) Figure 7 shows an SEM image of particles generated on a small scale, and Figure 8 shows an SEM image on a large scale. This indicates.

[0051] We ran batches of different large scales to examine the reproducibility of the recrystallization method. The results of particle size analysis by laser diffraction in the batch are shown below:

[0052] TIFF0007874687000001.tif43135

[0053] Laser diffraction assumes an equivalent sphere when calculating the results. The aspect ratio can range from 3 to 50, but the majority of aspect ratios are between 5 and 20. It is within the range.

[0054] The recrystallized fluticasone propionate conforms to USP standards, and fluticasone propionate is recrystallized. It has been confirmed that it is in the same polymorphic crystalline form (Form I) as the original commercially available form of casonpropionic acid ester. Confirmed. Figure 9 shows the X-rays of the FP crystal in its as-acquired form (morphology I) and recrystallized state. The linear diffraction patterns are compared. As shown, the polymorphism of morphology I did not change after recrystallization. Ta.

[0055] Example 3 Particle size modification of recrystallized fluticasone propionate Recrystallized fluticasone propionate crystals prepared by Example 1 or 2 The material was then pulverized using a rotor / stator type homogenizer. Figure 10 shows the low of the benchtop model. This shows a ta / stata type homogenizer.

[0056] An example set of operating parameters is as follows: 5~10% solid medium Carrier fluid: USP water 0.1%~0.5% polysorbate 80 (surfactant) Rotor speed: 15,000-20,000 rpm (crushing is within the range of 3,000-26,000 rpm) (Operable within the enclosure) Rotor configuration: Includes coarse, medium, or fine rotors, or combinations of two or more rotors. Number of times this cycle is executed: Maximum 5 times

[0057] Next, the crushed crystals are sieved through two separate sieves to separate the fine particles or remaining larger particles. The crystals were removed. Figure 11 shows drug crystals with modified particle size (grinding and subsequent sieving). The SEM image is shown.

[0058] Figure 12 shows the overall particle size distribution using a Malvern particle size analyzer. Therefore, the obtained drug crystals have a relatively narrow distribution, with a minimum amount of fine material, and are extremely There are no microscopic materials (no particles smaller than 9 μm exist).

[0059] Figure 13 shows commercially available FP crystals with very varying particle sizes and one embodiment of the present disclosure. This figure shows a comparison of FP drug crystals with target dimensions formed according to the state.

[0060] Example 4 Drug release behavior The narrow particle size distribution of drug crystals affects the coating process and, consequently, the encapsulated drug. The release profile was improved. In particular, particulate matter was removed from the drug crystal before coating. This improved both the quality and efficiency of the coating. Vivo testing is used for narrow particle size distributions (e.g., D 50 Coating (within the range of 50-250 microns) Emissions from coated particles are compared to those from coated particles with a broad particle size distribution. This demonstrated that it is slower and more stable.

[0061] Further embodiments can be provided by combining the various embodiments described above. U.S. patents referred to herein and / or listed in the application data sheet, U.S. patents Publication of patent applications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications ([insert list] All of the above (including, but not limited to) are incorporated herein by reference in their entirety. The embodiments of the model may be further described in various patents to provide additional embodiments as needed. It may be modified to use the concepts of application and publication.

[0062] These and other modifications may be made to the embodiments in light of the detailed description above. In general, the terms used in the following claims are intended to clarify the scope of the claims. It should be interpreted as being limited to the specific embodiments disclosed in the details and claims. not, but the entire scope of equivalents of the rights set forth by such claims, and all possible implementations It should be interpreted as including the form. Therefore, the scope of the claims is not limited by this disclosure. It will not be done.

[0063] This application is based on U.S. Provisional Application No. 62 / 832,179, filed on April 10, 2019. Priority rights are asserted, and the entirety thereof is incorporated herein by reference.

Claims

1. A process for providing fluticasone propionate crystals with a desired particle size distribution and morphology, A step of recrystallizing fluticasone propionate in methanol to obtain extra-large columnar crystals having an aspect ratio greater than 1 and less than 20, characterized in that the aspect ratio of a predetermined 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, and the cross-sections are substantially the same shape and size along the longitudinal axis. A step of shortening the recrystallized extra-large columnar crystals to provide an aggregate of particle-size-adjusted crystals having target dimensions, wherein shortening the recrystallized extra-large columnar crystals includes segmenting at least a portion of the recrystallized extra-large columnar crystals along each of the longitudinal axes while maintaining the dimensions of the cross-section perpendicular to the longitudinal axis, A process that includes this.

2. The aforementioned recrystallized extra-large columnar crystals meet the following criteria: (i) 90% by mass of the recrystallized extra-large columnar crystals have a diameter of 1200 microns or less; (ii) 50% by mass of the recrystallized extralarge columnar crystals have a diameter of less than 350 ± 180 microns; (iii) 10% by mass or less of the recrystallized extra-large columnar crystals have a diameter of less than 50 microns; and, (iv) More than 75% of the total volume of the recrystallized extra-large columnar crystals has an aspect ratio of 1 to 5 in diameter. The process according to claim 1, further satisfying one or more of the following conditions.

3. The aforementioned recrystallized extra-large columnar crystals meet the following criteria: (i) 50% by mass of the recrystallized extra-large columnar crystals are in the range of 80 to 600 microns in diameter; (ii) 75% by mass of the recrystallized extra-large columnar crystals are in the range of 50 to 800 microns in diameter; and, (ii) 90% by mass of the recrystallized extra-large columnar crystals are in the range of 20 to 1100 microns in diameter. The process according to claim 1, further satisfying one or more of the following conditions.

4. The aggregate of the particle-size-adjusted crystals has the following target dimensions: (i) 90% by mass of the particle-size-adjusted crystals have a diameter of 190 microns or less; (ii) 50% by mass of the particle-size-adjusted crystals have a diameter of less than 90 ± 20 microns; (iii) 10% by mass or less of the particle-size-adjusted crystals have a diameter of less than 30 microns; (iv) At least 75% of the total volume of the particle-size-adjusted crystals has an aspect ratio of 1 to 3. The process according to claim 1, which satisfies one or more of the following conditions.

5. The aggregate of the particle-size-adjusted crystals has the following target dimensions: (i) 50% by mass of the particle-size-adjusted crystals are in the range of 35 to 130 microns in diameter; (ii) 75% by mass of the particle-size-adjusted crystals are in the range of 30 to 145 microns in diameter; and, (ii) 90% by mass of the particle-size-adjusted crystals are in the range of 25 to 170 microns in diameter. The process according to claim 1, which satisfies one or more of the following conditions.

6. The process according to any one of claims 1 to 5, comprising shortening the longitudinal axis of the recrystallized extra-large columnar crystal in a rotor / stator homogenizer to provide a shortened crystal.

7. The process according to claim 6, wherein the particle size adjustment further comprises sieving off the shortened crystals to provide the sieved crystals.

8. The process according to claim 7, wherein the sieved crystals are rinsed once or more times with a rinsing solution containing a surfactant and one or more solvents selected from the group consisting of water, methanol, ethanol, and isopropanol.

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

10. The process according to any one of claims 1 to 9, wherein the particle-size-adjusted crystals are further individually coated with a polymer film by a fluidized bed coating apparatus.

11. The process according to claim 10, wherein the polymer film is formed from polyvinyl alcohol, polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), poly(trimethylene carbonate) (pTMC), or a combination thereof.

Images