Method for preparing round smooth block-shaped aripiprazole injection preparation based on stator rotor shearing

Abstract

The application relates to the field of medicine preparation, and discloses a method for preparing smooth block-shaped aripiprazole injection preparation based on fixed rotor shearing, which comprises the following steps: (1) dissolving a suspending agent, a freeze-drying protective agent and an acidity adjusting agent in water to obtain a weakly acidic auxiliary material solution; (2) dispersing aripiprazole drug particles in the auxiliary material solution to form a premixing suspension; (3) shearing the premixing suspension to a target average particle size by using a fixed rotor high-shear process to obtain a secondary suspension; and (4) adjusting the pH of the secondary suspension to 6.5-7.5 to obtain a final suspension. The fixed rotor shearing process with specific process parameters can be used to prepare aripiprazole preparation with high particle size consistency, high dispersibility and excellent sustained-release effect for the first time, the method has no risk of material blockage, insufficient grinding of large-particle material and medium pollution, and has the advantages of simple process, low cost and good controllability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation, and more particularly to a method for preparing a cylindrical aripiprazole injection formulation based on stator-rotor shearing. Background Technology

[0002] Schizophrenia is a mental illness characterized by hallucinations, delusions, mood disorders, and cognitive impairment. It has a high heritability and is one of the most common psychotic disorders. Because schizophrenia often requires long-term treatment, many patients can stabilize their symptoms with oral antipsychotic medications. However, it is estimated that up to 75% of patients struggle to adhere to their daily oral treatment regimen, exhibiting adherence problems. These adherence issues often lead to worsening symptoms, poor treatment response, frequent relapses and readmissions, and prevent patients from benefiting from rehabilitation and psychosocial therapy. This is one of the most challenging problems in the treatment of mental illness.

[0003] Aripiprazole is a novel atypical antipsychotic drug. Since 2002, the FDA has successively approved various dosage forms of aripiprazole, including regular tablets, oral solutions, orally disintegrating tablets, and injections. Aripiprazole is a poorly water-soluble drug. For poorly soluble drugs, long-acting formulations can be prepared using certain methods to achieve slow release of the drug at the local injection site. A significant advantage of long-acting formulations compared to oral formulations is that they greatly improve treatment adherence. By reducing the frequency of dosing and prolonging the duration of drug action after a single dose, the condition can be effectively controlled and relapse prevented.

[0004] Currently, the main methods for preparing aripiprazole injection formulations (suspensions) include ball milling and multi-process combined methods. For example: (1) Ball milling: Patent CN1870980B uses wet milling to reduce the average particle size of the primary suspension of aripiprazole to the range of 1-10 μm. This process has the problem that large drug particles may pass through the grinding medium, making them unable to be fully ground, and there is the possibility of medium contamination. (2) Multi-process combined method: Patent CN101801342B discloses a method for manufacturing aripiprazole suspension, which uses a two-stage pulverization method, such as using a high-shear high-speed mixer and a high-pressure homogenizer in succession, to reduce the average particle size of the primary suspension of aripiprazole to the range of 1-10 μm. Its preparation process is relatively complex and costly. Because the initial drug particles are large, if a high-pressure homogenizer is used directly for pulverization, large drug particles will block the homogenization chamber. Patent CN104906038B discloses an aripiprazole nanocrystal suspension and its preparation method, which uses a ball mill and a high-pressure homogenizer in combination to obtain a nanocrystal suspension with an average particle size of 10-1000 nm. However, this method also suffers from complex preparation processes, high costs, and high prices, hindering industrial production. Patent WO2022171513A uses a high-shear homogenizer combined with ball milling to prepare a secondary suspension with a D[4,3] of 1-10 μm. This prior art first uses a high-shear homogenizer to homogenize the aripiprazole particles to obtain a primary suspension, homogenizing the particle size until the aripiprazole particles D[4,3] have a particle size of 10-40 μm, more specifically 10-20 μm. Then, the suspension is ground and homogenized simultaneously until the target particle size aripiprazole suspension is obtained. It also suffers from problems such as complex preparation processes, susceptibility to contamination, and difficulty in industrial-scale production.

[0005] In summary, all existing technologies require grinding to prepare the final aripiprazole suspension with the target particle size, such as ball milling or a combination of ball milling and high-pressure homogenization. Existing technologies, even with high-shear treatment, still result in relatively large particle sizes, requiring the use of ball milling or high-pressure homogenizers and one or more cycles to achieve the target particle size, making the process cumbersome.

[0006] In addition, in the aripiprazole injection formulations obtained by existing preparation processes, the crystal particles of aripiprazole are mainly in the form of flakes or needles with sharp edges, which are prone to agglomeration and have poor sustained-release effects in vivo and in vitro, which need to be further improved. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a method for preparing aripiprazole injection formulations in the form of circular sliders based on stator-rotor shearing. This invention, for the first time, utilizes a stator-rotor shearing process with specific parameters to produce aripiprazole formulations with high particle size uniformity, high dispersibility, and excellent sustained-release effect. This method not only eliminates the risks of material blockage, insufficient grinding of large particles, and media contamination, but also features a simple process, low cost, and good controllability.

[0008] The specific technical solution of this invention is as follows: a method for preparing a circular block-shaped aripiprazole injection formulation based on stator-rotor shearing, comprising the following steps:

[0009] (1) Preparation of excipient solution: Dissolve the suspending agent, freeze-drying protectant and acidity regulator in water to obtain a weakly acidic excipient solution.

[0010] (2) Disperse aripiprazole drug particles in an excipient solution to form a premixed suspension.

[0011] (3) The principle of the equipment is to generate high shear force due to the high relative high speed motion between the stator and rotor. The rotor linear velocity of the equipment is adjusted to 35-70m / s, the stator-rotor distance is adjusted to 100-500μm, and the shear coefficient is ≥1.4×10 5 s -1 The pre-suspended solution is sheared to the target average particle size D50 = 3-6 μm to obtain the sub-suspension.

[0012] (4) Adjust the pH of the secondary suspension to 6.5-7.5 with a pH adjuster to obtain the final suspension.

[0013] Currently, aripiprazole final suspensions with the target particle size are mainly prepared by ball milling. However, this method suffers from the problem that large particles can easily pass through the grinding media and cannot be fully ground. If homogenization and other processes are combined, the process becomes more complex and the cost increases. In addition, ball milling also carries the risk of media contamination. This invention employs a stator-rotor high-shear preparation process, which has been found to directly obtain aripiprazole formulations with good consistency of the target particle size in one step under specific process conditions. Unlike ball milling, the product obtained by this process is not subject to media contamination, and the process does not require pressurization or ultra-high temperature treatment above 100°C. The process is simple, low-cost, and highly controllable.

[0014] In equipment where high shearing action is generated due to the high relative speed between the stator and rotor, the shearing head consists of a stator and a rotor, which mesh with each other. The high-speed rotation of the rotor generates a strong centrifugal force, forming a strong negative pressure zone that draws the material into the working chamber. Within the distance between the stator and rotor, the material is subjected to a combination of shearing, centrifugal compression, impact, turbulence, and strong friction, causing the drug particles to break down and reduce their particle size.

[0015] This invention discovers that by limiting the shear coefficient (shear coefficient = linear velocity / stator-rotor spacing) in the high-shear stator-rotor process, not only can the particle size of the material be reduced to the target particle size, but the slurry can also be homogenized, effectively suppressing the agglomeration of small particles. Furthermore, unlike ball milling, the initial particle size of the material does not significantly affect the final target particle size, ensuring consistency between different batches. This invention further discovers that if the shear coefficient is controlled at ≥1.4×10⁻⁶... 5 s -1 The target particle size of this invention can then be obtained. To achieve the target particle size required by this invention, the linear velocity and the stator-rotor spacing must be controlled to conform to the shear coefficient of this invention, i.e., rotor linear velocity = 35-70 m / s, stator-rotor spacing = 100-500 μm.

[0016] On the other hand, this invention also found that, compared to ball milling, aripiprazole formulations obtained through a stator-rotor high-shear process exhibit better formulation dispersibility and release stability. Our research revealed that this is because the absorption rate of aripiprazole depends on the dissolution rate of particles in the aripiprazole monohydrate suspension. Ball milling easily yields flake-like or needle-like particles with more sharp edges, which are prone to agglomeration and adhesion between small particles, and have high solubility due to their large specific surface area. In contrast, the method of this invention can alter or significantly change the morphology of aripiprazole crystal particles, resulting in particles that are mainly blocky with smoother surfaces, less prone to agglomeration, and dissolve more slowly than flake-like or needle-like particles, thus exhibiting superior dispersibility and in vitro / in vivo sustained-release effects. The fundamental reason for these differences lies in the different shear principles of the two processes and the different forces acting on the particles. Ball milling primarily reduces particle size through collisions between particles and the grinding media, lacking high shear force and cavitation effects, both of which significantly influence particle morphology and deagglomeration.

[0017] Preferably, in step (1), the pH of the excipient solution is 5-6; and in step (3), the shearing temperature is 2-65℃.

[0018] During experiments, our team unexpectedly discovered that the particle size reduction of drug particles during preparation is significantly affected by pH and shear temperature. Common knowledge suggests that a pre-suspension pH of 7-9 is more favorable for preparation, as suspending agents such as sodium carboxymethyl cellulose exhibit maximum viscosity and stability within this pH range. However, our research data shows that when preparing aripiprazole formulations using a stator-rotor high-shear process, significant particle agglomeration occurs when the feed solution temperature is ≥45℃ and the pre-suspension pH is ≥7. The feed solution exhibits thermal instability, limiting particle size reduction and preventing ideal shearing to the target particle size. This is attributed to two factors: firstly, higher temperatures increase the probability of particle collisions; secondly, the viscosity of the suspending agent decreases with increasing temperature, reducing steric hindrance and hindering particle stability. Only when the pre-suspension pH is adjusted to the range of 5-6, even at feed solution temperatures as high as 65℃ or as low as 2℃ or 25℃ during preparation, agglomeration is less likely to occur, allowing for ideal particle size reduction to the target size. At this temperature, the feed solution exhibits significant stability. The invention team investigated and found that, at 65°C, a slight decrease in pH value, compared to when the pre-suspension pH ≥ 7, inhibits carboxyl group dissociation, reduces the negative charge on the molecular surface, decreases the charge density on the polymer chains, causes long chains to entangle, and increases apparent viscosity. Shearing at lower temperatures (2-25°C) helps the suspending agent maintain its solution viscosity, and shearing also promotes uniform mixing of the solution, which is also beneficial for particle dispersion and stability. However, the pH value cannot be too low, as sodium carboxymethyl cellulose is prone to precipitation at such low temperatures. Therefore, this invention allows for obtaining samples with the target particle size within a preparation temperature range of 2-65°C when preparing the subsuspension.

[0019] Preferably, in step (3), the shearing temperature is 45-65℃.

[0020] Based on extensive research and experimentation by the team, when the feed solution is prepared at low temperatures within the scope of this invention (i.e., 2-45℃) to the target particle size, the large particles are blocky, with a relatively large number of small particles. The particle size distribution is slightly narrower than in existing technologies, and the particle edges are sharper, showing a slight improvement compared to the ball milling method which produces particles with more sharp edges. However, when the feed solution is prepared at higher temperatures within the scope of this invention (i.e., 45-65℃) to the target particle size, the resulting particle morphology changes more significantly, becoming mostly blocky with smooth surfaces, fewer small particles, and a narrow particle size distribution. Based on this, the research team found that increasing the temperature significantly increases the Ostwald ripening phenomenon (i.e., the saturated solubility of particles in the dispersion system varies with particle size; small particles gradually dissolve, while large particles gradually grow). Therefore, the sharper edges of aripiprazole particles result in higher solubility and surface energy, making them more easily dissolved and agglomerated onto the surface of larger particles under high-temperature shear. Simultaneously, the proportion of small particles in the liquid system significantly decreases, and the particle size of large particles tends to increase to a higher value within the target particle size range. This ideally controls the narrow particle size distribution in the pharmaceutical composition of this invention and significantly reduces burst release caused by small particles. Compared to low-temperature shear, this method is more conducive to improving particle morphology and exhibiting a more stable sustained-release effect. Therefore, this invention is prepared within a temperature range of 45-65℃, which not only yields ideal particle morphology and particle size distribution but also inhibits particle aggregation caused by high temperature through pH adjustment in step (1).

[0021] Preferably, in step (3), the equipment is a continuous high-shear emulsifying disperser, a colloid mill shearing machine, or a cone mill shearing machine.

[0022] Preferably, in step (1), the concentration of the suspending agent in the excipient solution is 0.15-1.3 wt%, and the concentration of the lyophilization protectant is 0.75-6.6 wt%. More preferably, the concentration of the suspending agent is 0.4-1 wt%, and the concentration of the lyophilization protectant is 2-5 wt%.

[0023] Using suspending agents of the above concentrations provides excellent suspending properties, and lower viscosity is preferable, which is beneficial for the preparation and filling of injections. Using lyophilization protectants of the above concentrations also helps to obtain lyophilized products with good appearance; after reconstitution, the suspended particles are uniformly dispersed and exhibit good stability.

[0024] Preferably, in step (2), the concentration of aripiprazole drug particles in the pre-suspension is 5-30 wt%. More preferably, it is 13-25 wt%.

[0025] According to common knowledge in the art, if the drug concentration is too low, the dosage volume needs to be increased accordingly; if the drug concentration is too high, although the dosage volume is small, there are problems such as excessive viscosity, which is not conducive to injection. Within the preferred drug concentration range of this invention, it is beneficial for both particle size control during the process and clinical administration.

[0026] Preferably, in step (2), the average particle size D50 of the aripiprazole drug particles is 10-500 μm.

[0027] As mentioned above, unlike ball milling, the initial particle size of the material in this invention does not significantly affect the final target particle size, ensuring consistency across different batches. Therefore, this invention is applicable to a very wide range of aripiprazole particle size processing, requiring no pretreatment steps.

[0028] Preferably, the suspending agent is selected from one or more of methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose or their sodium salts, gelatin, polyvinylpyrrolidone and gum arabic.

[0029] Preferably, the freeze-drying protectant is selected from at least one of lactose, mannitol, glycine, and sucrose.

[0030] Preferably, the acidity regulator is selected from at least one of sodium dihydrogen phosphate monohydrate, acetic acid, citric acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid, and phosphoric acid.

[0031] Preferably, the pH adjuster is selected from at least one of sodium hydroxide, disodium hydrogen phosphate, calcium carbonate, and magnesium hydroxide.

[0032] The aripiprazole drug particles are one or more mixtures of anhydrous aripiprazole and aripiprazole solvates.

[0033] Optionally, the method of the present invention further includes step (5): freeze-drying the final suspension to obtain a freeze-dried formulation.

[0034] The present invention may further include freeze-drying the final suspension to obtain a lyophilized formulation with the target particle size. The lyophilized formulation can be mixed with sterile water for injection to form a suspension before injection and administration.

[0035] More preferably, in step (5), the freeze-drying includes:

[0036] (5.1) Pre-freezing stage: Cooling at -30℃ to -50℃ under normal pressure;

[0037] (5.2) Sublimation stage: Vacuum drying at below 0°C.

[0038] The final suspension from step (4) is freeze-dried to obtain a lyophilized formulation with an average particle size of 3-6 μm, showing no significant change in particle size before and after freeze-drying. Therefore, the suspensions prepared using this invention exhibit ideal dispersibility at each stage, effectively inhibiting the aggregation of aripiprazole particles. After reconstitution and injection of the lyophilized formulation, aripiprazole can be continuously released for at least 4 weeks or longer. The drug can be administered via intramuscular or subcutaneous injection, preferably intramuscular.

[0039] Compared with the prior art, the beneficial effects of the present invention are:

[0040] (1) This invention is the first to use a stator-rotor shearing process with specific process parameters to prepare aripiprazole formulation to the target particle size. This process is simple to operate, has low equipment production cost, and is easy to scale up from the laboratory to production.

[0041] (2) Compared with the high-pressure homogenization method, the method of the present invention does not have the problem of possible blockage of large drug particles because the rotor is in continuous high-speed rotation; compared with the ball milling method, the method of the present invention does not have the problem of large drug particles not being fully ground, and does not have the problem of media contamination.

[0042] (3) The method of the present invention can effectively avoid the phenomenon of small particle agglomeration. The wide particle size distribution at low temperature still has significantly improved dispersibility, effectively inhibits the agglomeration of small particles, and the target particle size of the final product is controllable. It has a more ideal drug release than ball milling.

[0043] (4) Through this invention, the particle morphology can be significantly changed at higher temperatures, resulting in a more excellent stable sustained-release blood drug concentration curve, which is beneficial to further reduce the occurrence of adverse reactions of the final product.

[0044] (5) When this invention is used in the preparation of higher concentration formulations, the improved dispersibility helps to reduce the amount of suspension used, save costs, and improve product safety. Attached Figure Description

[0045] Figure 1 This is a scanning electron microscope image of the active pharmaceutical ingredient;

[0046] Figure 2 Scanning electron microscope (SEM) image of a sample prepared by ball milling;

[0047] Figure 3 This is a scanning electron microscope image of a sample prepared at low temperature according to the present invention;

[0048] Figure 4 Scanning electron microscope image of a sample prepared at a higher temperature according to the present invention;

[0049] Figure 5 This is a graph showing the blood drug release concentration in rats. Detailed Implementation

[0050] The present invention will be further described below with reference to embodiments.

[0051] General Implementation Examples

[0052] A method for preparing a circular block-shaped aripiprazole injection formulation based on stator-rotor shearing includes the following steps:

[0053] (1) Preparation of excipient solution: Dissolve the suspending agent, freeze-drying protectant and acidity regulator in water to obtain a weakly acidic (preferably pH=5-6) excipient solution; the concentration of the suspending agent is 0.15-1.3wt% (preferably 0.4-1wt%) and the concentration of the freeze-drying protectant is 0.75-6.6wt% (preferably 2-5wt%).

[0054] Preferably, the suspending agent is selected from one or more of methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose or their sodium salts, gelatin, polyvinylpyrrolidone and gum arabic; the freeze-drying protectant is selected from at least one of lactose, mannitol, glycine and sucrose; and the acidity regulator is selected from at least one of sodium dihydrogen phosphate monohydrate, acetic acid, citric acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid and phosphoric acid.

[0055] (2) Disperse aripiprazole drug particles with an average particle size D50 of 10-500 μm in an excipient solution to form a pre-suspension with a concentration of 5-30 wt% (preferably 13-25 wt%).

[0056] Preferably, the aripiprazole drug particles are one or more mixtures of anhydrous aripiprazole and aripiprazole solvate.

[0057] (3) The principle is to use equipment that generates high shear force due to the high relative high speed motion between the stator and rotor (preferably a continuous high-shear emulsifying disperser, colloid mill shearing machine, or cone mill shearing machine), adjust the rotor linear velocity of the equipment to 35-70 m / s, the stator-rotor spacing to 100-500 μm, and the shear coefficient ≥1.4×10 5 s -1 The pre-suspension is sheared to the target average particle size (preferably D50=3-6μm) at a shear temperature of 2-65℃ (preferably 45-65℃) to obtain a subsuspension.

[0058] (4) Adjust the pH of the secondary suspension to 6.5-7.5 with a pH adjuster to obtain the final suspension.

[0059] Preferably, the pH adjuster is selected from at least one of sodium hydroxide, disodium hydrogen phosphate, calcium carbonate, and magnesium hydroxide.

[0060] (5.1) Pre-freezing stage: Cool the final suspension at -30℃ to -50℃ and at normal pressure;

[0061] (5.2) Sublimation stage: Vacuum drying at below 0°C to obtain lyophilized formulation.

[0062] Specific embodiments and comparative examples

[0063] Example 1: Preparation of aripiprazole monohydrate suspensions at different concentrations

[0064] The prescription is shown in the table below:

[0065]

[0066] The preparation process is as follows:

[0067] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0068] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 245 μm) in the solution in (1) to form a premixed suspension;

[0069] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000) at a linear speed of 35 m / s, a stator-rotor spacing of 100 μm, and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at 48°C by a jacket water bath to obtain the secondary suspension.

[0070] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0071] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The results are shown in the table below.

[0072]

[0073] According to the particle size distribution results, aripiprazole monohydrate suspensions with concentrations of 6wt%, 18wt%, and 30wt% can be obtained as suspensions with a D50 between 3 and 6 μm after high shearing.

[0074] Example 2: Preparation of aripiprazole monohydrate suspension using different stator and rotor types

[0075] The prescription is shown in the table below:

[0076]

[0077] The preparation process is as follows:

[0078] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0079] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 245 μm) in the solution in (1) to form a premixed suspension;

[0080] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000), an IKA production shearing machine (cone mill shearing head, model MKO2000), and an IKA production shearing machine (three-layer stator and rotor shearing head <6F,8SF,8SF>, model DR) at a linear speed of 35 m / s, a stator and rotor spacing of 100 μm (except for model DR where the stator and rotor spacing is 200 μm), and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at 48℃ by a jacketed water bath to obtain a secondary suspension. The above three different stator and rotor types correspond to the following samples 01, 02, and 03, respectively.

[0081] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0082] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The results are shown in the table below.

[0083]

[0084] According to the particle size distribution results, using three different stators and rotors of the IKA production shearing machine, a suspension with a D50 between 3 and 6 μm can be obtained.

[0085] Example 3: Preparation of aripiprazole monohydrate suspension using different linear velocities

[0086] The prescription is shown in the table below:

[0087]

[0088] The preparation process is as follows:

[0089] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0090] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 245 μm) in the solution in (1) to form a premixed suspension;

[0091] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes at a stator and rotor spacing of 100 μm (IKA production shearing machine, colloid mill shearing head, model MK2000) with a linear velocity of 35 m / s and a flow rate of 4.5 L / min; and at a stator and rotor spacing of 500 μm (Quadro HVO high shearing machine) with a linear velocity of 70 m / s and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at about 48℃ by a jacket water bath to obtain a secondary suspension; the above two different linear velocities correspond to samples 01 and 02, respectively.

[0092] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0093] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer, and the particle size distribution of commercially available Abilify Maintena™ was also determined using the same method. The results are shown in the table below.

[0094]

[0095] According to the particle size distribution results, both of the above two high-shear mills with different linear velocities can produce suspensions with D50 between 3 and 6 μm, which is basically consistent with the D50 particle size of commercially available Abilify Maintena™.

[0096] Example 4: Preparation of aripiprazole monohydrate suspension using a high-shear mill with different stator-rotor spacings

[0097] The prescription is shown in the table below:

[0098]

[0099] The preparation process is as follows:

[0100] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0101] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 245 μm) in the solution in (1) to form a premixed suspension;

[0102] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000) at a linear speed of 35 m / s, with the stator and rotor spacing being 120 μm and 100 μm respectively, and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at around 48℃ by a jacket water bath to obtain a secondary suspension. The above two different stator and rotor spacings correspond to samples 01 and 02 respectively.

[0103] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0104] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The results are shown in the table below.

[0105]

[0106] According to the particle size distribution results, both of the above two high-shear mills with different stator-rotor spacings can obtain suspensions with D50 between 3-6μm.

[0107] Example 5: Preparation of aripiprazole monohydrate suspensions with APIs of different initial particle sizes

[0108] The prescription is shown in the table below:

[0109]

[0110] The preparation process is as follows:

[0111] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0112] (2) Aripiprazole monohydrates prepared by different crystallization processes and with different initial particle sizes were dispersed in the solution in (1) while stirring to form a premixed suspension. The average particle size D50 of the two aripiprazole monohydrates with different initial particle sizes were 12.6 μm and 446 μm, respectively. The above two initial particle sizes correspond to samples 01 and 02, respectively.

[0113] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000) at a linear speed of 35 m / s, a stator-rotor spacing of 100 μm, and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at around 48°C by a jacket water bath to obtain the secondary suspension.

[0114] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0115] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The results are shown in the table below.

[0116]

[0117] According to the particle size distribution results, both aripiprazole monohydrates with different initial particle sizes can be used to obtain suspensions with a D50 between 3 and 6 μm.

[0118] Example 6: Preparation of aripiprazole monohydrate suspension by fractional shearing and cyclic shearing

[0119] The prescription is shown in the table below:

[0120]

[0121] The preparation process is as follows:

[0122] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0123] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 178 μm) in the solution in (1) to form a premixed suspension;

[0124] (3) The above premixed suspension was sheared in stages using a Quadro HVO high shear machine with a linear velocity of 70 m / s, a stator-rotor spacing of 500 μm, and a flow rate of 4.5 L / min. The same process parameters were then used for continuous cyclic shearing for at least 60 min. During the shearing process, the material temperature was controlled at 30 °C by a jacketed water bath to obtain a secondary suspension. The above two different treatment methods correspond to samples 01 and 02, respectively.

[0125] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0126] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The results are shown in the table below.

[0127]

[0128] The particle size distribution results show that a suspension with a D50 between 3 and 6 μm can be obtained by using either cyclic shearing or multi-stage shearing. Therefore, when production capacity increases, parallel or series connection of stator and rotor shearing equipment can also be used.

[0129] Example 7: Preparation of aripiprazole monohydrate suspension at different material temperatures

[0130] The prescription is shown in the table below:

[0131]

[0132] The preparation process is as follows:

[0133] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to the range of 5-6;

[0134] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 228 μm) in the solution in (1) to form a premixed suspension;

[0135] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000) at a linear speed of 35 m / s, a stator-rotor spacing of 100 μm, and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at 48℃, 55℃, 65℃, 30℃, and 2℃ respectively through a jacketed water bath to obtain the secondary suspension. The above three different material temperatures correspond to samples 01, 02, 03, 04, and 05 respectively.

[0136] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0137] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The results are shown in the table below.

[0138]

[0139] The particle size distribution results show that suspensions with a D50 of 3-6 μm and a narrow particle size distribution can be prepared within a material-liquid temperature range of 2-65℃. Increasing the temperature within this range tends to result in an even narrower particle size distribution. Theoretically, higher material temperatures lead to easier aggregation of small particles and make particle size reduction more difficult. However, the results of this invention indicate that the target particle size can be achieved within the pH range of 5-6. At higher temperatures, the shearing exhibits a narrow particle size distribution, indicating a very small proportion of small particles, effectively preventing aggregation. At lower temperatures, a relatively wider particle size distribution is observed, indicating the presence of a relatively larger proportion of small particles.

[0140] (5) The cut sample 04 in this embodiment was filled into a 10mL vial with a filling volume of 3.8mL, and then freeze-dried according to the following freeze-drying process.

[0141]

[0142] After mixing the lyophilized product with sterile water for injection to prepare a suspension, the particle size of the reconstituted sample was found to be basically the same as that before lyophilization, with a D50 of 3.75 μm. The relatively large proportion of small particles was obtained under lower temperature conditions, and the material still had ideal dispersibility, effectively inhibiting the aggregation of small particles and ensuring that the particle size of the sample remained consistent before and after lyophilization.

[0143] Example 8: Preparation of aripiprazole monohydrate suspensions with different concentrations of sodium carboxymethyl cellulose

[0144] The prescription is shown in the table below:

[0145]

[0146] The preparation process is as follows:

[0147] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0148] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 245 μm) in the solution in (1) to form a premixed suspension;

[0149] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000) at a linear speed of 35 m / s, a stator-rotor spacing of 100 μm, and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at around 48 °C by a jacketed water bath to obtain a secondary suspension. The above two different sodium carboxymethyl cellulose concentrations correspond to samples 01 and 02, respectively.

[0150] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0151] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The results are shown in the table below.

[0152]

[0153] The particle size distribution results show that sodium carboxymethyl cellulose concentrations (as a percentage of the pre-suspension) of 0.24 wt% and 1.2 wt% both yield suspensions with a D50 between 3 and 6 μm. Therefore, when preparing high-concentration aripiprazole monohydrate suspensions, the method of this invention can achieve the target particle size even with reduced suspending agent dosage. This helps reduce the viscosity of the final product, facilitating clinical use.

[0154] Example 9: Preparation of aripiprazole monohydrate suspension at pH 5 of excipient solution

[0155] The prescription is shown in the table below:

[0156]

[0157] The preparation process is as follows:

[0158] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and appropriate amount of phosphoric acid in water to adjust the pH to 5;

[0159] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 228 μm) in the solution in (1) to form a premixed suspension;

[0160] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 60 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000) at a linear speed of 35 m / s, a stator-rotor spacing of 100 μm, and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at around 65°C by a jacket water bath to obtain the secondary suspension.

[0161] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0162] (5) The particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer, and the D50 was 4.21 μm.

[0163] According to the particle size distribution results, a suspension with D50 between 3 and 6 μm can be prepared when the pH of the excipient solution is 5.

[0164] Comparative Example 1: Preparation of aripiprazole monohydrate suspension by ball milling

[0165] The prescription is shown in the table below:

[0166]

[0167] The preparation process is as follows:

[0168] (1) Dissolve the prescribed amounts of sodium carboxymethyl cellulose, mannitol, and sodium dihydrogen phosphate monohydrate in water, and add an appropriate amount of sodium hydroxide to adjust the pH to about 7;

[0169] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 228 μm) in the solution in (1) to form a premixed suspension;

[0170] (3) Grind the above premixed suspension using a ball mill. The diameter of the grinding media is 0.5 mm, the screen aperture is 0.2 mm, the grinding speed is 1100 rpm, and the grinding is carried out for at least 60 minutes. The material temperature is controlled within the range of 2-30℃ by a jacketed water bath.

[0171] (4) The particle size distribution of the grinding suspension was determined using a Malvern MS3000 laser particle size analyzer. The D50 was 3.78 μm, which is similar to the particle size of sample 04 in Example 7.

[0172] (5) According to the freeze-drying process parameters in Example 7, Comparative Example 1 was freeze-dried. Similarly, the freeze-dried product was mixed with sterile water for injection to prepare a suspension. The particle size of the sample after reconstitution was found to be lower than that before freeze-drying, with D50 being 3.11 μm.

[0173] The particle size changes of the samples in Comparative Example 1 and Example 7-04 before and after freeze-drying are shown in the table below:

[0174]

[0175] Based on the particle size results before and after freeze-drying, it can be seen that the particle size of the sample prepared by ball milling in Comparative Example 1 decreased significantly after freeze-drying. The higher temperature preparation of this invention resulted in a narrower particle size fraction with fewer small particles, while the lower temperature preparation resulted in a relatively higher proportion of small particles. Therefore, Examples 7-04 were selected for comparison. The sample prepared by the high shear method showed no significant difference in particle size before and after freeze-drying. It is speculated that Comparative Example 1 may have produced more small particles after grinding. Because small particles have higher surface energy, some small particles agglomerate. During freeze-drying, these agglomerated particles disperse, resulting in a large difference in particle size before and after freeze-drying. Therefore, existing grinding techniques often require further deagglomeration methods such as stirring, shearing, or ultrasound. This invention reduces the particle size to the target size by subjecting the liquid to shearing, centrifugal compression, impact, turbulence, and strong friction within the stator-rotor spacing, while effectively inhibiting the agglomeration of small particles. After processing, it can be directly freeze-dried. The D50 is basically the same before and after freeze-drying, which is beneficial for controlling the actual particle size of the final product.

[0176] Comparative Example 2: Preparation of high-concentration aripiprazole monohydrate suspension by ball milling

[0177] The prescription is shown in the table below:

[0178]

[0179] The preparation process is as follows:

[0180] (1) Dissolve the prescribed amounts of sodium carboxymethyl cellulose, mannitol, and sodium dihydrogen phosphate monohydrate in water, and add an appropriate amount of sodium hydroxide to adjust the pH to about 7;

[0181] (2) While stirring, disperse aripiprazole monohydrate (average particle size D50 is about 228 μm) in the solution in (1) to form a premixed suspension;

[0182] (3) The above premixed suspension was ground using a ball mill with a grinding media diameter of 0.5 mm, a screen aperture of 0.2 mm, and a grinding speed of 1100 rpm. The grinding temperature was controlled below 30°C by a jacketed water bath. Severe blockage was found in the early stage of grinding, which would lead to excessive pressure in the grinding chamber, causing the grinder to alarm and stop. Therefore, when using the ball milling method to prepare the high-concentration aripiprazole monohydrate suspension in cases 01 and 02, due to the high proportion of large solid particles in the premixed suspension, a large number of large drug particles tend to be intercepted by the screen in the grinding chamber in the early stage of grinding, which poses a risk of screen blockage and failure to grind smoothly. However, when using the high-shear method to prepare the high-concentration aripiprazole monohydrate suspension, the high shear effect generated by the continuous high-speed relative motion between the stator and rotor reduces the size of the large drug particles, so there is no risk of blockage in actual operation.

[0183] Comparative Example 3: Preparation of aripiprazole monohydrate suspension by high shear method at low linear velocity

[0184] The prescription is shown in the table below:

[0185]

[0186] The preparation process is as follows:

[0187] (1) Dissolve the prescribed amount of sodium carboxymethyl cellulose, mannitol, and an appropriate amount of sodium dihydrogen phosphate monohydrate in water to adjust the pH to 6;

[0188] (2) While stirring, disperse the prescribed amount of aripiprazole monohydrate (average particle size D50 is about 228 μm) in the solution in (1) to form a premixed suspension;

[0189] (3) The above premixed suspension was subjected to continuous cyclic shearing for at least 120 minutes using an IKA production shearing machine (colloid mill shearing head, model MK2000). Sample 1 was subjected to a linear velocity of 12 m / s, a stator-rotor spacing of 100 μm, and a flow rate of 4.5 L / min. Sample 2 was subjected to a linear velocity of 24 m / s, a stator-rotor spacing of 200 μm, and a flow rate of 4.5 L / min. During the shearing process, the material temperature was controlled at around 48 °C by a jacket water bath to obtain the secondary suspension.

[0190] (4) Add an appropriate amount of sodium hydroxide to adjust the pH of the secondary suspension in (3) to about 7 to obtain the final suspension;

[0191] (5) The average particle size distribution of the final suspension was determined using a Malvern MS3000 laser particle size analyzer. The D50 of sample 1 was 7.21 μm and the D50 of sample 2 was 7.30 μm.

[0192] During the preparation of Comparative Example 3, it was found that, according to Sample 1, when the linear velocity of the high shear machine was 12 m / s, even if the shear coefficient according to the present invention was adjusted to the minimum stator-rotor spacing, the particle size could not be reduced to below 6 μm by extending the shearing time. According to Sample 2, even if the shearing preparation was carried out with a suitable linear velocity and stator-rotor spacing, it did not fall within the range of the shear coefficient of the present invention, and even if the shearing time was extended, the particle size could not be reduced to below 6 μm.

[0193] Therefore, in order to obtain the sample with the target particle size of the present invention, the requirements for stator-rotor shearing preparation must all be within the scope of the present invention, including linear velocity, stator-rotor spacing and shearing coefficient, and none of the three can be omitted.

[0194] In vitro release:

[0195] The in vitro release rates of samples from Comparative Example 1 and Samples 01 and 04 from Example 7 were determined using a Tianjin Tianfa RC8MD dissolution analyzer. The results are shown in the table below.

[0196]

[0197] According to the in vitro release results, the high-shear low-temperature method showed a slight improvement in release compared to the ball milling method, while the in vitro release of samples prepared at high temperature was significantly smoother.

[0198] Surface morphology characterization:

[0199] Comparative Example 1 ( Figure 2 ) and 01 in Example 7 Figure 3 ), 04 ( Figure 4 ) samples, and active pharmaceutical ingredients (APIs) Figure 1 The sample was characterized using scanning electron microscopy. The results are as follows: Figure 1-4 As shown.

[0200] Electron microscopy images revealed that the particles obtained by ball milling retained the morphology of the active pharmaceutical ingredient (API), with numerous sharp points and most particles exhibiting a planar, plate-like structure after grinding, making them prone to agglomeration and adhesion between small particles. However, the particle morphology of sample 04, obtained using this invention, was slightly altered compared to Comparative Example 1, with a slightly smoother surface, particularly noticeable in larger particles. Combined with the consistent particle size before and after freeze-drying of samples 7-04 in Comparative Example 1, sample 04 showed improved dispersibility. Sample 01 significantly altered the aripiprazole crystal particle morphology, differing from the original API morphology. The high-shear method resulted in particles that were mostly blocky with smooth surfaces. In vitro release results showed that altering the particle morphology was more conducive to the gradual release of the drug. This is presumably due to the different shearing principle of this invention, resulting in different forces acting on the particles. Ball milling primarily reduces particle size through collisions between the particles and the grinding media, lacking the high shear force and cavitation effect, both of which significantly influence particle morphology and deagglomeration.

[0201] Released in rats:

[0202] Samples from Comparative Example 1, Samples 02 and 03 from Example 1, and Sample 01 from Example 7 were selected and administered aripiprazole via intramuscular injection into the hind limbs of rats at a dose of 50 mg / kg. Blood samples were collected at 1 h, 6 h, 1 d, 2 d, 3 d, 4 d, 5 d, 6 d, 7 d, 8 d, 9 d, 14 d, 21 d, 28 d, 35 d, and 42 d after administration to detect the blood concentration of aripiprazole. The results are as follows: Figure 5 As shown.

[0203] The in vivo release results show that samples 02 and 03 in Example 1 and sample 01 in Example 7, prepared by the high-shear method, all exhibited low Cmax, more stable blood drug concentrations, and were more conducive to reducing the occurrence of adverse reactions.

[0204] according to Figure 5 In this application, the three samples obtained by the ball milling method all showed significantly lower Cmax values ​​than those obtained by the ball milling method in Comparative Example 1, which is beneficial for significantly reducing adverse reactions. The samples prepared by the ball milling method... Figure 2 Electron micrographs and the preparation obtained in this application Figure 4 Electron microscopy images suggest that particles prepared by conventional ball milling methods often exhibit sharp, flaky shapes in multiple areas, which can easily lead to rapid release. In contrast, the particles obtained in this application are relatively smooth, with consistent Cmax, resulting in more controllable and stable release.

[0205] Unless otherwise specified, the raw materials and equipment used in this invention are all commonly used in the field; unless otherwise specified, the methods used in this invention are all conventional methods in the field.

[0206] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, alterations, and equivalent transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A method for preparing a circular block-shaped aripiprazole injection formulation based on stator-rotor shearing, characterized in that... Includes the following steps: (1) Dissolve the suspending agent, lyophilization protectant and acidity regulator in water to obtain a weakly acidic excipient solution with a suspending agent concentration of 0.15-1.3wt% and a lyophilization protectant concentration of 0.75-6.6wt%; the suspending agent is sodium carboxymethyl cellulose; the lyophilization protectant is mannitol; (2) Disperse aripiprazole drug particles in an excipient solution to form a premixed suspension with an aripiprazole drug particle concentration of 5-30 wt%. (3) The principle of the equipment is to generate high shear force due to the high relative high speed motion between the stator and rotor. The rotor linear velocity of the equipment is adjusted to 35-70m / s, the stator-rotor distance is adjusted to 100-500μm, and the shear coefficient is ≥1.4×10 5 s -1 The pre-suspension is sheared to the target average particle size D50 = 3-6 μm to obtain the sub-suspension; (4) Adjust the pH of the secondary suspension to 6.5-7.5 with a pH adjuster to obtain the final suspension.

2. The method as described in claim 1, characterized in that: In step (1), the pH of the excipient solution is 5-6.

3. The method as described in claim 1, characterized in that: In step (3), the shearing temperature is 2-65℃.

4. The method as described in claim 3, characterized in that: In step (3), the shearing temperature is 45-65℃.

5. The method according to any one of claims 1-4, characterized in that: In step (3), the equipment is a continuous high-shear emulsifying disperser, a colloid mill shearing machine, or a cone mill shearing machine.

6. The method as described in claim 1, characterized in that: In step (2), the average particle size D50 of the aripiprazole drug particles is 10-500 μm.

7. The method according to any one of claims 1-4, characterized in that: The acidity regulator is selected from at least one of sodium dihydrogen phosphate monohydrate, acetic acid, citric acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid, malic acid and phosphoric acid; The pH adjuster is selected from at least one of sodium hydroxide, disodium hydrogen phosphate, calcium carbonate, and magnesium hydroxide; Aripiprazole drug particles are one or more mixtures of aripiprazole anhydrous and aripiprazole monohydrate.

8. The method according to any one of claims 1-4, characterized in that: It also includes step (5): freeze-drying the final suspension to obtain a freeze-dried formulation.

9. The method as described in claim 8, characterized in that: In step (5), the freeze-drying includes: (5.1) Pre-freezing stage: Cooling at -30℃ to -50℃ under normal pressure; (5.2) Sublimation stage: Vacuum drying at below 0°C.

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