Diroximel fumarate particles having improved flow properties and methods of making same

Abstract

Many active pharmaceutical ingredients (APIs) can be obtained in tablet form. The API particles should possess favorable compaction properties for compression into tablets, especially when the API is present in a large weight percentage of the tablet. This article discloses diroximel fumarate particles with improved tablet-forming characteristics and their production method.

Description

Prior Technology

[0001] Diroximel fumarate, marketed under the brand name Vumerity, is a drug used to treat relapsing-remitting multiple sclerosis. Diroximel fumarate was first disclosed in U.S. Patent No. 8,669,281 and was approved for medical use in the United States in October 2019.

[0002] The delivery of active pharmaceutical ingredients (APIs) in tablet form is highly desirable due to its ease of administration and convenience for patients. Tablets are formed by pressing powder blends containing API particles and additives. For successful tablet formulation preparation, the API particles used to form the tablets and / or the blends containing API particles and additives must possess several specific properties, including good flowability, compaction, and mechanical properties. Tablet preparation can be particularly challenging when high drug loadings are present, for example, in tablets containing more than 60% by weight of API. Summary of the Invention

[0003] It has been found that standard particle milling processes (such as dry milling) produce diroximate fumarate particles with undesirable tablet-forming properties. It has also been found that diroximate fumarate particles prepared by wet milling processes exhibit significantly improved mechanical and flow properties compared to particles prepared by dry milling processes. For example, tablets compacted from wet-milled diroximate fumarate have a more uniform hardness than those compacted from dry-milled diroximate fumarate (see Example 5). This is beneficial for tablet coating processes and dissolution behavior. Furthermore, the flow function coefficient for quantitatively pure wet-milled diroximate fumarate particles is higher than that for pure dry-milled diroximate fumarate particles (see Example 3). This higher flow function coefficient indicates that wet-milled diroximate fumarate has superior flow properties compared to dry-milled diroximate fumarate. The cohesive strength of the particles revealed is lower than that of dry-milled diroximate fumarate particles (see Example 3). When cohesion is low, the particles flow more smoothly and exhibit better storage properties. Diroximate fumarate particles with excellent flow and compaction properties are characterized by less size variability, as measured by particle size span and by a reduction in D10 (i.e., 10% diroximate fumarate particles have a smaller volume diameter). They are also characterized by increased smoothness. The disclosed diroximate fumarate particles have been found to have improved dissolution properties, which is beneficial to the API (see Example 7). Based on these findings, this paper discloses diroximate fumarate particles with excellent flow and compaction properties, a method for preparing diroximate fumarate particles with excellent flow and compaction properties, blends containing diroximate fumarate particles with excellent flow and compaction properties, and tablets containing diroximate fumarate particles with more uniform hardness.

[0004] In one embodiment, the present invention comprises diroximate fumarate particles having a span of 1.1 to 2.5, a D10 of 20-50 μm, a D50 of 70-130 μm, and a D90 of 150-250 μm.

[0005] Another embodiment of the present invention comprises a blend of the disclosed diroximate fumarate particles and one or more additives, fillers and / or excipients. In one sample, the blend comprises 60-92.5 wt.% diroximate fumarate particles based on the total weight of the blend.

[0006] Another embodiment of the present invention is an ingot comprising the disclosed diroximate fumarate particles or the disclosed blend.

[0007] Another embodiment of the present invention is a method for producing the disclosed diroximate fumarate particles. These particles are suitable for high-loading tablets. The method includes subjecting a slurry of pre-ground diroximate fumarate particles in a solvent to a wet milling step to produce ground diroximate fumarate particles; and subjecting the ground diroximate fumarate particles to a curing step to produce diroximate fumarate particles.

[0008] Another embodiment of the present invention is diroximate fumarate particles prepared by the disclosed method. Simple Explanation of the Diagram

[0009] [picture] [1] A scanning electron microscope image of dry-ground diroximate fumarate particles and the revealed diroximate fumarate particles. [picture] [2] is a bar graph of the flow function coefficients of pure dry-ground diroximate fumarate particles compared with pure diroximate fumarate particles as revealed. [picture] [3] is a bar graph showing the cohesive force of pure dry-milled dirosimertin fumarate particles compared with that of pure dirosimertin fumarate particles. [picture] [4] is a bar graph of the flow function coefficients of the blend containing dry-milled diroximate fumarate particles compared to the blend containing the disclosed diroximate fumarate particles. [picture] [5] is a graph showing the hardness of the tablets made from dry-milled diroximate fumarate particles and the diroximate fumarate particles disclosed therein as a function of compaction pressure. [picture] [6] is a graph showing the comparative dissolution curves of tablets made from dry-milled API (blue diamond, square and triangle plot) and wet-milled API (red square plot - leftmost curve). Implementation

[0010] [Related Applications] []

[0011] This application claims the benefits of U.S. Provisional Application Serial No. 63 / 245,476, filed September 17, 2021, and U.S. Provisional Application Serial No. 63 / 357,130, filed June 30, 2022, the entire teachings of which are incorporated herein by reference.

[0012] This article discloses diroximate fumarate particles with good tablet-forming mechanical properties (such as high flowability, consistent compaction, and low cohesion). The disclosed diroximate fumarate particles are characterized by a reduced particle size distribution (e.g., reduced size variation between particles) and / or a reduced number of small particles.

[0013] Particle size is expressed as volume diameter, and it is used to provide a dimensional description of non-spherical particles. "[Volume Diameter]" refers to the diameter of a sphere containing non-spherical particles of equal volume. Particle size can be measured using methods well known in this art, including laser diffraction techniques that correlate light scattering with the particle volume for calculating effective length or effective diameter.

[0014] Particle size distribution [D, 50 , ]、 [D, 10 , ]、 [D, 90 , ] and span representation. "[Span]" is a measure of particle size distribution. It is calculated based on the following equation: [span] [= (D , 90 , -D , 10 , ) / D , 5, ] 0 A lower span value means that the particle size is more consistent and there is a reduction in particle size variation.

[0015] " [D, 50 The value , ] (also known as the median diameter) corresponds to the value of 50% of particles having a lower volume diameter. [D, 90 , ]” corresponds to a value where 90% of the particles have a smaller volume diameter. [D, 10 , ]" corresponds to 10% of the particles having a smaller volume diameter. []

[0016] The revealed characteristic of deroximate fumarate particles lies in their reduced span, indicating a more uniform particle size within the sample. The revealed characteristic of deroximate fumarate particles also lies in the reduction of small particles (referred to as "fine particles") as measured by D10. Samples with larger D10 values ​​will have fewer fine particles than samples with smaller D10 values.

[0017] In the first embodiment, the disclosed diroximate fumarate particles have a particle size span of 1.1 to 2.5, a D10 of 20-50 μm, a D50 of 70-130 μm, and a D90 of 150-250 μm. In the second embodiment, the diroximate fumarate particles have a particle size span of 1.2 to 2.0, a D10 of 20-50 μm, a D50 of 70-130 μm, and a D90 of 150-250 μm. In the third embodiment, the diroximate fumarate particles have a particle size span of 1.3 to 1.8, a D10 of 20-50 μm, a D50 of 70-130 μm, and a D90 of 150-250 μm.

[0018] In the fourth embodiment, the disclosed deroximate fumarate particles have a D10 of 30-45 μm, a D50 of 80-120 μm, a D90 of 155-230 μm, and the span as described in the first, second, or third embodiments. In the fifth embodiment, the disclosed deroximate fumarate particles have a D10 of 36-42 μm, a D50 of 88-113 μm, and a D90 of 160-225 μm, and the span as described in the first, second, or third embodiments.

[0019] The disclosed deroximate fumarate particles and the disclosed powder blends containing deroximate particles are characterized by excellent flow properties, as measured by the flow function coefficient and cohesive force. Both the flow function coefficient and cohesive force are measured by shear testing. For the purposes of this application, "blend" and "powder blend" are synonymous.

[0020] " [Stream Function] [stream function coefficients] or [FFc] is a parameter commonly used to classify the flowability of particulate samples, which can be pure API particles or samples containing API particles and additives. The powder flowability is classified as follows: FFc < 1 means no flow 1 < FFc < 2 indicates very high cohesion. 2 < FFc < 4 cohesion 4 < FFc < 10 Easy to flow; FFc > 10 Free to flow

[0021] The measurements of FFc and cohesion outlined below follow the procedures described in ASTM D6773-16. Free-flowing powders have an FFc of 4 or greater, and free-flowing powders have an FFc of 10 or greater.

[0022] To test FFc and cohesion, particulate samples are added to a commercially available ring shear test apparatus (such as the Jenike-Johanson RST-XS ring shear tester). This test is familiar to those skilled in the art. Generally, powder is loaded into an annular groove to form a consolidated powder bed. A normal stress (σp) is applied to the consolidated powder bed, and the pre-shear stress (↊p) is measured. The normal stress is applied as a vertical load passing through the annular cap. The shear unit rotates relative to the cap, and the torque required for shearing is measured. Repeated measurements with a series of normal stress values ​​are applied. When the measured shear stress values ​​(Y-axis) are plotted as a function of the applied normal stress values ​​(X-axis), the linear relationship between them is called the yield trajectory. The yield trajectory line can be used to determine the unique relationship between normal stress and shear stress; this is called the Mohr circle. The yield trajectory line represents the tangent of all Mohr circles. The outer circle with the larger radius corresponds to the pre-shear condition (σp, ↊p) and defines the maximum principal stress MPS (σ1). The circle with the smaller radius defines the unconfined yield stress UYS (σc).

[0023] The ratio of the stream function coefficient or the maximum principal stress (MPS) to the unconfined yield strength (UYS) in the FFc system: FFc = MPS / UYS.

[0024] In the sixth embodiment, the disclosed deroximate fumarate particles (e.g., in Examples 1, 2, 3, 4, and 5) have a stream function coefficient between 3.5 and 20. In the seventh embodiment, the disclosed deroximate fumarate particles (e.g., in Examples 1, 2, 3, 4, and 5) have a stream function coefficient between 4.0 and 20, between 4.0 and 10, between 4.0 and 4.5, or between 4 and 5.

[0025] [Cohesion] refers to the tendency of particles within a sample to self-associate or "stick together." The ring shear tester measures cohesion simultaneously with the FFc (fine particulate matter). The intercept of the yield trajectory at zero normal stress (i.e., where the yield trajectory is extrapolated to the Y-axis) is called powder cohesion and is expressed in Pascals (Pa). Lower cohesion is associated with better powder flowability. Furthermore, cohesion predicts how a particulate sample will behave during storage (e.g., in a silo). Samples with cohesion greater than 250 Pa are at risk of forming clumps and voids due to excessive particle cohesion, while samples with cohesion of 250 Pa or less typically remain flowable or free-flowing powders even after extended storage (e.g., one month to one year). []

[0026] In the eighth embodiment, the disclosed derosime fumarate particles (e.g., in Examples 1, 2, 3, 4, 5, 6 and 7) have a cohesive force of 150 to 250 Pa, or 175 to 250 Pa, or 200 to 250 Pa, or 225 to 250 Pa, or 175 to 230 Pa, or 180 to 230 Pa, or 200 to 225 Pa, or 215 to 225 Pa. []

[0027] In the ninth embodiment, the disclosed deroximate fumarate particles can be combined to form a powder blend comprising one or more excipients, fillers, and / or additives. "Blend" or "powder blend" refers to a powder containing API particles and additives, fillers, and / or excipients, formulated for compression into tablets. The powder blend of the present invention comprises the deroximate fumarate particles disclosed in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiments. Additives present in the disclosed powder blend include (but are not limited to) conditioning agents and anti-caking agents (e.g., microcrystalline cellulose), disintegrants (e.g., cropovidone), flow aids (e.g., colloidal silica), and release and lubricants (e.g., magnesium stearate). In the tenth embodiment, the powder blend comprises the deroximate fumarate particles of the first, second, third, fourth, or fifth embodiments and has a flow function coefficient between 15 and 40. In the eleventh embodiment, the disclosed powder blend comprises deroximate fumarate particles of the first, second, third, fourth, or fifth embodiments and has a stream function coefficient between 17 and 37, 17 and 25, 18 and 22, or 19 and 21. In the twelfth embodiment, the disclosed powder blend comprises deroximate fumarate particles of the first, second, third, fourth, or fifth embodiments and has a stream function coefficient between 20 and 35, or 18 and 25.

[0028] In the thirteenth embodiment, the weight percentage of deroximate fumarate particles disclosed in the powder blends described in the ninth, tenth, eleventh, and twelfth embodiments is 87.5 wt.% based on the total weight of the powder blends. In the fourteenth embodiment, the weight percentage of deroximate fumarate particles disclosed in the powder blends described in the ninth, tenth, eleventh, and twelfth embodiments is 87-88 wt.% based on the total weight of the powder blends. In the twelfth embodiment, the weight percentage of the disclosed deroximate fumarate particles is 85-89 wt.% based on the total weight of the powder blends. In the fifteenth embodiment, the weight percentage of deroximate fumarate particles disclosed in the powder blends described in the ninth, tenth, eleventh, and twelfth embodiments is 84-90 wt.% based on the total weight of the powder blends. In the sixteenth embodiment, the weight percentage of deroximate fumarate particles disclosed in the powder blends described in the ninth, tenth, eleventh, and twelfth embodiments is 82-90 wt.% based on the total weight of the powder blends. In the seventeenth embodiment, the weight percentage of derosime fumarate particles disclosed in the powder blends described in the ninth, tenth, eleventh, and twelfth embodiments is 60-92.5% wt.% based on the total weight of the powder blend (e.g., 70-92.5% wt.%, 75-92.5% wt.%, 80-92.5% wt.%, 85-92.5% wt.%, or 87.5 wt.%).

[0029] In the eighteenth embodiment, the present invention is a tablet comprising diroximate fumarate particles disclosed in any one of Examples 1 to 8; or diroximate fumarate blends disclosed in any one of Examples 9 to 17. The disclosed tablet is a "high loading," that is, it comprises 60% by weight, 60-65% by weight, 65%-70% by weight, 70-75% by weight, 75-85% by weight, 85-87.5% by weight, 87.5% by weight, 87-88% by weight, 85-89% by weight, 84-90% by weight, 82-90% by weight, 70-92.5% by weight, 80-90% by weight, 60-92.5% by weight, or 70-92.5% by weight of the disclosed diroximate fumarate particles. method

[0030] This invention includes a method for producing the disclosed diroximate fumarate particles. These methods produce diroximate fumarate particles suitable for preparing high-loading tablets. The method includes subjecting a pre-ground diroximate fumarate particles to a slurry in a slurry solvent through a wet milling step to produce wet-milled diroximate fumarate particles; and subjecting the wet-milled diroximate fumarate particles to a curing step in a curing solvent to produce the disclosed diroximate fumarate particles. The milling and curing steps are performed under conditions suitable for obtaining particles suitable for high-loading tablets (e.g., obtaining the disclosed diroximate fumarate particles). Suitable conditions include suitable shearing and mixing for the milling step, as well as suitable solvents, temperatures, and milling and curing time periods. These conditions are described in more detail below.

[0031] " "[Pre-ground diroximate fumarate granules]" refers to diroximate fumarate granules prior to wet milling and aging. Depending on the circumstances, the pre-ground diroximate fumarate granules may be recrystallized prior to the wet milling step. For example, the pre-ground diroximate fumarate may be dissolved in a sufficient amount of isopropyl acetate (e.g., 1:3 to 1:4 by weight) at a temperature at which the granules dissolve in a solvent (e.g., 70-80°C). The solution may be filtered, depending on the circumstances. The solution is then cooled to a suitable temperature to precipitate the pre-ground diroximate fumarate.

[0032] " "[Pure diroximate fumarate granules]" refers to diroximate fumarate granules without any intentional addition of additives. Therefore, "pure diroximate fumarate granules" can be produced by dry or wet grinding and aging methods, and can be tested as pure granules before being incorporated into blends.

[0033] " "Wet milling" refers to the process of mixing diroximate fumarate particles in a slurry solvent under suitable shear, mixing speed, and temperature until a desired particle size reduction is achieved, such as a D50 of 35-70 μm. Alternatively, the desired particle size is 35-66 µm, 35-55 µm, 35-60 µm, or 55-66 µm with a D50. The slurry solvent and wet milling temperature are selected such that diroximate fumarate is substantially insoluble in the slurry solvent.

[0034] " "[Substantially insoluble]" means that diroximate fumarate is substantially insoluble in the slurry solvent at the grinding temperature. Substantially insoluble includes a solubility of less than 44 mg / mL, preferably less than 28 mg / mL, and even more preferably less than 22 mg / mL, in the slurry solvent at the temperature of the grinding particles. Isopropyl acetate is a suitable slurry solvent for pre-ground diroximate fumarate particles at wet grinding temperatures between -5°C and 30°C. Other solvents that may be used include, but are not limited to, ethyl acetate, methyl ethyl ketone, isobutyl acetate, toluene, and acetone; and combinations of one or more solvents with antisolvents such as: water, 1-butanol, 3-methyl-1-butanol, 2-butanol, 1-pentanol, 1-propanol, 2-propanol, ethanol, heptane, tributanol, acetonitrile, and methyl tributyl ether. []

[0035] The wet milling step comprises mixing the diroximate fumarate particles in a slurry solvent at a mixing speed of 600 to 1500 rpm under a shear rate of 11,500 s⁻¹ to 160,000 s⁻¹. Alternatively, the wet milling step comprises mixing the diroximate fumarate particles in a slurry solvent at a temperature of 0°C to 20°C at a mixing speed of 1000 to 1300 rpm under a shear rate of 11,500 s⁻¹ to 100,000 s⁻¹. Alternatively, the wet milling step comprises mixing the diroximate fumarate particles in a slurry solvent at a mixing speed of 1000 to 1300 rpm under a shear rate of 11,500 s⁻¹ to 25,000 s⁻¹. Wet milling can be performed using commercially available high-shear mixers (e.g., inline high-shear mixers (e.g., Silverson Verso inline mixers or IKA MagicLab inline mixers)).

[0036] The wet grinding step can be performed at temperatures ranging from -5°C to 30°C. In another sample, the wet grinding step is performed at temperatures ranging from -5°C to 15°C, 15°C to 25°C, or 25°C to 30°C. []

[0037] " "[Curing]" refers to heating the ground diroximate fumarate particles in a partially soluble curing solvent at the temperature required for curing. "[Partially soluble]" means that deroximate fumarate particles partially dissolve and subsequently reprecipitate in a solvent at the aging temperature. Partial solubility includes solubility in the aging solvent between 55 mg / mL and 107 mg / mL at the aging temperature of the particles. Isopropyl acetate is a suitable solvent for the aging process at temperatures between 35°C and 50°C, or 38°C and 49°C, and in another alternative, between 40°C and 48°C. Other solvents that may be used include, but are not limited to, ethyl acetate, methyl ethyl ketone, isobutyl acetate, toluene, and acetone; and combinations of one or more solvents with antisolvents such as water, 1-butanol, 3-methyl-1-butanol, 2-butanol, 1-pentanol, 1-propanol, 2-propanol, ethanol, heptane, tributanol, acetonitrile, and methyl tributyl ether. Aging results in an increase in particle size and a decrease in particle size distribution (e.g., span). Continue the ripening process until the desired particle size is achieved, for example, a D50 of 70-130 μm. Alternatively, the desired particle size is a D50 of 70-130 µm. In another alternative, the desired particle size is a D50 of 88-113 μm. Suitable ripening times include two to ten hours, two to eight hours, or two to four hours.

[0038] The method may include a cooling step following the curing step, depending on the circumstances. After the curing step, the mixture may be cooled to between -10°C and 20°C, or to between -5°C and 10°C. The diroximate fumarate particles are then separated.

[0039] This method is illustrated by the following example, which is not intended to be limited. [illustration] [] [Example] [1] [Comparison of dry grinding particles] []

[0040] Derosime fumarate particles were processed using a conventional Hammermill dry mill with hammer tip velocities ranging from 47 to 62 m / s (3500 - 6000 RPM) and feed rates ranging from 1.4 to 7.2 kg / min. The relatively large range of 2.9–3.4 indicates a lack of particle size uniformity within each sample. Particle size distribution data from four commercial batches of dry-milled particles show… [surface] [1] in. [surface] [1] [:] Particle size distribution (in micrometers) of dry-milled diroximate (API) fumarate. Item Number (Representative Commercial Batch) D 10(µm) D 50(µm) D 90(µm) span 1 17 96 347 3.4 2 17 106 347 3.1 3 18 101 307 2.9 4 16 95 302 3.0 Note: The span is calculated as (D 90 - D 10) / D 50, which is a measure of the particle size distribution around the average D 50. [Example] [2] [Particles that have undergone wet milling and aging] []

[0041] 507 kg of diroximate fumarate (API) was dissolved in 2771 kg of isopropyl acetate at 80 °C and then purified by filtration. The solution was then cooled to 40 °C over approximately 3 hours to allow partial crystallization of diroximate fumarate, followed by heating to 55 °C and holding at that temperature for 30 minutes, and then cooling to 0 °C.

[0042] After a period of stirring, the slurry is recirculated from the bottom of the reactor through a high-shear mixer (IKA DR2000-30 model, available from IKA, Staufen, Germany) and returned to the reactor. The mixer is operated at 1000-1300 RPM, with a shear value between 11,500 s⁻¹ and 25,000 s⁻¹, while maintaining a slurry temperature not exceeding 20°C. The total mass or volume of the slurry passing through the mixer is monitored using a mass flow meter, and the mill is stopped after at least 20 volumetric cycles. Grinding is considered complete when the median particle size is within 35-60 micrometers. PSD data is below. [surface] [2] is displayed as "PSD after wet refining".

[0043] After the grinding step, 500 kg of isopropyl acetate is added to flush the recirculation line and combine it with the grinding slurry in the reactor. The resulting slurry is matured at a selected temperature of 38-50°C for at least 2 h, held for 10-30 min, and cooled back to 0°C over 2-8 h. The product is filtered, washed with 439 kg of isopropyl acetate, and dried under vacuum at 40-50°C. PSD data is below. [surface] [2] is displayed as "Final PSD". [surface] [2] [:] Particle size distribution (in micrometers) of wet-milled and aged diroximate fumarate (API). Entry number Batch size (kg) PSD after wet polishing Aging temperature (°C) Final PSD after maturation D 10(µm) D 50(µm) D 90(µm) D 10(µm) D 50(µm) D 90(µm) span 1 507 11.6 53.0 155 40 37.2 89.3 162.5 1.4 2 507 12.4 66.3 179 43 40.7 96.1 204.5 1.7 3 507 9.15 35.2 116 48 41.0 111.9 222.9 1.6 Note: The span is calculated as (D90-D10) / D50, which is a measure of the density of the distribution around the average d50.

[0044] By comparing the particle size and particle size distribution (PSD) of dry-milled diroximate fumarate in Comparative Example 1, it is evident that the D10 (value: 16-18 µm) of the comparative particles in Example 1 is lower than that of the wet-milled and cured particles (value: 37.2-41.0 µm). Furthermore, the span of the comparative particles in Example 1 is higher (value: 2.9-3.4) compared to the lower span (value: 1.4-1.7) of the wet-milled and cured particles. Therefore, wet-milled and cured particles are expected to have better tablet-forming properties than dry-milled particles.

[0045] exist [picture] [1] Scanning electron microscopy was used to visualize particles from dry-milled versus wet-milled samples. Images were acquired using a scanning electron microscope (SEM) (JEOL USA Inc., Peabody, MA JSM-6510LV) at magnifications of 350X to 500X. Note the presence of fine particles in the two dry-milled batches of diroximate fumarate (left and middle images); these batches also contained highly irregularly shaped particles. In contrast, the wet-milled batch of diroximate fumarate (right image) contained almost no fine particles, and the particles were regular, flat, rectangular parallelepiped shapes. [Example] [3] [Comparison of Stream Function Coefficient and Cohesion of Pure Deroximate Fumarate Particles] []

[0046] As described above, the flow function coefficient (FFc) was measured to quantify the flow properties of pure diroximate fumarate particles from Examples 1 (dry milling) and 2 (wet milling and aging). The particles were tested in a Jenike-Johanson RST-XS ring shear tester according to the manufacturer's procedures and using the software provided with the tester. Each particle or powder sample (one at a time) was loaded into the annular groove of the tester. A preload of 3 kPa was first applied to the powder blend. Subsequent loads ranging from 0.5 kPa to 3 kPa were then applied to determine the flow properties of each sample. The ring shear tester calculated the yield trajectory, FFc (i.e., the slope of the yield trajectory), and cohesion (i.e., the Y-intercept of the extrapolated yield trajectory).

[0047] Those familiar with this technique will understand that FFc and cohesion will vary from batch to batch; therefore, it is important to consider both the individual batch values ​​and the uniformity or tightness of the measurements obtained from different batches of material processed by any given method.

[0048] [picture] [2] This is a bar graph comparing the FFc of four batches of pure diroximate fumarate particles (gray bars) prepared by comparative dry milling of diroximate fumarate (Example 1) with that of four batches of pure wet milled and cured diroximate fumarate particles (black bars) from Example 2. The four wet-milled batches have an average FFc of approximately 4, compared to an average FFc of less than 4 for the four dry-milled batches. An FFc of 4 is extremely important because 4 is the threshold value for the range of free-flowing powders, as described in the detailed explanation above. Therefore, the wet-milled pure diroximate fumarate particles have improved flowability compared to the comparative dry-milled pure diroximate fumarate particles. More importantly, the particles shown are classified as free-flowing powders with an FFc of 4 or greater.

[0049] [picture] [3] illustrates a comparison of the cohesive strength of four batches of pure diroximate fumarate particles obtained by dry milling in a hammer mill versus four batches of pure wet-milled and aged diroximate fumarate particles. Lower cohesive strength indicates better flowability of the sample relative to samples with higher cohesive strength. The wet-milled particles (black strips) have an average cohesive strength of 219 Pa, and therefore have lower cohesive strength than the dry-milled particles (gray strips) which have an average cohesive strength of 270 Pa. The lower cohesive strength of the diroximate fumarate particles results in better compaction and storage properties of the particle-containing blends. Furthermore, there is less variation between the invention batches compared to the comparative batches. [, , ] [Example] [4] [Comparison of flow function coefficients of powder admixtures with high particle loading] []

[0050] Four batches were prepared using the wet-milled and aged diroximate fumarate granules produced in Example 2. [surface] [3] Powder blends. Four batches containing comparative dry-milled particles from Example 1 were also prepared. [surface] [3] [:] Powder admixture composition source quantity diroximate fumarate Example 2 81-92.5% w / w Microcrystalline cellulose Avicel 102 DuPont Nutrition, Ireland 3-6% w / w Kollidone C BASF, Germany 3-6% w / w Colloidal silicon dioxide 200 Evonik, NJ, USA 1-3% w / w magnesium stearate Spectrum Chemical MFG. Corp. NJ, USA 0.5-2% w / w

[0051] The flow function coefficient was also used to quantify the flow properties of the powder blends prepared according to Table 3. [picture] [4] is a bar graph comparing the FFc of four batches of the blend (gray bars) prepared by dry-milled diroximate fumarate of Example 1 with the FFc of four batches of the blend (black bars) containing wet-milled and cured diroximate fumarate particles of Example 2. As mentioned above, an FFc value greater than 10 indicates free-flowing powder. The wet-milled and cured diroximate fumarate consistently exhibited a higher FFc (average FFc value of about 20) than the dry-milled diroximate fumarate blend (average FFc value of about 15), which means that the blend containing wet-milled particles has better flow properties than the blend containing dry-milled diroximate fumarate of the same properties, as demonstrated by the improvement in FFc from about 15 to about 20. [Example] [5] [Compaction characteristics of tablets] []

[0052] The formulated powder blends were compacted at varying pressures (4-20 kN) on a compaction simulator (Romaco Kilian STYL'ONE, Cologne, Germany); the simulated ingot compactor was a GEA-Courtoy Modul P. A 16-point tool with a 2 mm concave punch (Natoli Engineering Company, USA) was used. The compaction speed was set to 20 rpm, and the target ingot weight was 8.5 (±0.5) mg. All prepared micro-ingots were stored in sealed plastic bags for further characterization.

[0053] The hardness of the tablets was measured under radial compression testing in a texture analyzer (Texture Technologies Corp., USA). The average tablet hardness (n=10) was recorded. [picture] [5] illustrates a comparison of compaction characteristics (hardness versus compaction pressure) of tablets made from diroximate fumarate granules obtained using dry-process batches and wet-milled and cured batches obtained by hammer milling. The dry-milled batches (square) and wet-milled batches (star-shaped) show comparable compaction characteristics at lower compaction pressures (below 10 kN), which means they have similar tablet hardness at the same compaction pressure. However, the error bars of the wet-milled batches are much smaller than those of the two hammer-milled batches. This indicates that the tablet hardness is more uniform than that of tablets made by dry milling; more uniform hardness is beneficial for tablet coating processes and dissolution behavior of pressed tablets. [Example] [6] [Isopropyl acetate] [(IPAC)] [and isopropanol] [(IPA)] [Particles that have undergone wet milling and aging in a solvent mixture] []

[0054] At 75–85 °C, 55.2 kg of deroximate fumarate was dissolved in a solvent mixture consisting of 137.4 kg of IPAC and 183.3 kg of IPA. After complete dissolution of the deroximate fumarate, the mixture was cooled to 0–5 °C over 8 hours. The resulting slurry of deroximate fumarate was then subjected to wet milling by recirculating it through a DR-2000-10 type IKA high-shear mixer operating at 2600–4200 rpm (shear value within 30,000–50,000 sec⁻¹). Recirculation was stopped after 23 volumetric cycles, after which in-process measurements showed a median particle size reduction to D₅₀ = 43 μm. 45.8 kg of IPA / IPac (6:4 v / v) mixture was added as a pipeline flushing agent. The combined pipeline flushing material and reactor contents were stirred at 0–5 °C for 1 hour, and then matured under the following conditions: heated to 43 °C over 2 hours, held at 43 °C for 2 hours, cooled to 2 °C over 3–5 hours, and stirred again at 0–5 °C for 2 hours. The product was filtered, washed with a 45.8 kg IPA / IPAc (6:4 v / v) mixture, and dried under vacuum at 35–45 °C for 20–28 hours to obtain 50.2 kg of wet-milled diroximate fumarate product with the following particle size distribution: D10 = 40 µm, D50 = 92 µm, and D90 = 173 µm.

[0055] By comparing the particle size and particle size distribution (PSD) of dry-milled diroximate fumarate in Comparative Example 1, it is evident that the D10 (value: 16-18 µm) of the comparative particles in Example 1 is lower than that of the wet-milled and cured particles in this example, which have a higher D10 (value: 40 µm). Furthermore, the span of the comparative particles in Example 1 is higher (value: 2.9-3.4) compared to the lower span (value: 1.4) of the wet-milled and cured particles in this example. Therefore, wet-milled and cured particles are expected to have better tablet-forming properties than dry-milled particles. [Example] [7] [Compare dissolution properties] []

[0056] The formulated powder blend is pressed into micro-ingots using a double-sided pressing machine (Fette Compacting GmbH, Germany) equipped with multi-precision tools (Natoli Engineering Company, USA). The micro-ingots are dusted and passed through a metal detector. The intact micro-ingots are stored in a bin, and the sealed bin is prepared for ingot coating. For enteric coating, a coating solution is prepared in two separate components: a solution of the coating polymer Eudragit and the plasticizer triethyl citrate (TEC) is prepared in approximately half of a 60:40 isopropanol (IPA) / water mixture. Talc and colloidal silica are suspended in the remaining half of the 60:40 isopropanol (IPA) / water mixture. The two solution components are mixed together to form an enteric coating suspension. At the end of the preheating stage, the solvent-based enteric coating is applied to the ingot core to achieve a theoretical weight gain of 15% relative to the core's mass. IPA and water are removed during the film coating process. The application of this enteric coating is used to control the release of the API in the gastrointestinal tract.

[0057] The coated microtablets (33 tablets) were encapsulated into size 0 capsules. The capsules were inserted into a probe sinker, and 750 mL of degassed 0.1 M HCl medium was added to each vessel. The vessel was then heated to 37 °C ± 0.5 °C for an acid phase dissolution test. Two hours later, an additional 200 mL of preheated 0.2 M trisodium phosphate dissolution medium was added to each dissolution vessel for a buffer phase dissolution test. HPLC (Waters Corp, USA) was used for dissolution analysis.

[0058] [picture] [6] illustrates a comparison of dissolution curves for tablets made from diroximate fumarate granules obtained using a dry milling batch versus wet milling and curing batches. The leftmost red diamond-shaped curve (wet milling) and the blue diamond, square, and triangle-shaped curves (dry milling) show comparable dissolution behavior during the acid phase (0–120 min). However, the tablets made from wet-milled API batches dissolve much faster (120–200 min) compared to all dry-milled batches. This indicates that wet-milled API granules have better dissolution performance when used in pharmaceutical products. This faster dissolution behavior can be attributed to the uniform particle size distribution, smooth surface, and uniform coating. [surface] [4] [:] Particle properties of the batch of diroximate fumarate granules tested in Example 7. DP batch 1310000447 1310000448 1310000449 1310000463 API grinding process dry grinding mill dry grinding mill dry grinding mill wet grinding mill API batch 8005663000 8005685000 8005684000 21600T0003 PSD D10 (µm) 17 17 18 40.7 PSD D50 (µm) 91 91 98 96.1 PSD D90 (µm) 255 270 279 205 PSD span 2.62 2.78 2.66 1.71

[0059] As shown by the leftmost curve in Figure 6, wet-milled diroximate fumarate particles showed a dissolution rate of over 50% at 130 minutes, over 70% at 140 minutes, over 90% at 150 minutes, and nearly 100% at 160 minutes.

Claims

1. A diroximel fumarate particle having a size range of 1.1 to 2.5, a D10 of 20-50 μm, a D50 of 70-130 μm, and a D90 of 150-250 μm.

2. Derosime fumarate granules as requested in item 1, wherein the span is 1.2 to 2.

0.

3. Derosime fumarate granules as requested in item 1, wherein the span is 1.3 to 1.

8.

4. The diroximate fumarate particles, as described in any of the claims 1 to 3, have a D10 of 30-45 μm, a D50 of 80-120 μm, and a D90 of 155-230 μm.

5. The diroximate fumarate particles as described in any of the claims 1 to 3 have a D10 of 36-42 μm, a D50 of 88-113 μm, and a D90 of 160-225 μm.

6. The diroximate fumarate particles, as described in any of requests 1 to 3, have a stream function coefficient between 4 and 20.

7. The dirosime fumarate particles of any one of claims 1 to 3 have a cohesive strength between 150 and 250 Pa.

8. A blend comprising dirosime fumarate particles as claimed in any one of claims 1 to 5 and one or more additives, fillers and / or excipients, wherein the blend has a flow function coefficient between 15 and 40.

9. A blend comprising dirosime fumarate particles as claimed in any one of claims 1 to 5 and one or more additives, fillers and / or excipients, wherein the blend has a flow function coefficient between 17 and 37.

10. The blend as claimed in claim 8 or 9, wherein the blend comprises 60-92.5 wt.% of dirosime fumarate particles based on the total weight of the powder blend.

11. The blends of claim 8 or 9, wherein the additives, fillers or excipients are microcrystalline cellulose, crosspovidone, colloidal silica, or magnesium stearate.

12. An tablet comprising dirosime fumarate granules as claimed in any one of claims 1 to 7 or an admixture as claimed in any one of claims 8 to 11.

13. A method for producing derosimere fumarate granules suitable for high-loading tablets as claimed in any one of claims 1 to 7, comprising: Pre-ground diroximate fumarate particles are subjected to a wet milling step in a slurry solvent to produce ground diroximate fumarate particles; and the ground diroximate fumarate particles are subjected to a curing step in a curing solvent to produce the diroximate fumarate particles.

14. The method of claim 13, wherein the pre-ground diroximate fumarate particles are substantially insoluble in the slurry solvent at the temperature at which the pre-ground diroximate fumarate particles are ground.

15. The method of claim 13 or 14, wherein the wet milling comprises subjecting the pre-milled dirosime fumarate particles in the slurry solvent to mixing at a mixing speed of 600 to 1500 rpm under shear of 11,500 s⁻¹ to 160,000 s⁻¹.

16. The method of claim 15, wherein the wet milling step comprises subjecting the pre-milled diroximate fumarate particles to a slurry solvent in which the slurry is mixed at a mixing speed of 1,000 to 1,300 revolutions per minute (RPM) under shear of 11,500 to 25,000 s⁻¹.

17. The method of claim 13 or 14, wherein the slurry solvent is isopropyl acetate.

18. The method of claim 13 or 14, wherein the wet milling step is performed at a temperature of 0°C to 20°C.

19. The method of claim 13 or 14, wherein the wet milling step is continued until the wet-milled diroximate fumarate particles achieve a D50 of 35-70 μm.

20. The method of claim 13 or 14, wherein the wet milling step is continued until the wet-milled dirosimermet fumarate particles achieve a D50 of 35-60 μm.

21. The method of claim 13 or 14, wherein the curing step comprises heating the wet-milled diroximate fumarate particles in a curing solvent in which the wet-milled diroximate fumarate particles are partially soluble at a curing temperature for curing the wet-milled diroximate fumarate particles.

22. The method of claim 21, wherein the aging solvent is isopropyl acetate.

23. The method of claim 13 or 14, wherein the temperature for aging the wet-milled diroximate fumarate particles is 38°C to 50°C.

24. The method of claim 13 or 14, wherein the temperature for aging the wet-milled diroximate fumarate particles is 40°C to 48°C.

25. The method of claim 13 or 14, wherein the ripening step is continued until the ripened diroximate fumarate particles achieve a D50 of 70-130 μm.

26. The method of request item 13 or 14, wherein the ripening step is performed for 2 to 10 hours.

27. The method of claim 13 or 14, wherein the pre-ground diroximate fumarate is recrystallized prior to the wet milling step.

28. The method of claim 13 or 14, further comprising a cooling step following the curing step.

29. The method of claim 28, wherein the temperature of the cooling step is -10°C to 10°C.

30. A derosime fumarate granule produced by any one of claims 13 to 29.

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