Method for eliminating foam in a pharmaceutical production process

Abstract

The present application relates to a method for eliminating foam in the production of pharmaceutical preparations. The method can significantly improve the defoaming efficiency by dynamically cycling the pressure in the production vessel between low and high pressure, and is beneficial to improving the particle size control efficiency and ensuring the uniformity of product quality.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to a method for eliminating foam during the production of pharmaceutical preparations. Background Technology

[0002] In the field of pharmaceutical formulation, microcrystalline / nanocrystalline suspensions can solve the drug-likeness problem of poorly soluble drugs and have advantages such as no need for carrier materials, a wide range of adjustable drug concentrations, and a relatively simple preparation process, leading to their increasing importance. Currently, there are more than a dozen injectable microcrystalline / nanocrystalline formulations on the market globally, with many more in clinical or preclinical development stages.

[0003] When preparing microcrystalline / nanocrystalline suspensions, foaming is easily generated during the production process due to the use of wetting agents. This is especially true for suspension formulations where the active ingredients are micron- or nano-sized particles, which also stabilize the foam. Adsorption of active ingredient particles onto the foam reduces the efficiency of grinding or high-pressure homogenization, disrupts the homogeneity of the suspension, and can even affect process smoothness and the stability and uniformity of product quality.

[0004] Foam itself is a thermodynamically unstable system, and it gradually collapses over time due to the interactions of merging, maturation, and drainage. However, this spontaneous foam elimination process is poorly controllable and can take tens of hours or even days, posing a significant risk to the aseptic assurance of the preparation of injectable microcrystalline / nanocrystalline suspensions. Therefore, eliminating the adverse effects of foam is a problem that must be solved in the preparation of microcrystalline / nanocrystalline suspensions. Summary of the Invention

[0005] This application provides a method for eliminating foam during the production of pharmaceutical preparations. By dynamically circulating the pressure in the production container between low and high pressure, the defoaming efficiency is significantly improved, ensuring the smooth progress of steps such as dispersion, particle size control, dilution, and filling. This solves problems such as uneven dispersion, low efficiency in particle size control, and poor uniformity of suspension caused by foam during the preparation of microcrystalline / nanocrystalline suspensions, thus ensuring the stability and uniformity of the final product quality.

[0006] The first aspect of this application provides a method for eliminating foam during the production of pharmaceutical preparations, the method comprising the following steps: controlling the pressure in the production container to dynamically circulate between low pressure and high pressure, with a circulation cycle of not less than 2 times.

[0007] In some implementations, the dynamic cycle refers to controlling the pressure in the production vessel through the following steps:

[0008] Step (1): Adjust the pressure in the production container to a low pressure and maintain the low pressure for a period of time;

[0009] Step (2): Adjust the pressure in the production container to a high pressure and maintain the high pressure for a period of time;

[0010] Step (3): Repeat steps (1) and (2) in sequence.

[0011] In some implementations, one cycle consists of performing steps (1) and (2) above once.

[0012] In some implementations, the pressure in the production container is controlled to dynamically cycle between low and high pressures until the foam is completely eliminated.

[0013] In some implementations, the pressure in the production container is controlled to dynamically cycle between low and high pressures until the foam is largely eliminated.

[0014] Preferably, the pressure in the production container is dynamically circulated automatically by setting a program.

[0015] In some implementations, the cycle number is not less than 2, preferably not less than 10, more preferably not less than 20, and even more preferably not less than 50, for example, 2, 5, 10, 20, 50, 100, 500, 1000, or 2000.

[0016] In some embodiments, the low pressure is below 0.0 MPa, preferably -0.09 MPa to -0.01 MPa, more preferably -0.09 MPa to -0.02 MPa, even more preferably -0.09 MPa to -0.05 MPa, for example -0.09 MPa, -0.07 MPa, -0.05 MPa, -0.03 MPa, -0.02 MPa or -0.01 MPa.

[0017] In some embodiments, the high pressure is 0 MPa to 0.2 MPa, preferably 0.0 MPa to 0.1 MPa, more preferably 0.0 MPa to 0.05 MPa, even more preferably 0.0 MPa to 0.02 MPa, for example 0 MPa, 0.01 MPa, 0.02 MPa, 0.05 MPa, 0.1 MPa or 0.2 MPa.

[0018] In some implementations, the pressure is gauge pressure, also known as indicated pressure, which refers to the pressure measured by a pressure gauge or pressure transmitter. One standard atmosphere is equivalent to 0 MPa. The relationship between gauge pressure and absolute pressure is: Gauge pressure = Absolute pressure - Atmospheres.

[0019] In some embodiments, the low pressure holding time in the cycle is 1s to 5min, preferably 5s to 1min, more preferably 5s to 10s, or even more preferably 1min to 5min, for example 1s, 2s, 3s, 5s, 8s, 10s, 20s, 30s, 40s, 50s, 1min, 2min, 3min, 4min, 5min.

[0020] In some embodiments, the high pressure holding time in the cycle is 1s to 5min, preferably 5s to 1min, more preferably 5s to 20s, and even more preferably 5s to 10s, for example 1s, 2s, 3s, 5s, 8s, 10s, 20s, 30s, 40s, 50s, 1min, 2min, 3min, 4min, and 5min.

[0021] In some embodiments, during the cycle, the liquid medicine in the production container is continuously stirred at a speed of 200 to 700 rpm, preferably 200 to 500 rpm, more preferably 300 to 500 rpm, for example 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm or 700 rpm.

[0022] In some embodiments, during the cycle, the temperature of the liquid medicine in the production container is controlled to be no lower than 15°C, preferably no lower than 25°C, more preferably no lower than 40°C, and even more preferably no lower than 60°C, for example, 15°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or 90°C. During the cycle, the temperature of the liquid medicine should be lower than the boiling point of the dispersion medium at the set pressure.

[0023] In some implementation schemes, the temperature of the liquid medicine in the production container is controlled at 80°C, and the pressure in the production container is dynamically cyclical: -0.02 MPa, held for 5 seconds, then the pressure is adjusted to 0.0 MPa, held for 5 seconds, and this cycle is repeated.

[0024] In some implementation schemes, the temperature of the liquid medicine in the production container is controlled at 60°C, and the pressure in the production container is dynamically cyclical: -0.05 MPa, held for 5 seconds, then the pressure is adjusted to 0.0 MPa, held for 5 seconds, and this cycle is repeated.

[0025] In some implementation schemes, the temperature of the liquid medicine in the production container is controlled at 60°C, and the pressure in the production container is dynamically cyclical: -0.05 MPa, maintained for 10 seconds, then the pressure is adjusted to 0.0 MPa, maintained for 5 seconds, and this cycle is repeated.

[0026] In some implementation schemes, the temperature of the liquid medicine in the production container is controlled at 30°C, and the pressure in the production container is dynamically cyclical: -0.05 MPa, maintained for 20 seconds, then the pressure is adjusted to 0.0 MPa, maintained for 5 seconds, and this cycle is repeated.

[0027] In some implementation schemes, the temperature of the liquid medicine in the production container is controlled at 25°C, and the pressure in the production container is dynamically cyclical: -0.05 MPa, held for 5 seconds, then the pressure is adjusted to 0.0 MPa, held for 5 seconds, and this cycle is repeated.

[0028] In some implementation schemes, the temperature of the liquid medicine in the production container is controlled at 25°C, and the pressure in the production container is dynamically cyclical: -0.09 MPa, maintained for 1 minute, then the pressure is adjusted to 0.0 MPa, maintained for 10 seconds, and this cycle is repeated.

[0029] In some embodiments, the pharmaceutical preparation is a suspension, preferably a microcrystalline suspension or a nanocrystalline suspension.

[0030] In some embodiments, the suspension comprises active substance particles and a dispersion medium, wherein the active substance particles are slightly soluble or insoluble in the dispersion medium.

[0031] In some embodiments, the solubility of the active substance in water is not higher than 1% (w / v, g / mL), preferably not higher than 0.1% (w / v, g / mL), more preferably not higher than 0.01% (w / v, g / mL), including but not limited to antipsychotic compounds, hormonal compounds, anticancer active compounds, cyclooxygenase-2 (COX-2) inhibitors, penicillin compounds, and non-ergot dopamine receptor agonists.

[0032] In some embodiments, the antipsychotic compound is, for example, risperidone and its esters, paliperidone and its esters, aripiprazole and its secondary amino-substituted derivatives, and bripiprazole and its secondary amino-substituted derivatives. Paliperidone esters include, but are not limited to, paliperidone palmitate, and aripiprazole secondary amino-substituted derivatives include, but are not limited to, lauroyl aripiprazole.

[0033] In some embodiments, the hormonal compound is, for example, progesterone, testosterone, hydroxyprogesterone caproate, or triamcinolone acetonide.

[0034] In some embodiments, the anticancer active compound is, for example, paclitaxel, cyclophosphamide, or docetaxel.

[0035] In some implementations, the COX-2 inhibitor is, for example, celecoxib, etoricoxib, rofecoxib, meloxicam, or etoricoxib.

[0036] In some embodiments, the penicillin compound is, for example, benzathine penicillin G or procaine penicillin.

[0037] In some embodiments, the non-ergot dopamine receptor agonist is, for example, pramipexole dihydroxynaphthyl salt.

[0038] In some embodiments, the active substance particles in the suspension are 0.1 to 90% (w / w) of the suspension, preferably 5 to 60% (w / w), more preferably 10 to 50% (w / w), and even more preferably 20 to 40% (w / w).

[0039] In some embodiments, the dispersion medium comprises a wetting agent and a solvent. Optionally, the dispersion medium further comprises one or more of a stabilizer, a pH adjuster, an osmotic pressure adjuster, and a lyophilization protectant.

[0040] In some embodiments, the wetting agent has an HBL value of 4 to 18, preferably 5 to 17, more preferably 7 to 17, and even more preferably 7 to 11.

[0041] In some embodiments, the wetting agent is selected from one or more of ionic surfactants (e.g., ursodeoxycholic acid and its salts, deoxycholic acid and its salts, glycocholic acid and its salts), nonionic surfactants (e.g., Tween 20, Tween 80, Span 20, Span 80, polyethylene glycol (15)-hydroxystearate, lecithin), sodium carboxymethyl cellulose, preferably sodium deoxycholate, Tween 20, Tween 80, polyethylene glycol (15)-hydroxystearate, sodium carboxymethyl cellulose.

[0042] In some embodiments, the mass of the wetting agent is 0.01 to 50% (w / w) of the suspension, preferably 0.1 to 5% (w / w), more preferably 0.5 to 5% (w / w), and even more preferably 1 to 3% (w / w).

[0043] In some embodiments, the solvent is water, or a mixture of water and an organic solvent, preferably water.

[0044] In some embodiments, the organic solvent is selected from ICH Class III organic solvents that are miscible with water, such as ethanol, acetone, and propanol.

[0045] In some embodiments, the proportion of water in the mixed solvent consisting of water and organic solvent is not less than 50% (v / v).

[0046] In some embodiments, the stabilizer is selected from one or more of polyethylene glycols (e.g., polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000), polyvinylpyrrolidones (e.g., PVP K12, PVP K17, PVP K30), and cellulose derivatives (e.g., sodium carboxymethyl cellulose, sodium hydroxypropyl cellulose), preferably one or more of polyethylene glycol 4000, PVP K17, and sodium carboxymethyl cellulose.

[0047] In some embodiments, the stabilizer is 0.1% to 50% (w / w) of the suspension, preferably 0.1% to 10% (w / w), more preferably 0.5% to 5% (w / w), and even more preferably 1% to 2% (w / w).

[0048] In some embodiments, the pH adjuster is selected from one or more of sodium hydroxide, potassium hydroxide, hydrochloric acid, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium bicarbonate, preferably one or more of sodium hydroxide and hydrochloric acid.

[0049] In some embodiments, the pH adjuster is 0% to 1% (w / w) of the suspension, preferably 0% to 0.5% (w / w), and more preferably 0% to 0.1% (w / w).

[0050] In some embodiments, the pH value of the suspension is adjusted to 4-10, preferably 5-9, by the pH adjuster.

[0051] In some embodiments, the osmotic pressure regulator is selected from one or more of sodium chloride, sucrose, glucose, and mannitol, preferably sodium chloride, sucrose, or mannitol.

[0052] In some embodiments, the osmotic pressure regulator is 0.1% to 50% (w / w) of the suspension, preferably 0.5% to 20% (w / w), and more preferably 3% to 15% (w / w).

[0053] In some embodiments, the freeze-drying protectant is selected from one or more of mannitol, sorbitol, trehalose, and lactose, preferably one or more of mannitol and lactose.

[0054] In some embodiments, the lyophilization protectant is 0.1% to 50% (w / w) of the suspension, preferably 1% to 20% (w / w), and more preferably 5% to 20% (w / w).

[0055] In some embodiments, the pharmaceutical formulation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, particle size control, dilution, and filling. Foam is generated by the combined effect of any one or more of these steps. The defoaming method of this application can be used in any step after foam generation.

[0056] In some embodiments, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, particle size control, drug solution delivery, dilution, and filling.

[0057] In some embodiments, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, particle size control, drug solution delivery, defoaming, dilution, and filling.

[0058] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, particle size control, dilution, drug solution delivery, defoaming, and filling.

[0059] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, particle size control, drug solution delivery, defoaming, dilution, drug solution delivery, defoaming, and filling.

[0060] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, particle size control, drug solution delivery, dilution, drug solution delivery, defoaming, and filling.

[0061] In some embodiments, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, particle size control, drug solution delivery, defoaming, dilution, and filling.

[0062] In some implementations, the particle size control step is performed by grinding.

[0063] In some implementations, the particle size control step employs a homogenization method.

[0064] In some implementations, the particle size control step employs a microjets approach.

[0065] In some implementations, the particle size control step employs grinding and homogenization.

[0066] In some implementations, the particle size control step employs grinding and microfluidics.

[0067] In some implementations, the particle size control step may be performed in two ways, with a drug delivery step between the two methods.

[0068] In some implementations, the particle size control step may employ two methods, with a defoaming step potentially interspersed between the two methods.

[0069] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, grinding, drug solution delivery, defoaming, dilution, and filling.

[0070] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, grinding, drug solution delivery, defoaming, dilution, drug solution delivery, defoaming, and filling.

[0071] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, homogenization, drug solution delivery, defoaming, dilution, and filling.

[0072] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, grinding, defoaming, homogenization, drug solution delivery, defoaming, dilution, and filling.

[0073] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, grinding, drug solution delivery, defoaming, homogenization, drug solution delivery, defoaming, dilution, and filling.

[0074] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, microfluidization, drug solution delivery, defoaming, dilution, and filling.

[0075] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, grinding, defoaming, microfluidization, drug solution delivery, defoaming, dilution, and filling.

[0076] In some implementations, the pharmaceutical preparation manufacturing process includes the following steps: raw material dispersion, drug solution delivery, defoaming, grinding, drug solution delivery, defoaming, microfluidization, drug solution delivery, defoaming, dilution, and filling.

[0077] In some embodiments, the grinding media of the grinding method has a size of 0.1mm to 0.6mm, preferably 0.3mm to 0.6mm, more preferably 0.4mm to 0.5mm, for example 0.1mm, 0.2mm, 0.3mm, 0.4mm, 0.5mm, or 0.6mm.

[0078] In some embodiments, the amount of grinding beads used in the grinding method is 50% to 70% of the filling amount of the ball mill cavity, for example, 50% to 60% or 60% to 70%.

[0079] In some embodiments, the linear velocity of the grinding method is 3m / s to 10m / s, preferably 4m / s to 8m / s, more preferably 5m / s to 7m / s, for example 3m / s, 5m / s, 6m / s, 7m / s, 8m / s, 9m / s, 10m / s.

[0080] In some embodiments, the homogenization pressure is 500 bar to 2000 bar, preferably 500 bar to 1500 bar, and more preferably 800 bar to 1200 bar. In some embodiments, the homogenization time is 30 min to 200 min, preferably 30 min to 120 min, and more preferably 60 min to 90 min.

[0081] In some embodiments, the pressure of the microjet method is 500 bar to 2000 bar, preferably 500 bar to 1500 bar, and more preferably 800 bar to 1200 bar. In some embodiments, the number of cycles is 10 to 50, preferably 20 to 30.

[0082] The second aspect of this application provides a method for improving the efficiency of particle size control of active substances in the production of pharmaceutical formulations, the method comprising the following steps: eliminating foam in the pharmaceutical solution using the method described in the first aspect before the particle size control process.

[0083] A third aspect of this application provides a method for improving the uniformity of pharmaceutical preparation content during filling, the method comprising the following steps: eliminating pharmaceutical foam using the method described in the first aspect before the filling process.

[0084] The fourth aspect of this application provides a pharmaceutical formulation with good content uniformity, wherein the method described in the first aspect is used to eliminate foam in the pharmaceutical solution before the filling process of the pharmaceutical formulation production.

[0085] Preferably, the RSD of the content is not higher than 3%. More preferably, the RSD of the content is not higher than 1%. Even more preferably, the RSD of the content is not higher than 0.5%.

[0086] In some embodiments, the pharmaceutical preparation is a suspension, preferably a microcrystalline suspension or a nanocrystalline suspension.

[0087] Definitions and Explanations

[0088] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0089] As used herein, the term “particle size” refers to the size of a particle, which can be measured using conventional particle size measurement techniques and instruments well known to those skilled in the art.

[0090] As used herein, the term "microcrystalline suspension" refers to a pharmaceutical preparation in which the active ingredient is a micron-sized particle. In microcrystalline suspensions, the particle size of the active ingredient is typically 1–300 μm, expressed as Dv50. Dv50 represents the particle size corresponding to the cumulative 50% of particles in the volume distribution, and can be measured using conventional particle size measurement techniques and instruments well known to those skilled in the art, such as a Malvern laser particle size analyzer.

[0091] As used herein, the term "nanocrystalline suspension" refers to a pharmaceutical preparation in which the active ingredient is a nanoscale particle. In nanocrystalline suspensions, the particle size of the active ingredient is typically 10–1000 nm, expressed as Z-Average. Z-Average represents the average particle size measured by the principle of light scattering and can be measured using conventional particle size measurement techniques and instruments well known to those skilled in the art, such as a Malvern nanoparticle size analyzer.

[0092] As used herein, the term "raw material dispersion" refers to the step of dispersing one or more active material particles in a suspension in a dispersion medium.

[0093] As used herein, the term "medicinal liquid transport" refers to the process of transporting medicinal liquid between production containers or equipment using clean gas as the power source at a pressure ≤0.5 MPa during the production process. The gas is selected from air, nitrogen, or other gases that meet cleanliness requirements.

[0094] As used herein, the term "particle size control" refers to the process of reducing the particle size of active materials to a target particle size (micron or nanometer-sized particles) through one or more techniques such as grinding and high-pressure homogenization. This particle size control can be achieved using one or more devices, including but not limited to horizontal ball mills, vertical ball mills, high-pressure homogenizers, and microjets. In some embodiments, these devices can be used in combination.

[0095] As used herein, the term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0096] Unless otherwise specified, the temperature used in this document refers to the temperature of the liquid medicine controlled within ±2°C during the production process.

[0097] All technical features disclosed in this specification, or all steps in all disclosed methods or processes, may be combined in any way, except for mutually exclusive technical features and / or steps.

[0098] Beneficial effects of the present invention

[0099] 1. The foam elimination method provided in this application can significantly improve the defoaming efficiency in the pharmaceutical preparation production process. For example, the foam of microcrystalline suspension can be completely eliminated within 10 minutes, and the foam of nanocrystalline suspension can be completely eliminated within 5 hours.

[0100] 2. The pharmaceutical solution treated by the foam elimination method provided in this application can improve the efficiency of suspension particle size control and ensure the smoothness of the production process.

[0101] 3. The pharmaceutical solution treated by the foam elimination method provided in this application has better uniformity of filling content, which is conducive to ensuring the stability and uniformity of product quality.

[0102] 4. The foam elimination method provided in this application is simple to operate and can be flexibly applied before any step in the production process that requires defoaming. It can be widely used in the pharmaceutical formulation industry. Detailed Implementation

[0103] To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0104] Example 1

[0105] Raw material dispersion: Tween 20 was dissolved in water for injection, sterilized and filtered into a premixing tank. Sterile paliperidone palmitate was added to the premixing tank in an isolator, and sheared at 1200 rpm for 45 min to form a microcrystalline suspension containing 37% (w / w) paliperidone palmitate and 3% (w / w) Tween 20, with a total preparation volume of 10 kg. The sampled particle size was 50.31 μm.

[0106] Drug delivery: The suspension was pumped to the intermediate storage tank using clean air (pressure: 0.2MPa). After the drug transfer was completed, the foam volume was observed to be about 1 / 5 of the drug volume.

[0107] Defoaming: Turn on the agitator at 300 rpm and perform defoaming treatment according to the defoaming method in Table 1. Defoaming is considered complete when there are no bubbles on the surface of the suspension under normal pressure.

[0108] Grinding: The defoamed drug solution was ground under the following conditions: grinding media size: 0.5 mm; grinding media filling volume: 50% of the grinding chamber volume; grinding linear speed: 6 m / s. The particle size change of the suspension was monitored during grinding until the particle size was approximately 1 μm. The results are shown in Table 1.

[0109] Table 1. Defoaming effect of microcrystalline suspension

[0110]

[0111] In Table 1, "defoaming time" refers to the time required for the foam to completely disappear.

[0112] According to the results in Table 1, while low pressure can improve the defoaming rate to some extent without dynamic cyclic pressure control, the foam is difficult to completely eliminate within an acceptable timeframe for pharmaceutical formulation production. Insufficient defoaming necessitates longer grinding of the suspension to achieve a similar particle size, thus affecting grinding efficiency. Dynamic cyclic pressure control can significantly shorten the defoaming time, controlling the defoaming time of the microcrystalline suspension to no more than 10 minutes and the grinding time to no more than 180 minutes. Increasing the suspension temperature or decreasing the low pressure during the circulation cycle can further improve defoaming efficiency.

[0113] Example 2

[0114] Raw material dispersion: Sucrose, sodium deoxycholate, and povidone K17 were dissolved in water for injection and then filtered through a sterile filter into a premixing tank. Sterile celecoxib was added to the premixing tank in an isolator and sheared at 1200 rpm for 30 min to form a microcrystalline suspension containing 20% ​​(w / w) celecoxib, 1% (w / w) sodium deoxycholate, 14% (w / w) sucrose, and 1% (w / w) povidone K17. The total preparation volume was 10 kg.

[0115] Drug delivery: The suspension was pumped to the intermediate storage tank using clean air (pressure: 0.2MPa). After the drug transfer was completed, the foam volume was observed to be about 1 / 5 of the drug volume.

[0116] Defoaming: Turn on the stirrer, stir speed 300 rpm, liquid temperature 60℃±2℃, dynamic circulation pressure control: -0.05MPa for 5s, adjust to 0.0MPa and hold for 5s, repeat the cycle, defoaming for 10 minutes, and observe that defoaming is complete.

[0117] Grinding: Grinding media size: 0.3 mm; grinding media filling volume: 60% of the grinding chamber volume; grinding linear speed: 8 m / s. During grinding, fine bubbles gradually accumulated on the surface of the drug solution. Samples were taken after 4 hours of grinding, and the particle size was 353.0 nm. The volume of the fine foam was approximately 1 / 5 of the drug solution volume.

[0118] Defoaming: Defoaming is performed according to the defoaming method in Table 2. Defoaming is considered complete when there are no bubbles on the surface of the suspension under normal pressure.

[0119] High-pressure homogenization: The defoamed nanocrystalline suspension was subjected to high-pressure homogenization at a pressure of 1000 bar to control the particle size to approximately 250–300 nm. The results are shown in Table 2.

[0120] Table 2. Defoaming effect of nanocrystalline suspension

[0121]

[0122] In Table 2, "defoaming time" refers to the time required for the foam to completely disappear.

[0123] Sample 6 was not completely defoamed before homogenization. During homogenization, the presence of air bubbles in the solution damaged the homogenization valve.

[0124] Based on the investigation results, nanocrystalline suspensions tend to generate fine foam, and the foam stability is significantly stronger than that of microcrystalline suspensions. Low-pressure stirring is more effective at defoaming than atmospheric pressure stirring; however, constant-pressure defoaming cannot effectively defoam within the expected time, posing a certain risk to the aseptic assurance of pharmaceutical manufacturing processes. Foam in the drug solution not only affects the particle size control efficiency of the homogenization process but may also damage homogenization equipment, affecting the smoothness of the production process. Using a dynamic cyclic pressure control defoaming method can significantly improve defoaming efficiency; bubbles in nanocrystalline suspensions can be completely eliminated in 5 hours, with subsequent homogenization steps taking no more than 90 minutes. Reducing the low pressure during the defoaming cycle can further improve defoaming efficiency.

[0125] Example 3

[0126] Drug preparation: Sodium dihydrogen phosphate, sodium hydroxide, mannitol, and sodium carboxymethyl cellulose were dissolved in water for injection, then filtered sterilely into a premixing tank. Sterile aripiprazole was added to the premixing tank in an isolator, and the mixture was sheared at 1200 rpm for 30 min to form a microcrystalline suspension containing 20% ​​(w / w) aripiprazole, 1% (w / w) sodium carboxymethyl cellulose, 4% (w / w) mannitol, 0.1% (w / w) sodium dihydrogen phosphate, and 0.01% (w / w) sodium hydroxide, with a total preparation volume of 10 kg. The particle size measured by sampling was 138.25 μm.

[0127] Drug delivery: The suspension was pumped to the intermediate storage tank using clean air (pressure: 0.2MPa). After the drug transfer was completed, the foam volume was observed to be about 1 / 10 of the drug volume.

[0128] Defoaming: Defoaming was performed at different stirring speeds, with the solution temperature controlled at 60℃±2℃. Dynamic circulating pressure control was used: -0.05MPa held for 10s, adjusted to 0.0MPa held for 5s, and this cycle was repeated. The defoaming was observed; the absence of bubbles on the suspension surface under normal pressure was considered a successful defoaming test. The results are shown in Table 3.

[0129] Table 3. Stirring speed and defoaming effect

[0130]

[0131] According to the results in Table 3, a stirring speed range of 200–700 rpm can meet the defoaming requirements without generating a large amount of new foam. If the speed is less than 200 rpm, it may lead to particle deposition and / or aggregation in the suspension, resulting in uneven content distribution. If the speed is greater than 700 rpm, it will promote the generation of new foam and affect the defoaming effect.

[0132] Example 4

[0133] In Example 2, after high-pressure homogenization, a layer of fine foam was observed floating on the liquid surface of samples 7 and 9 under normal pressure. The volume of the foam was approximately 1 / 10 of the drug liquid volume. Before filling, sample 7 was defoamed, while sample 9 was not defoamed. The effect of defoaming on the uniformity of the filling content was investigated.

[0134] Sample 7: Defoaming and filling: Stirring speed 500 rpm, drug solution temperature 25℃±2℃, dynamic circulating pressure control: -0.09MPa maintained for 1 min, adjusted to 0.0MPa, maintained for 10 s, repeated for cycle, to perform defoaming treatment. After 1 hour of defoaming, no bubbles appeared on the liquid surface under normal pressure, indicating defoaming was complete. The solution was diluted with sterile filtered water for injection, resulting in a celecoxib content of 100 mg / mL. The solution was then filled using an automatic filling machine at a filling specification of 1.0 ml: 100 mg.

[0135] Sample 9 filling: The mixture was stirred at 500 rpm and diluted with sterile filtered water for injection. The diluted solution contained 100 mg / mL of celecoxib. The solution was then filled using an automatic filling machine at a specification of 1.0 ml: 100 mg.

[0136] During the filling process, samples were taken from the same filling needle at the pre-filling, middle-filling, and post-filling stages to test the content, and the RSD values ​​of the content at the pre-filling, middle-filling, and post-filling stages were calculated. The results are shown in Table 4.

[0137] Table 4. Uniformity of Filling Content

[0138]

[0139] According to the results in Table 4, the filling samples treated with defoaming before the dilution and filling steps showed better uniformity of content, indicating smaller batch-to-batch differences and better guarantee of the uniformity of final product quality.

[0140] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A method for eliminating foam during the production of pharmaceutical preparations, characterized in that, The pressure in the production container is controlled to dynamically circulate between low and high pressure, with a cycle of no less than two times.

2. The method according to claim 1, characterized in that, The low pressure is below 0 MPa, preferably -0.09 MPa to -0.01 MPa, more preferably -0.09 MPa to -0.02 MPa, and even more preferably -0.09 MPa to -0.05 MPa.

3. The method according to claim 1 or 2, characterized in that, The high pressure is 0 MPa to 0.2 MPa, preferably 0 MPa to 0.1 MPa, and more preferably 0 MPa to 0.05 MPa.

4. The method according to any one of claims 1-3, characterized in that, During the cycle, the low pressure is maintained for 1 second to 5 minutes, preferably 5 seconds to 1 minute.

5. The method according to any one of claims 1-4, characterized in that, During the cycle, the high pressure is maintained for 1 second to 5 minutes, preferably 5 seconds to 1 minute, and more preferably 5 seconds to 10 seconds.

6. The method according to any one of claims 1-5, characterized in that, During the cycle, the liquid medicine in the production container is continuously stirred at a speed of 200-700 rpm, preferably 200-500 rpm, and more preferably 300-500 rpm.

7. The method according to any one of claims 1-6, characterized in that, During the cycle, the temperature of the liquid medicine in the production container is controlled to be no less than 15°C, preferably no less than 25°C, more preferably no less than 40°C, and even more preferably no less than 60°C.

8. The method according to any one of claims 1-7, characterized in that, The pharmaceutical preparation is a suspension, preferably a microcrystalline suspension or a nanocrystalline suspension.

9. A method for improving the efficiency of particle size control of active substances in pharmaceutical formulation production, characterized in that, Before the particle size control process, the method described in any one of claims 1-8 is used to eliminate chemical foam.

10. A method for improving the uniformity of content in pharmaceutical preparations during filling, characterized in that, Before the filling process, the method described in any one of claims 1-8 is used to eliminate foam in the pharmaceutical solution.

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