CN116640129A - Refining method - Google Patents

Abstract

The invention relates to a refining method, and belongs to the field of pharmaceutical chemistry. The method of the invention is simple and easy to operate, has low cost, can obtain high-quality products, and is suitable for industrial production.

Description

Refining method

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a refining method of crystals.

Background

Eppiprazole (english name Brexpiprazole) chemical name 7- [4- (4-benzo [ b ] thiophen-4-yl-piperazin-1-yl) butoxy ] -1H-quinolin-2-one having the formula:

eperizole is a 5-HT1A and D2 receptor partial agonist, a 5-HT2A receptor antagonist, and is clinically useful in the treatment of schizophrenia and in the adjuvant treatment of major depression.

Numerous documents currently report processes for the preparation of epipiprazole and crystallization of various crystalline forms. The polymorphic forms of epipiprazole exist, including anhydrate, hydrate and other solvates. According to the common organic solvent classification and residual limit standard of ICH (International pharmaceutical registration Consortium) or the standard stipulated in Chinese pharmacopoeia, the residual amount of the solvent used in the process of preparing the medicine needs to be controlled within the limit standard, and the lower the residual amount is, the more beneficial; wherein, N-hexane (290 ppm), methylene dichloride (600 ppm), tetrahydrofuran (720 ppm), N-dimethylformamide (880 ppm), toluene (890 ppm), methanol (3000 ppm) and the like belong to two solvents, the use needs to be limited, the allowable daily contact amount needs to be strictly controlled, and the residual amount in the product needs to be respectively controlled within limit standards; ethanol, acetone, ethyl acetate, dimethyl sulfoxide and the like belong to three solvents, the use is limited according to the requirement, and the residual amount of the solvents in the product is controlled within 5000 ppm. These commonly used solvents of the second or third class are also often used in the preparation of the epipiprazole in different steps or steps, where each solvent may be transitive (i.e. the solvent remaining in the previous step may remain after the next reaction and be transitive to the next step, especially some solvents that are difficult to remove).

In the prior art, DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), dichloromethane, tetrahydrofuran or acetonitrile and the like are mostly used as reaction solvents in the process of synthesizing the epipiprazole, and the impurity and/or solvent residues in the obtained product often exceed pharmacopoeia limiting standards and are difficult to meet the pharmacopoeia quality standards. In order to obtain high-purity and high-quality epipiprazole, the prior art generally adopts a method of forming hydrochloride and then dissociating to obtain the epipiprazole, the method has complicated steps and long process period, and the residual solvent is still difficult to ensure not to exceed the specified limit range. For the final product or the product before the salt for the patent medicine, the control of the purity of the product and the reduction of the solvent residue in the crystallization process are very important, and if the purity is ensured and the residual solvent is removed without an effective and stable refining method, the product purity, the solvent residue and the like can not meet the quality requirements, and the product is difficult to be applied to the production of the pharmaceutical preparation.

Crystals and dihydrate crystals of an anhydrous substance of epipiprazole, XRD information thereof, crystallization methods thereof, and the like are disclosed in patent applications WO2006112464, WO2013162046, WO2017134038, and the like, wherein the XRD of the anhydrous substance crystals has diffraction peaks at 2Theta of 6.8,10.0,10.8,14.5,14.9,17.4,19.2,20.3,21.3 and 23.2 (unit degrees/°, error ± 0.2 degrees) and the like. The anhydrous substance of the epipiprazole is a common form in the production and preparation of the crude drug of the epipiprazole, and the obtained anhydrous substance of the epipiprazole has high quality, particularly the anhydrous substance with solvent residue meeting limit requirements, and has important significance for the production of the crude drug and the subsequent production and preparation of pharmaceutical preparations.

However, the solubility of the epipiprazole in most solvents is very poor (see table 1 in patent application CN201611236458.2, the methanol and anhydrate of the epipiprazole are almost insoluble in various solvents), and it is difficult to obtain a product meeting the quality standards of pharmacopoeia using conventional solution crystallization methods and/or the process is difficult to implement for industrial production. Therefore, it is necessary and difficult to find an effective, stable, economical purification process of epipiprazole.

Disclosure of Invention

The invention provides a refining method of epipiprazole, which is simple and convenient, is easy to operate, control and implement, and can obtain a product with solvent residue meeting the common organic solvent residue limit standard of ICH.

A method for refining epinastine, comprising: mixing the raw material of the epipiprazole, water and ethanol, stirring, and heating to obtain a solution; cooling the obtained solution to-5-10 ℃ within 2.5-13.5 hours, preserving heat and stirring for 0.5-5 hours, filtering, and drying the obtained solid at 45-85 ℃ for 12-48 hours to obtain the epipiprazole product.

The epipiprazole starting material can be any form of starting material such as anhydrous crystals, amorphous solids, hydrate crystals, solvates or other forms of starting material. The epipiprazole starting material may contain residual solvents including but not limited to ethanol, water, methylene chloride, DMF, DMSO, toluene, tetrahydrofuran, n-hexane, cyclohexane, methanol, isopropanol, t-butanol, etc. The residual solvent content of the feed may exceed the residual limit criteria for the corresponding solvent in the ICH, such as a methylene chloride content of the feed of greater than 600ppm (i.e., a residual methylene chloride content of greater than 600 ppm). In some embodiments, the epipiprazole starting material contains residual solvent dichloromethane. In some embodiments, the epipiprazole starting material contains residual solvent dichloromethane, and the dichloromethane soluble residue is greater than 600ppm.

The inventors found that in the refining method, the proper water amount and the proper ethanol amount have important influence on the process operation control and the quality of the final product.

According to embodiments of the present invention, the amount of water used may be 4ml to 6ml, preferably 4.5ml to 5.5ml, per gram of the raw material of epipiprazole. In some embodiments, the amount of water used is 5ml per gram of epinastine material. Too much or too little water will affect the yield of the product or be difficult to dissolve during operation.

According to embodiments of the present invention, the amount of ethanol used per gram of the raw material of epipiprazole may be 40ml to 60ml, preferably 45ml to 55ml. In some embodiments, the amount of ethanol used is 50ml per gram of the raw material of epezil. Too much or too little ethanol will affect the yield of the product or be difficult to dissolve during operation.

According to embodiments of the present invention, the volume ratio of water to ethanol may be controlled to be 1:6 to 1:15, preferably to be 1:9 to 1:15, which is advantageous for operation and high yield of the product.

In some embodiments, water is used in an amount of 5ml and ethanol is used in an amount of 50ml per gram of the epipiprazole starting material, facilitating handling and high yield of the product.

In the method, the stirring speed may be 100 to 200 rpm, preferably 120 to 180rpm, or preferably 140 to 160 rpm, or preferably 150 rpm.

In the method, the raw materials can be further promoted to be dissolved in a solvent system by heating to obtain a solution, and the heating temperature can be any temperature exceeding the ambient temperature. Heating to reflux of the solvent system, according to embodiments of the present invention, is more advantageous for raw material dissolution. In some embodiments, heating is at 70 ℃ to 90 ℃. In some embodiments, heating is performed at 70 ℃ to 90 ℃ for 0.1 to 1.5 hours.

After the raw materials are dissolved in the solvent system, if insoluble matters exist, the raw materials can be filtered while the raw materials are hot, insoluble matters are removed, and then a solution is obtained. In some embodiments, the solution is obtained directly after heating to reflux. In some embodiments, after heating to reflux, the solution is filtered while hot.

In order to obtain a product with better quality, such as a product with lower solvent residue and/or a product with relatively larger particle size, the cooling rate or cooling time of the crystallization system needs to be controlled to reduce the temperature to a proper temperature range. According to an embodiment of the present invention, the temperature of the crystallization system may be lowered to-5 to 10 ℃, or-5 to 5 ℃, or 0 ℃ within 2.5 to 13.5 hours after the heat reflux. The cooling rate is controlled, which is helpful to obtain products with higher quality. In some embodiments, after the heat reflux, the temperature of the crystallization system is reduced to-5 ℃ to 5 ℃, or 0 ℃ within 4-11 hours. In some embodiments, after the heat reflux, the temperature of the crystallization system is reduced to-5 ℃ to 5 ℃ over a period of 4-11 hours. In some embodiments, after the heat reflux, the temperature of the crystallization system is reduced to-5 ℃ to 5 ℃ over a period of 4-8 hours. In some embodiments, after the heat reflux, the temperature of the crystallization system is reduced to 0 ℃ over a period of 4-8 hours.

After the temperature of the crystallization system is reduced to a suitable temperature range, the crystallization system may be stirred for a certain period of time at this temperature range to obtain more crystals, and according to embodiments of the present invention, the stirring may be maintained for 0.1 to 5 hours, preferably 1 to 4 hours or 1.5 to 3 hours or 2 hours.

In the refining method, after filtration, the obtained solid needs to be dried to remove moisture or/and solvent. The inventors have found that if only dried, it is difficult to remove the residual organic solvent in the solid of the eppiprazole, and that the residual organic solvent is not significantly reduced by drying at 60 c for 12 hours and drying for 24 hours. The drying process has an important effect on the moisture content and the dihydrate can be converted to the anhydrate by controlling the appropriate drying temperature and/or drying time. According to embodiments of the present invention, the temperature may be controlled at 45-85 ℃ or 50-70 ℃ during drying. In some embodiments, the drying is at a controlled temperature of 45 ℃ to 85 ℃ for 12 to 48 hours. In some embodiments, it is preferred to control the temperature between 50 ℃ and 70 ℃ and dry for 12 to 24 hours. Drying may be performed under conditions such as blowing and/or reduced vacuum.

In some embodiments, the refining method comprises: mixing the raw material of the epipiprazole, water and ethanol, stirring at the speed of 120-180 rpm, and heating and refluxing to obtain a solution; cooling the obtained solution to-5 ℃ within 4-8 hours, then preserving heat and stirring for 1-4 hours at 120-180 rpm, and filtering; drying the obtained solid at 50-70 ℃ for 12-48 hours to obtain an epipiprazole product; wherein, the dosage of water is 4ml-6ml, and the volume ratio of water to ethanol is 1:9-1:15.

The solvent residue of the product obtained by the method can be controlled within the solvent residue limit standard of the corresponding solvent of ICH, for example: using a feedstock containing more than 600ppm of dissolved residues of methylene chloride, the process of the present invention yields a product with less than 600ppm of dissolved residues of methylene chloride. In some embodiments, using a feedstock containing more than 600ppm of dissolved residues of methylene chloride, the resulting product has a residual dissolved residues of methylene chloride that are at or below the detection limit, or are undetected, using the methods of the present invention.

The method provided by the invention has the advantages that the obtained product has relatively large particle size, and the product with larger particle size is beneficial to the transfer, transportation, storage and the like of the subsequent raw material medicines and is also beneficial to the preparation of the subsequent medicinal preparations, such as the preparation of oral tablets. The particle size of the product obtained by the method has the following characteristics: the particle size D50 is 100-145 microns. In some embodiments, the resulting product has a particle size D50 of 110 to 140 microns or 110 to 135 microns. The particle size of the product obtained by the method of the invention also has the following characteristics: d90 is 220-340 microns. In some embodiments, the resulting product has a particle size D90 of 230-330 microns or 240-320 microns. In some embodiments, the resulting product has a particle size D50 of 100 to 145 microns and a D90 of 220 to 340 microns. In some embodiments, the resulting product has a particle size D50 of 110 to 140 microns or 110 to 135 microns and a particle size D90 of 230 to 330 microns or 240 to 320 microns. In some embodiments, the resulting product has a particle size D50 of 110 to 140 microns and a D90 of 230 to 330 microns. In some embodiments, the resulting product has a particle size D50 of 110 to 135 microns and a D90 of 240 to 320 microns.

Definition of terms:

the term "D90" refers to the particle size corresponding to a sample having a cumulative distribution of particles up to 90%, and is physically meant to be smaller than 90% of its particles, e.g. "D90 no greater than 100 μm" means "no greater than 100 μm particles 90%"; d50 refers to the particle size corresponding to a sample particle cumulative distribution of 50%.

In the context of the present invention, all numbers disclosed herein are approximations, whether or not the word "about" or "about" is used. Based on the numbers disclosed, there is a possibility that the values of each number may differ by within + -10% or a reasonable difference as recognized by those skilled in the art, such as + -1%, + -2%, + -3%, + -4%, or + -5%.

Solvent residue or solvent residue refers to the solvent or content thereof remaining in the solid, e.g., 600ppm solvent residue of methylene chloride refers to the residual methylene chloride content in the solid being 600ppm; ppm refers to parts per million; the residual solvent content of methylene chloride in a solid was found to be 600ppm, and the residual solvent content of ethanol in a solid was found to be 5000ppm, which was found to be 0.5%.

Solvent residue can be measured according to the method of Gas Chromatography (GC), as disclosed in the prior art.

In the present invention, XRD refers to X-ray powder diffraction, which can be measured according to the methods disclosed in the prior art.

Polarized light microscopy image (PLM): pictures were taken using a germany Leica DM1000 front microscope, a 2.5-fold objective lens, a Leica MC170 HD microscope lens.

In the invention, the particle size can be detected by adopting a Markov laser particle size analyzer (Mastersizer 2000) Scirocco 2000 (A) dry sample injector, and the whole pipeline is purged by adopting proper air pressure and air flow (for example, 3.5bar and 70 percent) for 30 seconds and then is withdrawn; then, manually measuring, and observing background shading degree, wherein the shading degree is more than or equal to 70.0%; otherwise, cleaning the sample injection pool and the measuring pool, and then sweeping the whole pipeline until the shading degree range meets the requirement; then, a proper amount of the sample (single sample amount) is taken into a sample tray, instrument parameters are set according to the following table, and the sample is measured for 3 times in parallel, and an average value is obtained.

Drawings

FIG. 1 shows a polarized microscopic view (PLM, 25 Xmagnification) of the epipiprazole starting material used in the present invention;

FIG. 2 shows a polarized light microscopic view (PLM, 25 times magnification) of the product of example 1.

FIG. 3 shows the particle size distribution of the raw material of epipiprazole used in the present invention;

fig. 4 shows the particle size distribution of the product of example 1.

Fig. 5 to 8 show particle size distribution diagrams of the products of examples 2 to 5, respectively.

Detailed Description

In order to better understand the technical solution of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.

In the following experiments or examples, the epipiprazole starting material was used as anhydrous crystals, see FIGS. 1 and 3 of the accompanying drawings, wherein the residual dichloromethane soluble content was 4530ppm; by XRD, it was confirmed that the solid (wet product) obtained after filtration was an epipiprazole dihydrate crystal and the dried product was an anhydrate crystal (anhydrate and dihydrate related XRD data can be found in patent applications WO2006112464, WO2013162046, WO2017134038, etc.).

In the invention, when referring to time, h represents hours and s represents seconds; rpm represents revolutions per minute; μm represents micrometers; ml represents milliliters; g represents g.

Drying experiment:

putting 1g of epipiprazole raw material into a glass vessel, drying in a vacuum drying oven at 60 ℃, sampling and detecting at 24 hours and 48 hours respectively, detecting 2 times respectively, taking an average value, and obtaining 4958ppm of dichloromethane soluble residue after 24 hours of drying; after 48 hours of drying, the methylene chloride residue was 4979ppm. From the results (small increases in front and back as measurement errors), it can be seen that drying has substantially no effect on the solvent residue of epipiprazole, and the solvent residue is substantially leveled before and after drying, and the residual dichloromethane cannot be removed.

Example 1

100g of epipiprazole raw material is put into a reaction kettle, 500ml of purified water and 4500ml of absolute ethyl alcohol are sequentially added at 25 ℃, after the addition is finished, the temperature is gradually increased to 82 ℃ under mechanical stirring at 150rpm, at the moment, the solution is refluxed, completely dissolved and stirred for 1h; then starting program cooling, cooling to 0 ℃ in 4 hours, preserving heat and stirring for 1 hour, filtering, and placing the obtained solid in a vacuum drying oven at 60 ℃ for drying for 20 hours to obtain 90.90g of the epipiprazole product, wherein the yield is 90.9%, and the HPLC purity is 99.90%; after detection, methylene dichloride (dissolved residue is 0 ppm) is not detected, and ethanol dissolved residue is 2088ppm; d50 PLM plot of the product, 116 μm, d90=262 μm, as shown in fig. 2, particle size distribution see fig. 4.

Example 2

Adding 100g of epipiprazole raw material into a reaction kettle, sequentially adding 600ml of purified water and 5400ml of absolute ethyl alcohol at 20 ℃, gradually heating to 82 ℃ under mechanical stirring at 120rpm after the addition is finished, boiling the solution, completely dissolving, and stirring for 20 minutes; then starting program cooling, cooling to 0 ℃ within 6h, preserving heat and stirring for 3h, filtering, and placing the obtained solid in a vacuum drying oven at 70 ℃ for drying for 18h to obtain 94.20g of the epipiprazole product with the yield of 94.2%; after detection, methylene dichloride (dissolved residue is 0 ppm) is not detected, and the dissolved residue of ethanol is lower than 2500ppm; HPLC purity 99.91%; d50 =114 μm, d90=240 μm, and the particle size distribution is shown in fig. 5.

Example 3

100g of epipiprazole raw material is put into a reaction kettle, 500ml of purified water and 4500ml of absolute ethyl alcohol are sequentially added at 25 ℃, after the addition is finished, the temperature is gradually increased to 82 ℃ under mechanical stirring at 150rpm, at the moment, the solution is boiled, completely dissolved and stirred for 1.5h; then starting program cooling, cooling to 0 ℃ within 5h, preserving heat, stirring for 2h, filtering, and placing the obtained solid in a vacuum drying oven at 60 ℃ for drying for 24h to obtain 90.11g of the epipiprazole product with the yield of 90.1%; after detection, methylene dichloride (dissolved residue is 0 ppm) is not detected, and the dissolved residue of ethanol is lower than 2500ppm; HPLC purity 99.91%; d50 =131 μm, d90=281 μm, particle size distribution see fig. 6.

Example 4

100g of epipiprazole raw material is put into a reaction kettle, 500ml of purified water and 4500ml of absolute ethyl alcohol are sequentially added at 18 ℃, after the addition is finished, the temperature is gradually increased to 82 ℃ under the mechanical stirring of 180rpm, at the moment, the solution is boiled, completely dissolved and stirred for 1h; then starting program cooling, cooling to 0 ℃ in 8h, preserving heat and stirring for 1h, filtering, and placing the obtained solid in a 55 ℃ vacuum drying oven for drying for 24h to obtain 93.14g of the epipiprazole product with the yield of 93.1%; after detection, methylene dichloride (dissolved residue is 0 ppm) is not detected, and the dissolved residue of ethanol is lower than 2500ppm; HPLC purity 99.93%; d50 =124 μm, d90=272 μm, and the particle size distribution is shown in fig. 7.

Example 5

Adding 60g of epipiprazole raw material into a reaction kettle, sequentially adding 300ml of purified water and 2700ml of absolute ethyl alcohol at 20 ℃, gradually heating to 82 ℃ under mechanical stirring at 150rpm after the addition, boiling and refluxing the solution, completely dissolving, and stirring for 0.5h; then starting program cooling, cooling to 0 ℃ in 4 hours, preserving heat and stirring for 2 hours, filtering, and placing the obtained solid in a vacuum drying oven at 60 ℃ for drying for 20 hours to obtain 96.62g of the epipiprazole product with the yield of 92.6%; after detection, methylene dichloride (dissolved residue is 0 ppm) is not detected, and the dissolved residue of ethanol is lower than 2500ppm; HPLC purity 99.90%; d50 =134 μm, d90=320 μm, and the particle size distribution is shown in fig. 8.

Comparative example 1

50g of epipiprazole raw material is put into a reaction kettle, 800ml of DMF is added at 20 ℃, after the addition is finished, the temperature is gradually increased to 80 ℃ under the mechanical stirring of 150rpm, and the mixture is completely dissolved and stirred for 0.5 hour; then cooling to room temperature, dropwise adding 800ml of purified water, filtering, and drying the obtained solid in a vacuum drying oven at 60 ℃ for 24 hours to obtain 45.01g of the epinastine product, wherein the yield is 90.0%; as a result of detection, methylene chloride was not detected (solvent residue: 0 ppm), but DMF solvent residue was 1178ppm (solvent residue: exceeding standard).

Comparative example 2

50g of epipiprazole raw material is put into a reaction kettle, 400ml of DMSO is added at 24 ℃, after the addition is finished, the temperature is gradually increased to 80 ℃ under the mechanical stirring of 120rpm, and the mixture is completely dissolved and stirred for 1 hour; then cooling to room temperature, dropwise adding 400ml of purified water, filtering, and placing the obtained solid in a vacuum drying oven at 60 ℃ for drying for 24 hours to obtain 42.01g of the epinastine product, wherein the yield is 84.0%; on detection, no methylene chloride was detected (dissolved residue was 0 ppm), but DMSO dissolved residue was 9526ppm (dissolved residue exceeded).

Comparative example 3

Adding 50g of epipiprazole raw material into a reaction kettle, adding 1200ml of Tetrahydrofuran (THF) at 25 ℃, gradually heating to 60 ℃ under mechanical stirring at 150rpm after the addition, completely dissolving, and stirring for 0.5 hour; then cooling to room temperature, dropwise adding 1200ml of purified water, filtering, and placing the obtained solid in a vacuum drying oven at 60 ℃ for drying for 24 hours to obtain 43.00g of the epinastine product with the yield of 86.0%; as a result of detection, methylene chloride was not detected (solvent residue was 0 ppm), but THF solvent residue was 2167ppm (solvent residue was out of standard).

In the description of the present specification, the descriptions of the terms "some embodiments," "some implementations," "one particular example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (10)

1. A method for refining epinastine, comprising: mixing the raw material of the epipiprazole, water and ethanol, stirring, and heating to obtain a solution; cooling the obtained solution to-5-10 ℃ within 2.5-13.5 hours, preserving heat and stirring for 0.5-5 hours, filtering, and drying the obtained solid at 45-85 ℃ for 12-48 hours to obtain the epipiprazole product.

2. The refining method according to claim 1, wherein the amount of water is 4ml to 6ml and the amount of ethanol is 40ml to 60ml per gram of the raw material of epipiprazole.

3. The refining method according to claim 1, wherein the heating is performed at 70℃to 90℃for 0.1 to 1.5 hours.

4. The refining process according to claim 1, wherein the resulting solution is cooled to-5 ℃ to 5 ℃ within 4 to 11 hours; or cooling the obtained solution to-5 ℃ within 4-8 hours.

5. The refining method according to claim 1, wherein the stirring speed is 100 to 200 rpm.

6. The refining method according to claim 1, wherein the stirring time is 1 to 4 hours.

7. The refining process according to claim 1, wherein the obtained solid is dried at 50℃to 70 ℃.

8. The refining method according to any one of claims 1 to 7, comprising: mixing the raw material of the epipiprazole, water and ethanol, stirring at the speed of 120-180 rpm, and heating and refluxing to obtain a solution; cooling the obtained solution to-5 ℃ within 4-8 hours, then preserving heat and stirring for 1-4 hours at 120-180 rpm, and filtering; drying the obtained solid at 50-70 ℃ for 12-48 hours to obtain an epipiprazole product; wherein, the dosage of water is 4ml-6ml, and the volume ratio of water to ethanol is 1:9-1:15.

9. The purification process according to any one of claims 1 to 8, wherein the solvent residue of the raw material of epipiprazole exceeds the standard of the limit of the solvent residue of the common organic solvent for ICH, and the solvent residue of the product of epipiprazole is lower than the standard of the limit of the solvent residue for the common organic solvent for ICH; optionally, the residual methylene chloride solvent in the epiprazole starting material is more than 600ppm.

10. The refining process according to any one of claims 1 to 8, wherein the obtained epipiprazole product is anhydrous crystals, has a particle size D50 of 100 to 145 μm and a D90 of 220 to 340 μm; or the obtained epipiprazole product is anhydrous crystal, the particle size D50 is 110-140 microns or 110-135 microns, and the particle size D90 is 230-330 microns or 240-320 microns.