CN113956200A - Crystallization process of roxasistat bulk drug with controlled particle size - Google Patents
Crystallization process of roxasistat bulk drug with controlled particle size Download PDFInfo
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- CN113956200A CN113956200A CN202111539432.6A CN202111539432A CN113956200A CN 113956200 A CN113956200 A CN 113956200A CN 202111539432 A CN202111539432 A CN 202111539432A CN 113956200 A CN113956200 A CN 113956200A
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- roxasistat
- particle size
- crystallization process
- aqueous solution
- acetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0077—Screening for crystallisation conditions or for crystal forms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a crystallization process of a roxasistat bulk drug with controlled particle size. Salifying the roxasistat (I) with alkali, filtering, heating, adding a first part of acetic acid aqueous solution to adjust the pH value to 6.4-6.7, adding a roxasistat seed crystal and a second part of acetic acid aqueous solution, crystallizing, centrifuging and drying to obtain the particle size-controlled roxasistat bulk drug. The particle size D (90) of the raw material medicine of the roxasistat prepared by the process method is 25-45 microns, meets the requirement of a preparation and is suitable for industrial production.
Description
Technical Field
The invention relates to a particle size controlled crystallization process of a raw material medicine of roxasistat, belonging to the technical field of pharmaceutical chemistry.
Background
The first oral small molecule HIF-PHI developed by Fabricius Advance (FibroGen) company for treating renal anemia is roxastat (FG-4592), which can inhibit HIF-prolyl hydroxylase, stabilize HIF-alpha, promote endogenous EPO production, improve iron absorption and utilization, and comprehensively regulate and promote erythropoiesis. In 12 months in 2018, the national drug administration approves the rosisastat capsules to be listed by a priority evaluation and approval program, and the specification is as follows: 20mg, 50 mg; the indications are anemia treatment for chronic kidney disease dialysis patients; the Chinese patent application is approved in 8 months in 2019 to be applicable to anemia treatment of non-dialysis dependent chronic kidney disease (NDD-CKD).
In the production of bulk drugs, particle size is an indispensable index. According to the requirements of dissolution rates of different preparations, the particle sizes of the raw material medicines are controlled in different particle size sections so as to maximize the drug effect. The particle size distribution of the drug substance may have a significant effect on the properties of the final product, such as solubility, bioavailability, content uniformity and stability. In addition, the particle size distribution of the drug substance also affects the flowability, the total mixing uniformity, the compressibility and other producibility of the drug, and then may affect the safety, effectiveness and quality of the drug. In the evaluation of the pharmaceutical imitation consistency, the particle size is a key quality attribute of part of solid preparations, if the particle size is larger, the dissolution is too slow to be consistent with a reference preparation, and if the particle size is too small, the dissolution is too fast.
At present, no research report aiming at the aspect of particle size control of raw materials of the roxasistat exists, and original patents CN103435546A and CN103539735A disclose a crystallization process of the roxasistat, wherein the crystallization process is obtained by directly regulating acid and crystallizing in an aqueous solution. However, the particle size of the raw material medicine obtained by the process method is small, the distribution is not uniform, and the dissolution of the preparation is too fast.
Generally, the particle size of the drug substance can be controlled by controlling the parameters of drug pulverization or improving the crystallization process. The applicant finds that currently, the raw material medicine of the roxasistat with qualified particle size cannot be obtained by the conventional crushing method:
(1) the particle size of the raw materials of the roxasistat cannot be crushed to be below 45 mu m by a disc tooth mill, and is larger;
(2) the particle size of the raw material medicine of the roxasistat is crushed to be below 25 mu m through air flow crushing, the particle size is too fine, and the dissolution is too fast.
Therefore, a crystallization process of the raw material medicine of the roxasistat with the particle size D (90) of 25-45 μm meeting the preparation requirement is urgently needed at present. .
Disclosure of Invention
The invention aims to solve the technical problem of how to provide a roxasistat bulk drug with the particle size D (90) of 25-45 mu m, which meets the preparation requirement.
In order to solve the technical problems, the technical scheme provided by the invention is a crystallization process of a grain size-controlled raw material medicine of the roxasistat,
comprises the following steps:
(1) putting the roxasistat (I) and water into a reaction kettle, adding inorganic base or an aqueous solution of the inorganic base, dissolving the roxasistat (I), filtering, putting a mother solution into a crystallization kettle, heating to 65-90 ℃, slowly dropping a first part of an acetic acid aqueous solution, and adjusting the pH to 6.4-6.7;
(2) keeping the temperature of the crystallization kettle at 65-90 ℃, adding the crystal seeds of the roxasistat at one time, quickly adding a second part of acetic acid water solution, and keeping the system stirred;
(3) centrifuging while hot, and drying the filter cake to obtain the raw material medicine of the roxasistat with controlled particle size.
The particle size D (90) of the raw material medicine of the roxasistat prepared by the crystallization process is 25-45 mu m.
In the crystallization process, the roxasistat (I) further comprises the steps of dissolving and cleaning with an aqueous solution of inorganic base, filtering, and recrystallizing and purifying with an aqueous solution of acetic acid.
In the crystallization process, the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate.
In the crystallization process, the temperature of the crystallization kettle is preferably 70-80 ℃.
According to the crystallization process, the pH of the mother liquor is adjusted to 6.4-6.7 by adding the first part of acetic acid aqueous solution; the molar ratio of the second part of the acetic acid aqueous solution to the roxasistat (I) is 1.0: 1.0-2.0, and preferably 1.0: 1.5-2.0.
Further, the roxasistat (I) is prepared by the following method,
and (3) reacting the compound (II) with glycine or sodium glycinate to prepare the roxasistat (I).
Wherein: r is selected from H or C1-8Alkyl, preferably H, methyl or ethyl.
In the embodiment of the invention, the compound (II) reacts with sodium glycinate to prepare the roxasistat (I), wherein R is methyl.
The rosxastat (I) of the present invention can also be prepared by any other disclosed preparation method or obtained directly by market purchase.
The invention has the beneficial effects that:
the crystallization process can be used for preparing the raw material medicine of the roxasistat with the particle size D (90) of 25-45 mu m, which meets the preparation requirement. The crystallization process is safe and simple, has high yield and is suitable for industrial production.
Drawings
Fig. 1 and the cumulative dissolution chart of the prescribed preparation of the bulk drugs with different particle sizes in example 1.
Fig. 2 and the particle size distribution diagram of the crude drug of the S26122107002S lot of roxasistat in example 5.
Detailed Description
Example 1 dissolution comparison experiment of prescription preparations of bulk drugs with different particle sizes
And (3) inspecting the influence of the particle size of the raw material medicine of the roxasistat on the dissolution rate of the capsule and the cumulative dissolution rate of the dissolution endpoint.
1) The raw materials of the roxasistat with different particle sizes are obtained by adjusting the crystallization process and combining the crushing means, and are shown in table 1:
TABLE 1
2) The raw materials of the roxasistat with different particle sizes are respectively prepared into capsules according to the following processes:
mixing the roxasistat, lactose, microcrystalline cellulose, croscarmellose sodium and povidone by sieving through a cone granulator, stirring and mixing in a wet granulation pot, then stirring at 200 rpm, adding purified water for granulation under the condition of cutting at 1500 rpm, drying by a fluidized bed, granulating through a 0.8 mm screen, adding magnesium stearate, mixing and filling into capsules.
Wherein the raw material D (90) of the No. 008 roxasistat is less than 10 μm, the electrostatic force among the raw materials is observed to be serious, the processing is not easy, and the roxasistat is not prepared into capsules.
3) The reference preparation and the capsule prepared by the process method are subjected to dissolution test in a medium with the rotating speed of 75 rpm and the pH value of 6.8, and the test results are shown in table 2:
TABLE 2
Wherein: the reference preparation is from Ehree, a product on the market in China.
And (4) experimental conclusion:
when the particle size D (90) of the raw material medicine is less than 10 mu m, the electrostatic force among the raw materials is serious and is not easy to process;
when the particle diameter D (90) of the raw material medicine is 15.3 mu m, the capsule preparation is dissolved too fast;
when the particle size D (90) of the raw material medicine is 25.6-45.7 mu m, the capsule preparation has better dissolution behavior, and the 15 min cumulative dissolution rate is more than or equal to 85 percent and is similar to a reference preparation;
when the particle size D (90) of the raw material medicine is more than or equal to 65.3 mu m, the dissolution is slowed down, and the cumulative dissolution of the capsule preparation for 15 min is less than 85 percent and is not similar to the reference;
when the particle diameter D (90) of the raw material medicine is more than or equal to 93.3 mu m, the cumulative dissolution rate of the capsule preparation in 45 min is less than 85 percent, and the dissolution end point is not reached; therefore, the D (90) is 25-45 mu m, which meets the particle size range of raw materials of the roxasistat in the preparation requirement.
Example 2 screening of crystallization conditions
(a) Temperature screening
In the crystallization process, the influence of different dropping temperatures on the particle size was examined at the same stirring speed.
Putting the roxasistat (I) and water into a reaction kettle, adding a sodium hydroxide aqueous solution, dissolving the roxasistat (I), filtering, putting mother liquor into a crystallization kettle, heating to different temperatures, dripping a first part of acetic acid aqueous solution, and adjusting the pH to 6.6; adding a crystal seed of the roxasistat, quickly adding a second part of acetic acid aqueous solution, and keeping the system stirred; centrifuging while hot, drying the filter cake to obtain the raw material medicine of the roxasistat, sampling and detecting the particle size, wherein the experimental result is shown in the table 3:
TABLE 3
And (4) conclusion: in the crystallization process, under the same stirring speed, the lower the dropping temperature is, the smaller the particle size is, and the acetic acid is added at the temperature of 65-90 ℃ with little difference in particle size.
(b) pH value screening
Putting the roxasistat (I) and water into a reaction kettle, adding a sodium hydroxide aqueous solution, dissolving the roxasistat (I), filtering, putting a mother solution into a crystallization kettle, heating to 70 ℃, dropping a first part of acetic acid aqueous solution, and adjusting the pH of the mother solution to different ranges; adding a crystal seed of the roxasistat, quickly adding a second part of acetic acid aqueous solution, and keeping the system stirred; centrifuging while hot, drying the filter cake to obtain the raw material medicine of the roxasistat, sampling and detecting the particle size, wherein the experimental results are shown in the table 4:
TABLE 4
And (4) conclusion: when the pH value of the system is about 6.0, a large amount of solids are separated out when the system is stirred for about 3-5 min; when the pH of the system is about 7.0, the turbidity of the system just appears when the seed crystal is added to 10 percent; in order to better control the crystallization process and ensure the induced crystallization in the presence of the seed crystal, the pH of the system is preferably controlled to be 6.4-6.7.
(c) The second part of acetic acid aqueous solution is added for screening
Putting the roxasistat (I) and water into a reaction kettle, adding a sodium hydroxide aqueous solution, dissolving the roxasistat (I), filtering, putting a mother solution into a crystallization kettle, heating to 80 ℃, dripping a first part of acetic acid aqueous solution, and adjusting the pH to 6.4; adding a crystal seed of the roxasistat, adding a second part of acetic acid aqueous solution in two ways, and keeping the system stirred; centrifuging while hot, drying the filter cake to obtain the raw material medicine of the roxasistat, sampling and detecting the particle size, wherein the experimental results are shown in table 5:
TABLE 5
And (4) conclusion: in the crystallization process, the dripping mode of the second part of acetic acid has great influence on the grain diameter of the finished product of the roxasistat, when the acid solution is dripped slowly, the grain diameter of the precipitated product is larger, and the dripping mode of the second part of acetic acid is preferably added rapidly at one time.
(d) Second part acetic acid water solution adding amount screening
Putting the roxasistat (I) and water into a reaction kettle, adding a sodium hydroxide aqueous solution, dissolving the roxasistat (I), filtering, putting a mother solution into a crystallization kettle, heating to 75 ℃, dropping a first part of acetic acid aqueous solution, and adjusting the pH to 6.5; adding a crystal seed of the roxasistat, and quickly adding a second part of acetic acid aqueous solution with different equivalent weights, and keeping the system stirred; centrifuging while hot, drying the filter cake to obtain the raw material medicine of the roxasistat, sampling and detecting the particle size, wherein the experimental results are shown in table 6:
TABLE 6
And (4) conclusion: the dosage of the second part of acetic acid is 1.5-2.0 eq, the obtained particle sizes meet the requirement, and when the dosage of the second part of acetic acid is 1.0 eq, the crystallization yield is low; when the dosage of the second part of acetic acid exceeds 2.0 eq, the particle size is larger, so the dosage of the second part of acetic acid aqueous solution is preferably 1.5 to 2.0 eq.
Example 3
Placing 5.3 Kg of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-methyl formate (compound II-1), 5.83 Kg of sodium glycinate and 51 Kg of methanol in a reaction kettle for reflux reaction for 12 hours, cooling and filtering, separating filter cakes by using ethyl acetate and water, heating a water layer to 70 ℃, adding an acetic acid aqueous solution, cooling and centrifuging to obtain a crude product of the roxasistat. Adding the wet crude product of the roxasistat into water, adding a sodium hydroxide aqueous solution, filtering the system, heating the filtrate to 65-75 ℃, adding an acetic acid aqueous solution, filtering while hot, and drying to obtain 55.6 Kg of roxasistat (I), wherein the purity is as follows: 99.5%, yield: 90 percent.
Example 4
825 g of glycine, 2.33 Kg of sodium carbonate, 10L of water and 10L of tetrahydrofuran in the reaction kettle 1 for later use;
adding 14L of tetrahydrofuran, 2.95 Kg of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-formic acid (compound II-2), 2.95 Kg of 1-hydroxybenzotriazole and 2.58 Kg of diisopropylethylamine into a reaction kettle 2, cooling to-10 ℃, adding 1.5 Kg of N, N' -diisopropylcarbodiimide, stirring for 30 minutes, adding the mixture into the reaction kettle 1, and reacting for 1 hour at the temperature of 25-30 ℃. Adding 40 Kg of purified water, filtering, adjusting the pH of the water phase to 2-3 with hydrochloric acid, filtering, and drying the filter cake to obtain the roxasistat (I).
Example 5
Placing 5.3 Kg of roxasistat (I) and 53 Kg of purified water in a reaction kettle, adding an aqueous solution of sodium hydroxide to dissolve the roxasistat (I), filtering, placing a mother solution in a crystallization kettle, heating to 70-80 ℃, slowly dropping a first part of an acetic acid aqueous solution, and adjusting the pH to 6.4-6.7; keeping the temperature of the crystallization kettle at 70-80 ℃, adding 0.26 Kg of crystalline seeds of the roxasistat at one time, quickly adding a second part of acetic acid water solution, and keeping stirring the system for 6 hours; centrifuging while hot, washing the crystallization kettle and the pipeline by using 10.6 Kg of purified water, transferring the crystallization kettle and the pipeline into a centrifuge, drying a filter cake to obtain 5.4 Kg of the raw material medicine of the roxasistat with controlled particle size, and deducting the yield of the seed crystal: 97 percent.
The experiment was repeated 3 times and the particle size distribution of the obtained particle size controlled raw material of roxasistat is shown in table 7:
TABLE 7
The crystallization process can be used for preparing the raw material medicine of the roxasistat with the particle size D (90) of 25-45 mu m, which meets the preparation requirement, and is safe and simple, high in yield and good in repeatability.
Claims (10)
1. A process for the crystallization of a raw material medicine of roxasistat with controlled particle size is characterized in that,
comprises the following steps:
(1) putting the roxasistat (I) and water into a reaction kettle, adding inorganic base or an aqueous solution of the inorganic base, dissolving the roxasistat (I), filtering, putting a mother solution into a crystallization kettle, heating to 65-90 ℃, slowly dropping a first part of an acetic acid aqueous solution, and adjusting the pH to 6.4-6.7;
(2) keeping the temperature of the crystallization kettle at 65-90 ℃, adding the crystal seeds of the roxasistat at one time, quickly adding a second part of acetic acid water solution, and keeping the system stirred;
(3) centrifuging while hot, and drying the filter cake to obtain the raw material medicine of the roxasistat with controlled particle size.
2. The crystallization process of a particle size controlled rosmarin drug substance according to claim 1, characterized in that: the particle size D90 of the raw material medicine of the roxasistat is 25-45 mu m.
3. The crystallization process of a particle size controlled rosmarin drug substance according to claim 1, characterized in that: the roxasistat (I) also comprises the steps of dissolving and cleaning with an aqueous solution of inorganic base, filtering, and recrystallizing and purifying with an aqueous solution of acetic acid.
4. The crystallization process of a particle size controlled rosmarin drug substance according to claim 1, characterized in that: the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate.
5. The crystallization process of a particle size controlled rosmarin drug substance according to claim 1, characterized in that: the temperature of the crystallization kettle is 70-80 ℃.
6. The crystallization process of a particle size controlled rosmarin drug substance according to claim 1, characterized in that: the molar ratio of the roxasistat (I) to the second part of the acetic acid aqueous solution is 1.0: 1.0-2.0.
7. The crystallization process of a particle size controlled rosmarin drug substance according to claim 6, characterized in that: the molar ratio of the roxasistat (I) to the second part of the acetic acid aqueous solution is 1.0: 1.5-2.0.
8. The crystallization process of a particle size controlled rosmarin drug substance according to any of claims 1-7, characterized in that: the roxasistat (I) is prepared by the following method,
wherein R is selected from H or C1-8An alkyl group;
and (3) reacting the compound (II) with glycine or sodium glycinate to prepare the roxasistat (I).
9. The crystallization process of a particle size controlled rosmarin drug substance according to claim 8, characterized in that: r is selected from H, methyl or ethyl.
10. The crystallization process of a particle size controlled rosmarin drug substance according to claim 9, characterized in that: and (3) reacting the compound (II) with sodium glycinate to prepare the roxasistat (I), wherein R is selected from methyl.
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