Process for the preparation of aripiprazole monohydrate with low initial release

Abstract

The application relates to the pharmaceutical technical field and discloses a preparation method of aripiprazole monohydrate with low initial release degree, which comprises the following steps: firstly, adding aripiprazole raw medicine into mixed solvent A, heating, stirring, cooling, crystallizing, stirring, filtering and drying to obtain a crude product crystal; secondly, adding the crude product crystal into mixed solvent B, stirring, cooling and crystallizing; finally, filtering the crystal, rinsing the crystal with cold mixed solvent C and drying to obtain aripiprazole monohydrate with low initial release degree. The aripiprazole monohydrate raw medicine with high purity and low burst release can be obtained by the method, wherein the proportion of anhydride in the aripiprazole monohydrate crystal form is reduced from 20% to 10% or below, the proportion of sub-micron size small particles in the medicine is obviously reduced through scanning electron microscope observation, and the initial release degree (10 min) of in-vitro release is reduced from 36-46% to 12-30%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing aripiprazole monohydrate with low initial release. Background Technology

[0002] Aripiprazole is an antipsychotic drug, and the marketed dosage form is aripiprazole oral tablets (brand name) administered once daily. Aripiprazole is available in two formulations: aripiprazole long-acting intramuscular lyophilized powder (trade name: ABILIFY MAINTENA KIT) and aripiprazole long-acting intramuscular injection lyophilized powder (once a month). Aripiprazole anhydrous form has good solubility; in gastric fluid, its dissolution rate typically reaches over 80% within a few hours, resulting in high bioavailability for its oral tablets. Since schizophrenia patients often require long-term maintenance therapy, extending the drug release cycle can reduce the frequency of administration. Converting aripiprazole anhydrous form to its monohydrate crystal form reduces solubility, allowing the drug to slowly dissolve into the bloodstream after intramuscular injection, maintaining the blood drug concentration within the therapeutic window. These drugs typically utilize nanocrystallization technology, where the drug is first crystallized into larger particles, and then top-down pulverization is used to break down these coarse particles into micron- or submicron-sized particles, thus obtaining a long-acting sustained-release formulation with a specific release cycle.

[0003] According to the Ostwald-Freundlich equation, log(S2 / S1) = 2σM(1 / r2 - 1 / r1) / ρRT. Where: S1 and S2 are the solubility of the drug with radii r1 and r2, respectively; σ is the surface tension; ρ is the density of the solid drug; M is the molecular weight; R is the gas constant; and T is the absolute temperature. For poorly soluble drugs, according to this formula, the particle size of the drug will affect its solubility. When the drug is in a micropowder state, if r2 < r1, the solubility S2 of r2 is greater than the solubility S1 of r1. After administration, the small particles in the drug will dissolve rapidly, leading to a sharp increase in blood drug concentration. This initial drug expulsion can cause toxic side effects. Therefore, controlling the size and particle size distribution of drug crystals has always been a technical challenge in this field.

[0004] Aripiprazole has a monohydrate crystal form and several anhydrous crystal forms. During the pulverization process, the applied energy can cause the drug to transform between the monohydrate and anhydrous crystal forms. After aripiprazole monohydrate is converted to anhydrous form, its solubility increases, which can also lead to a higher blood drug concentration in the early stage of administration. Therefore, controlling the crystal transformation of compounds in the crystallization-drying process of active pharmaceutical ingredients is also a technical challenge in this field.

[0005] In the prior art, the drug is usually dissolved in a crystallization solvent at high temperature, the cooling rate is controlled to make the drug crystallize and precipitate, the precipitated crystals are collected, and the solvent and the drug that has not formed crystals are separated by filtration. This method usually only controls the average particle size, and does not control the small-sized crystal particles in the crystallized compound. For example, the crystallization process is controlled in patent CN1817882B, the solvent and the crystallized compound are separated by filtration, and high-purity aripiprazole monohydrate crystal form is obtained by controlling the drying temperature. This method does not control small particles, and only filtration under reduced pressure or increased pressure can effectively separate solid crystals and liquid solvents, but cannot achieve good separation effect on small-sized crystal particles.

[0006] Drug crystallization includes crystal nucleation and growth steps. When the temperature drops below the saturation solubility, higher supersaturation will make the drug nucleate rapidly, i.e. primary nucleation. When the drug concentration decreases, the supersaturation decreases, and the crystal nucleus growth rate will be greater than the nucleation rate, i.e. crystal nucleus growth, i.e. the size of the crystal particles increases. However, the disadvantage of this method is that the size of the primary nucleation particles is usually small, and after the drug crystallization is completed, there are still many small-sized particles in the drug crystals. These small particles are usually difficult to remove in the formulation process using the Top-down crushing technology, and if they are brought into the formulation, they will cause drug dumping at the initial stage of administration. The size of the drug particles in the formulation is usually 1-10 μm, and the size of the small particles is usually several tens to several hundred nanometers. Whether from a theoretical point of view or in actual industrial production, it is very difficult to separate small particles with similar sizes in the formulation process using filtration technology, and removal will cause loss of active ingredients and excipients. From the technical difficulty, production efficiency and cost, it is difficult to achieve. SUMMARY

[0007] To solve the above technical problems, the present application provides a preparation method of aripiprazole monohydrate with low initial release. The present application controls the proportion of anhydrous aripiprazole monohydrate in the raw material and the number of small particles below 10 μm, especially below 1 μm, to reduce the burst release at the initial stage of administration of the formulation.

[0008] The specific technical scheme of the present application is as follows:

[0009] Step 1: Aripiprazole raw material is added to mixed solvent A with an alcohol concentration of 30-80 vol% at a mass-volume ratio of 1 g:(10-60) mL, heated and stirred to dissolve, cooled to 0-25℃, precipitated crystals, filtered under stirring, and dried to obtain crude crystals.

[0010] Step 2: The crude crystal is added to the mixed solvent B with the organic solvent concentration of 15-80 vol% at the mass volume ratio of 1 g: (4-30) mL, and stirred to dissolve the small particles and aripiprazole anhydrate in the crude crystal; cooled to maintain the temperature, and the dissolved drug is further crystallized on the surface of aripiprazole monohydrate crystal.

[0011] Step 3: The product obtained in step 2 is filtered to obtain the crystal, and the crystal surface is rinsed with the cold mixed solvent C with the organic solvent concentration of not more than 80 vol%.

[0012] Step 4: The crystal obtained in step 3 is dried to obtain aripiprazole monohydrate with low initial release.

[0013] The present application directly controls the proportion of small particles (10 μm or less, especially 1 μm or less) in the crude drug at a low level without worrying about the influence of the separation and purification step on the preparation prescription. The particle size of the crude drug is usually tens to hundreds of microns, and the present application controls the crystallization process, utilizes the solubility difference between different crystal forms and different size particles in the crude crystal, purifies the crystal form in the crude crystal, and utilizes the small particle recrystallization characteristics to dissolve the small particles and then recrystallize them on the surface of the large particles. In combination with the improved filtration technology, the small particles of tens to hundreds of nanometers can be separated and removed, and finally the aripiprazole monohydrate crystal with high purity and low burst is obtained.

[0014] The technical points of the present application are:

[0015] (1) The small size particles in the crude crystal are dissolved using a specific solvent, and the small size particles have higher surface energy and higher solubility than the large particles, and tend to dissolve, deposit and grow on the surface of the large size particles, so that the proportion of small size particles is reduced, and the filtration technology is used to separate the small size crystals (separate the undissolved small particles and the small particles attached to the surface of the large particles), and further reduce the proportion of small particles in the aripiprazole monohydrate crude drug. Specifically, the specific mixed solvent B is added to the crude crystal, and during the heating process, the solubility of the small particles is higher than that of the large particles, and the small particles in the crude crystal will dissolve faster in the mixed solvent; when cooled, the solubility of the drug in the mixed solvent decreases, and the dissolved drug tends to crystallize, but at this time there are a large number of undissolved crystal particles in the solvent, which can act as crystal nuclei, and the dissolved drug tends to grow on the surface of the large particles. Therefore, after the temperature rising and falling process, the small particles in the crude crystal will be reduced. However, considering that the cooling process will be accompanied by secondary nucleation, this step cannot completely eliminate the small particles, and the remaining small particles and the small particles attached to the surface of the large particles need to be further separated by filtration technology.

[0016] (2) The anhydrate is further dissolved in the aqueous solvent to form a monohydrate crystal, so as to improve the purity of aripiprazole monohydrate in the crude drug.

[0017] As a preference, in step 1: the alcohol in the mixed solvent A includes one or more of ethanol, methanol, isopropyl alcohol and tert-butyl alcohol.

[0018] As a preference, in step 2: the stirring temperature is 20-60℃.

[0019] As a preference, in step 2: the cooling temperature is below room temperature.

[0020] As a preference, in step 4: the drying temperature is 20-40℃.

[0021] As a preference, in steps 2 and 3: the mixed solvent B or C is composed of at least one of ethanol, isopropyl alcohol, tert-butyl alcohol and methanol and water.

[0022] As a preference, in step 3: a filter with a pore size of 1-10μm is used for filtration or a 0.6-1.2μm hollow fiber column is used for tangential flow filtration.

[0023] As a preference, in step 3: the organic solvent concentration of the mixed solvent C is 50-80% and the temperature is not higher than 40℃.

[0024] Compared with the prior art, the present application has the following advantages: the aripiprazole monohydrate raw material obtained by the method of the present application has high purity and low burst release, the proportion of anhydrous substance in the aripiprazole monohydrate crystal form is reduced from 20% to within 10%, the proportion of small size particles in the drug is significantly reduced as observed by scanning electron microscopy, and the initial release rate (10min) is reduced from 36-46% to 12-30%. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 Scanning electron microscope (SEM) images of the crude product crystalline A1 obtained in Comparative Example 1 (left) and aripiprazole monohydrate (right);

[0026] Figure 2 XRPD pattern of the product obtained in Example 2. DETAILED DESCRIPTION

[0027] The present application will be further described below in conjunction with examples.

[0028] Overall Examples

[0029] A process for the preparation of aripiprazole monohydrate with low initial release comprising the following steps: Step 1: Aripiprazole drug substance is added to mixed solvent A (consisting of ethanol, methanol, isopropyl alcohol or tert-butyl alcohol and water) with an alcohol concentration of 30-80 vol% at a mass to volume ratio of 1 g:(10-60) mL, heated and stirred to dissolve, cooled to 0-25 °C, and crystallization is induced, filtered under stirring, and dried to obtain crude crystals;

[0030] Step 2: The crude crystals are added to mixed solvent B (consisting of ethanol, isopropyl alcohol, tert-butyl alcohol or methanol and water) with an organic solvent concentration of 15-80 vol% at a mass to volume ratio of 1 g:(4-30) mL, stirred at 20-60 °C to dissolve small particles and aripiprazole anhydrate from the crude crystals, and cooled to below room temperature to maintain the temperature to allow further crystallization of the dissolved drug substance on the surface of aripiprazole monohydrate crystals;

[0031] Step 3: The product from Step 2 is filtered using a filter with a pore size of 1-10 μm or tangential flow filtration using a hollow fiber column with a pore size of 0.6-1.2 μm, and the crystals are rinsed with cold (not higher than 40 °C) mixed solvent C (consisting of ethanol, isopropyl alcohol, tert-butyl alcohol or methanol and water) with an organic solvent concentration of not higher than 80 vol% (preferably 50-80%);

[0032] Step 4: The crystals from Step 3 are dried at 20-40 °C to obtain aripiprazole monohydrate with low initial release.

[0033] Comparative Examples 1-5 (preparation of crude crystals)

[0034] Comparative Example 1

[0035] To 1 kg of aripiprazole drug substance, 20 liters of 80% aqueous ethanol solution is added, heated and stirred to dissolve at 72-78 °C, cooled to 8 °C, and crystallization is induced, filtered under stirring using a 5-10 μm flat filter at a pressure of 1-3 bar, and dried in a 35 °C drying oven for 48 h to obtain crude crystals Al.

[0036] Comparative Example 2

[0037] To 0.3 kg of aripiprazole drug substance, 3 liters of 80% aqueous isopropyl alcohol solution is added, heated and stirred to dissolve at 70-80 °C, cooled to 0 °C, and crystallization is induced, filtered under stirring using a 5-10 μm flat filter at a pressure of 0.5-2 bar, and dried under a stream of nitrogen at 40 °C to obtain crude crystals A2.

[0038] Comparative Example 3

[0039] To 0.2 kg of aripiprazole bulk drug, 12 liters of 30% aqueous tert-butanol was added and dissolved by heating and stirring at 75-82°C. The solution was cooled to room temperature and crystals were precipitated. The crystals were filtered under stirring using a 5-10 μm flat filter at 1-2 bar pressure and dried with hot air at 40°C to obtain crude crystals A3.

[0040] Comparative Example 4

[0041] To 0.2 kg of aripiprazole bulk drug, 8 liters of 60% aqueous methanol was added and dissolved by heating and stirring at 60-64°C. The solution was cooled to room temperature and crystals were precipitated. The crystals were filtered under stirring using a 5-10 μm flat filter at 1-2 bar pressure and dried with hot air at 40°C to obtain crude crystals A4.

[0042] Comparative Example 5

[0043] 0.4 kg of crude crystals A1 from Comparative Example 1 was dried in a drying oven at 50°C for 8 hours to obtain crude crystals A5.

[0044] Examples 1-6 (Preparation of purified crystals)

[0045] Example 1

[0046] 0.2 kg of crude crystals A1 from Comparative Example 1 was dissolved in 0.8 liters of 20% ethanol by stirring at 40-50°C. The solution was cooled to 8-15°C to recrystallize. The crystals were filtered using a 5 μm mesh filter and the filter cake was washed with 80% cold ethanol. The crystals were dried under a stream of nitrogen at 20-40°C.

[0047] Example 2

[0048] 0.1 kg of crude crystals A5 from Comparative Example 5 was dissolved in 2 liters of 40% ethanol by stirring at 40°C. The solution was cooled to 2-8°C to recrystallize. The temperature was raised to 40°C and then lowered rapidly to below 10°C. The crystals were filtered using a 5 μm flat filter and the filter cake was washed with 70% cold ethanol. The crystals were dried under a stream of nitrogen at room temperature.

[0049] Example 3

[0050] 0.2 kg of crude crystals A2 from Comparative Example 2 was dissolved in 6 liters of 15% isopropanol by stirring at room temperature. The solution was cooled to 8-15°C to recrystallize. The crystals were filtered using a 10 μm mesh filter and the concentrated solution was collected. The filter cake was washed with 60% cold isopropanol. The crystals were dried under a stream of nitrogen at 25-40°C.

[0051] Example 4

[0052] 0.3 kg of crude crystals A3 from Comparative Example 3 was dissolved in 6 liters of 15% tert-butanol by stirring at 60°C. The solution was cooled to 2-10°C to recrystallize. The crystals were microfiltered using a 0.6 μm hollow fiber cartridge and the concentrated solution was collected. The crystals were dried under a stream of nitrogen at room temperature.

[0053] Example 5

[0054] Take 0.3 kg of crude product crystalline A4 in Comparative Example 4; add 1.2 liters of 80% methanol, stir at 30°C; cool to 2-10°C for recrystallization, filter on a flat plate with 5 μm pore size, rinse the filter cake with 80% cold methanol; dry under nitrogen flow at room temperature.

[0055] Example 6

[0056] Take 0.1 kg of crude product crystalline A5 in Comparative Example 5; add 40% ethanol, stir at 40°C; cool to 2-8°C for recrystallization; raise the temperature to 40°C and then quickly lower it to below 10°C; microfiltration on a hollow fiber column with 1.2 μm pore size, rinse with 70% cold ethanol, collect and filter the concentrated solution; dry under nitrogen flow at room temperature.

[0057] Performance test

[0058] SEM test

[0059] Figure 1 The scanning electron microscope (SEM) image of the crude product crystalline A1 obtained in Comparative Example 1 is shown in Figure 1 (left), and the scanning electron microscope (SEM) image of the aripiprazole monohydrate obtained after recrystallization of A1 by the method of Example 1 is shown in Figure 1 (right). As can be seen from the images, the proportion of small particle crystalline material is significantly reduced after the crude product crystalline is refined by the recrystallization process.

[0060] XRPD test

[0061] The XRPD pattern of the product obtained in Example 2 is shown in Figure 2 , which shows the crystallinity of the drug, and is compared with the XRPD of aripiprazole monohydrate in patent CN1817882B Figure 1 , which shows that the crystal form obtained by the crystallization process of the present application is mainly aripiprazole monohydrate crystal form.

[0062] Particle size and small particle test

[0063] The crystalline material in each example is micronized by airflow crushing to an average particle size of 4.0-5.0 μm, and a Malvern laser particle size analyzer MS3000 is used to detect the particle size, and the proportion of volume below 1 μm in the particle size distribution is calculated as the proportion of small particles, and the results are shown in Table 1.

[0064] Moisture test

[0065] The moisture content of the crystalline material is detected by thermogravimetric analysis (TGA), and the proportion of anhydrous material in the crystalline material is estimated according to the results. The calculation formula is anhydrous material proportion = 100% - water loss rate / 3.86%, wherein the theoretical moisture content of aripiprazole monohydrate is 3.86%, and the results are shown in Table 1.

[0066] Dissolution test

[0067] The micronized crystalline substance was uniformly dispersed in a carboxymethylcellulose sodium and sodium dihydrogen phosphate solution with pH = 7.0, and the in vitro release method in the FDA dissolution database was used to detect the dissolution, and the method was as follows: USP II paddle method, rotation speed 50 rpm, dissolution medium was 0.25% SDS aqueous solution, volume 900 ml, temperature 37℃, sample detection of dissolved drug concentration at 5 min and 10 min, and calculation of dissolution rate was used to evaluate the possible drug burst at the initial stage of administration.

[0068] The specific results are shown in Table 1:

[0069] Table 1: Dissolution, particle size and small particle ratio, and anhydrous substance ratio evaluation results of samples of each embodiment

[0070]

[0071] Comparative Example 5: The crude crystalline A1 was continuously dried at 50℃, and the anhydrous substance ratio increased to 20%, and the initial release became faster, indicating that higher drying temperature would cause partial aripiprazole monohydrate to crystallize. The over-dried crude crystalline A5 was recrystallized by Example 2, and the anhydrous substance would be converted into monohydrate crystal form. Compared with the crude crystalline obtained by Comparative Examples 1-5, the aripiprazole monohydrate obtained by the crystallization process of Examples 1-6 using the crude crystalline A1-A5, the dissolution of the micronized product at 5 min and 10 min was lower than that of the corresponding crude crystalline, and the initial release (10 min) was reduced from 25-50% to 10-30%. The number of small particles and the dissolution of aripiprazole monohydrate prepared by different crystallization processes were different, indicating that different solvent systems and crystallization process temperatures would affect the particle size distribution of the crystalline particles. The tangential flow filtration process was used to separate the small particles, which could further improve the burst compared with other filtration processes. From the above results, the aripiprazole monohydrate obtained by the crystallization process of the present application can improve the burst phenomenon of the preparation.

[0072] The raw materials and equipment used in the present application are conventional raw materials and equipment in the art unless otherwise specified; the methods used in the present application are conventional methods in the art unless otherwise specified.

[0073] The above is only a preferred embodiment of the present application, and does not limit the present application in any way. Any simple modification, change and equivalent transformation of the above embodiment based on the technical essence of the present application still belongs to the protection scope of the technical solution of the present application.

Claims

1. A method for preparing aripiprazole monohydrate with low initial release, characterized in that... Includes the following steps: Step 1: Add aripiprazole raw material to mixed solvent A with an alcohol concentration of 30-80 vol% at a mass-volume ratio of 1 g: (10-60) mL, heat and stir to dissolve, cool to 0-25℃, crystals precipitate, filter and dry under stirring to obtain crude crystals; The alcohol in mixed solvent A is one or more of ethanol, methanol, isopropanol, and tert-butanol; Step 2: Add the crude crystals to a mixed solvent B with an organic solvent concentration of 15-80 vol% at a mass-to-volume ratio of 1 g: (4-30) mL, and stir to dissolve the small particles and anhydrous aripiprazole in the crude crystals; Cooling and maintaining the temperature allows the dissolved drug to crystallize further on the surface of aripiprazole monohydrate crystals; mixed solvent B consists of at least one of ethanol, isopropanol, tert-butanol, and methanol, and water; Step 3: Filter the product obtained in step 2 to obtain crystals, and rinse the surface of the crystals with a mixed solvent C with an organic solvent concentration of not more than 80 vol% and a temperature of not more than 40°C. Step 4: Dry the crystals obtained in Step 3 to obtain aripiprazole monohydrate with low initial release.

2. The preparation method according to claim 1, characterized in that, In step 2: the stirring temperature is 20-60℃.

3. The preparation method according to claim 1, characterized in that, In step 2: Cool the temperature to below room temperature.

4. The preparation method according to claim 1, characterized in that, In step 4, the drying temperature is 20-40℃.

5. The preparation method according to claim 1, characterized in that, In step 3: the mixed solvent C consists of at least one of ethanol, isopropanol, tert-butanol and methanol and water.

6. The preparation method according to claim 1, characterized in that, In step 3: use a filter with a pore size of 1-10μm or use a hollow fiber column with tangential flow filtration of 0.6-1.2μm.

7. The preparation method according to claim 6, characterized in that, In step 3: Tangential flow filtration using 0.6-1.2μm hollow fiber columns.

8. The preparation method according to claim 6, characterized in that, In step 3: the organic solvent concentration of the mixed solvent C is 50-80%.

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