CN116444516A - Paliperidone palmitate nanocrystals and preparation method thereof, paliperidone palmitate nanocrystal suspension injection and preparation method thereof - Google Patents

Paliperidone palmitate nanocrystals and preparation method thereof, paliperidone palmitate nanocrystal suspension injection and preparation method thereof Download PDF

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CN116444516A
CN116444516A CN202310279892.2A CN202310279892A CN116444516A CN 116444516 A CN116444516 A CN 116444516A CN 202310279892 A CN202310279892 A CN 202310279892A CN 116444516 A CN116444516 A CN 116444516A
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paliperidone palmitate
carbon dioxide
nanocrystals
crystallization
parts
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肖川
李明丽
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Jining University
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Abstract

The invention provides paliperidone palmitate nanocrystals, a preparation method thereof, paliperidone palmitate nanocrystal suspension injection and a preparation method thereof, and relates to the technical field of drug production. According to the invention, the paliperidone palmitate is dissolved in the organic solvent and then subjected to carbon dioxide supercritical crystallization, the obtained paliperidone palmitate nanocrystals reach nanoscale, the separation speed of the crystals and the organic solvent is high in the crystallization process, a large amount of energy is taken away in the carbon dioxide gasification process, the prepared nanocrystals have no charge accumulation, the surface free energy is low, agglomeration and aggregation among particles are difficult, no stabilizer is required to be additionally added after the paliperidone palmitate nanocrystal suspension injection is prepared, and the production cost of the paliperidone palmitate nanocrystal suspension injection is reduced. In addition, the organic solvent is taken away by carbon dioxide in the crystallization process, no solvent residue exists, and further drying treatment is not needed, so that the problem of solvent residue in the traditional solvent crystallization method is solved, and the phenomenon of agglomeration of paliperidone palmitate nanocrystals in the drying process is avoided.

Description

Paliperidone palmitate nanocrystals and preparation method thereof, paliperidone palmitate nanocrystal suspension injection and preparation method thereof
Technical Field
The invention relates to the technical field of medicine production, in particular to paliperidone palmitate nanocrystals, a preparation method thereof, paliperidone palmitate nanocrystal suspension injection and a preparation method thereof.
Background
Paliperidone palmitate is a second generation novel antipsychotic developed by the Qiangsheng company, can effectively overcome the time lag barrier of other long-acting antipsychotics, and can be used for treating the acute phase and the maintenance phase of schizophrenia at the same time. In addition, paliperidone does not cause the extensive metabolism of liver, and is secreted in a large amount through the kidney without change, and is superior to the olanzapine which is a traditional medicine in the aspects of safety, drug resistance and the like, and meanwhile, metabolic disorder is less, so that the paliperidone has good application prospect.
The paliperidone palmitate is prepared into fine particles, the surface area of the particles is increased, the water solubility is improved, an aqueous suspension preparation suitable for intramuscular injection administration is formed, and the absorption rate and the bioavailability of the medicine are also improved. Two paliperidone palmitate nanocrystalline suspension products are marketed by the western ampelopsis pharmaceutical company in 2009 and 2015, and both products adopt nanocrystalline preparation technology. At present, the preparation technology of paliperidone palmitate nanocrystalline mainly adopts a grinding method and a solvent method.
For example, chinese patents CN106137985A, CN1093762a and CN1160074a disclose that the particle size of paliperidone palmitate is reduced to nano-scale by wet ball milling, thereby increasing the specific surface area and bioavailability of paliperidone palmitate. However, the use of ball milling to prepare the paliperidone palmitate nanocrystalline suspension requires the reliance on ball mill equipment, and the process involves replacement of the milled zirconium beads under aseptic conditions, not only increasing the risk of sterility challenges, but also the use of milled zirconium beads presents a risk of media residue. In addition, the milling process results in a significant increase in the surface energy of the drug particles, and a challenge is how to select appropriate adjuvants/stabilizers to avoid re-agglomeration of the drug particles into a wet milling dispersion process that can successfully obtain nanocrystals.
Compared with the grinding method, the solvent method has the advantages of no special requirements on equipment, low cost and no residues of the grinding zirconium beads. For example, chinese patent CN109400602a discloses the preparation of smaller size drug particles by anti-solvent precipitation, taking advantage of the difference in solubility of paliperidone palmitate in dichloromethane and n-heptane. Foreign patent WO2016199170 discloses that the dissolution of paliperidone palmitate in hot ethanol, and the momentary precipitation of paliperidone palmitate by rapid cooling, makes it possible to obtain nano-sized drug particles. However, the above solvent crystallization methods all use an organic solvent, and require further drying to remove the solvent residue. The drying process inevitably leads to aggregation and agglomeration of the drug particles, and the drug suspension with nano-scale and uniform dispersion cannot be prepared; moreover, the agglomeration of the drug particles during the drying process easily results in the inability of the organic solvents to be removed effectively, and the risk of drug safety is extremely high.
Disclosure of Invention
In view of the above, the invention aims to provide paliperidone palmitate nanocrystals and a preparation method thereof, paliperidone palmitate nanocrystal suspension injection and a preparation method thereof, and the paliperidone palmitate nanocrystals prepared by the invention have no solvent residue and crystal grains do not agglomerate.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of paliperidone palmitate nanocrystals, which comprises the following steps:
and dissolving paliperidone palmitate in an organic solvent, and performing carbon dioxide supercritical crystallization on the paliperidone palmitate solution to obtain paliperidone palmitate nanocrystals.
Preferably, the concentration of the paliperidone palmitate solution is 10-100 g/mL;
the organic solvent comprises one or more of methanol, ethanol and acetone.
Preferably, the supercritical crystallization of carbon dioxide comprises:
introducing carbon dioxide into a crystallization kettle, spraying paliperidone palmitate solution into the crystallization kettle through a nozzle positioned at the top of the crystallization kettle, and performing supercritical carbon dioxide crystallization.
Preferably, the temperature of the crystallization kettle is 35-55 ℃ and the pressure is 10-30 MPa.
Preferably, the temperature of the nozzle is 40-45 ℃.
Preferably, after the paliperidone palmitate solution is stopped from being sprayed, the carbon dioxide is continuously introduced for 30-60 min.
Preferably, the flow rate ratio of the paliperidone palmitate solution to the carbon dioxide is 15-60: 1.
the invention provides paliperidone palmitate nanocrystals prepared by the preparation method in the technical scheme, and the particle size distribution range is as follows: d (D) 10 Is 0.3-0.6 mu m, D 50 Is 0.9-1.4 mu m, D 90 2.0-4.4 μm.
The invention provides paliperidone palmitate nanocrystalline suspension injection, which comprises the following components in parts by mass: 100 parts of paliperidone palmitate nanocrystals, 2.5-3.5 parts of citric acid, 2.5-3.5 parts of disodium hydrogen phosphate, 1.4-1.9 parts of sodium hydroxide, 15-21 parts of polyvinyl alcohol and 1000-1100 parts of water for injection.
The invention also provides a preparation method of the paliperidone palmitate nanocrystalline suspension injection, which comprises the following steps:
mixing citric acid, disodium hydrogen phosphate, sodium hydroxide, polyvinyl alcohol and water for injection to obtain an auxiliary material mixed solution;
and mixing the auxiliary material mixed solution with paliperidone palmitate nanocrystals to obtain paliperidone palmitate nanocrystal suspension injection.
The invention provides a preparation method of paliperidone palmitate nanocrystals, which comprises the following steps: and dissolving paliperidone palmitate in an organic solvent, and performing carbon dioxide supercritical crystallization on the paliperidone palmitate solution to obtain paliperidone palmitate nanocrystals. The invention adopts a carbon dioxide supercritical crystallization mode to prepare the nano paliperidone palmitate crystals, the separation speed of the crystals and the organic solvent is high in the carbon dioxide supercritical crystallization process, a large amount of energy is taken away in the carbon dioxide gasification process, the prepared nanocrystals have no charge accumulation, the free energy of the surfaces is lower, agglomeration and aggregation among the nanocrystal particles are difficult, and the paliperidone palmitate nanocrystals prepared by the invention are used for preparing suspension without adding a stabilizer, so that the production cost of paliperidone palmitate nanocrystal suspension injection is reduced. In addition, the organic solvent is taken away by carbon dioxide in the crystallization process, no solvent residue exists, and further drying treatment is not needed, so that the problem of solvent residue in the traditional solvent crystallization method is solved, and the phenomenon of agglomeration of paliperidone palmitate nanocrystals in the drying process is avoided.
Detailed Description
The invention provides a preparation method of paliperidone palmitate nanocrystals, which comprises the following steps:
and dissolving paliperidone palmitate in an organic solvent, and performing carbon dioxide supercritical crystallization on the paliperidone palmitate solution to obtain paliperidone palmitate nanocrystals.
The raw materials adopted by the invention are all commercial products unless specified.
In the present invention, the organic solvent preferably includes one or more of methanol, ethanol and acetone, more preferably methanol, ethanol or acetone. In the present invention, the concentration of the paliperidone palmitate solution is preferably 10 to 100g/mL, more preferably 20 to 80g/mL, and even more preferably 40 to 60g/mL.
In the present invention, the supercritical carbon dioxide crystallization specifically includes: introducing carbon dioxide into a crystallization kettle, spraying paliperidone palmitate solution into the crystallization kettle through a nozzle positioned at the top of the crystallization kettle, and performing supercritical carbon dioxide crystallization.
In the present invention, the flow rate of the carbon dioxide is preferably 1 to 2L/min, more preferably 1.2 to 1.8L/min, and still more preferably 1.4 to 1.5L/min; according to the invention, before the paliperidone palmitate solution is sprayed, the carbon dioxide is introduced for a period of time not limited, so that the pressure of the crystallization kettle is kept between 10 and 30MPa, and the pressure of the crystallization kettle is more preferably between 15 and 25MPa, and further preferably 20MPa; the temperature of the crystallization vessel is preferably 35 to 55 ℃, more preferably 40 to 50 ℃, and even more preferably 40 ℃.
In the present invention, the temperature of the nozzle is preferably 40 to 45 ℃, more preferably 41 to 44 ℃, and even more preferably 42 to 43 ℃. In the present invention, the flow rate ratio of paliperidone palmitate solution to carbon dioxide is preferably 15 to 60:1, more preferably 20 to 50:1, more preferably 30 to 40:1. in the present invention, the flow rate of the paliperidone palmitate solution is preferably 30 to 60mL/min, more preferably 35 to 55mL/min, and even more preferably 40 to 50mL/min. In the present invention, the continuous carbon dioxide supply time after the paliperidone palmitate solution is stopped from being sprayed is preferably 30 to 60 minutes, more preferably 35 to 55 minutes, and even more preferably 40 to 50 minutes.
The supercritical crystallization of the carbon dioxide is completed, and the invention preferably further comprises stopping introducing the carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, and collecting paliperidone palmitate nanocrystals.
The invention provides paliperidone palmitate nanocrystals prepared by the preparation method, wherein the particle size distribution range of the paliperidone palmitate nanocrystals is as follows: d (D) 10 Is 0.3-0.6 mu m, D 50 Is 0.9-1.4 mu m, D 90 2.0-4.4 μm. In the present invention, the paliperidone palmitate nanocrystals D 10 Preferably 0.4 to 0.5 μm, D 50 Preferably 1 to 1.2 μm, D 90 Preferably 3 to 4. Mu.m.
The invention provides paliperidone palmitate nanocrystalline suspension injection, which comprises the following components in parts by mass: 100 parts of paliperidone palmitate nanocrystals, 2.5-3.5 parts of citric acid, 2.5-3.5 parts of disodium hydrogen phosphate, 1.4-1.9 parts of sodium hydroxide, 15-21 parts of polyvinyl alcohol and 1000-1100 parts of water for injection.
The paliperidone palmitate nanocrystalline suspension injection provided by the invention comprises 100 parts of paliperidone palmitate nanocrystalline according to the technical scheme.
The paliperidone palmitate nanocrystalline suspension injection provided by the invention comprises 2.5-3.5 parts of citric acid, preferably 2.8-3.2 parts of citric acid, and more preferably 3 parts of citric acid.
The paliperidone palmitate nanocrystalline suspension injection provided by the invention comprises 2.5-3.5 parts by weight of disodium hydrogen phosphate, preferably 2.8-3.2 parts by weight of paliperidone palmitate nanocrystalline, and more preferably 3 parts by weight of paliperidone palmitate nanocrystalline suspension injection.
The paliperidone palmitate nanocrystalline suspension injection provided by the invention comprises 1.4-1.9 parts of sodium hydroxide, preferably 1.5-1.8 parts of sodium hydroxide, and more preferably 1.6-1.7 parts of paliperidone palmitate nanocrystalline.
The paliperidone palmitate nanocrystalline suspension injection provided by the invention comprises 15-21 parts of polyvinyl alcohol, preferably 16-20 parts, more preferably 17-19 parts, and even more preferably 18 parts by mass of paliperidone palmitate nanocrystalline. In the present invention, the polyvinyl alcohol is preferably polyvinyl alcohol 4000.
The paliperidone palmitate nanocrystalline suspension injection provided by the invention comprises 1000-1100 parts of water for injection, preferably 1020-1080 parts, more preferably 1040-1060 parts, and even more preferably 1050 parts, based on the mass parts of paliperidone palmitate nanocrystals.
The invention also provides a preparation method of the paliperidone palmitate nanocrystalline suspension injection, which comprises the following steps:
mixing citric acid, disodium hydrogen phosphate, sodium hydroxide, polyvinyl alcohol and water for injection to obtain an auxiliary material mixed solution;
and mixing the auxiliary material mixed solution with paliperidone palmitate nanocrystals to obtain paliperidone palmitate nanocrystal suspension injection.
The invention mixes citric acid, disodium hydrogen phosphate, sodium hydroxide, polyvinyl alcohol and water for injection to obtain auxiliary material mixed solution. The mode of the mixing is not particularly limited in the present invention, and the raw materials may be dissolved in water for injection, and specifically, the raw materials may be mixed by stirring.
After the auxiliary material mixed solution is obtained, the auxiliary material mixed solution is mixed with paliperidone palmitate nanocrystals to obtain paliperidone palmitate nanocrystal suspension injection. The mode of the mixing is not particularly limited in the present invention, and the raw materials may be uniformly mixed, and in particular, the raw materials may be mixed by stirring.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Paliperidone palmitate 10g was dissolved in 1000mL of methanol to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 35 ℃ and the temperature of a nozzle to be 40 ℃; introducing carbon dioxide at a flow rate of 1L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 15MPa. Opening a high-pressure metering pump, setting the sampling rate of the paliperidone palmitate methanol solution to be 30mL/min, spraying the paliperidone palmitate solution into the crystallization kettle through a nozzle at the top of the crystallization kettle by the high-pressure metering pump, and after the paliperidone palmitate methanol solution is completely added, closing the high-pressure metering pump, and continuously introducing carbon dioxide for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, collecting and obtaining 8.5g of white paliperidone palmitate nanocrystals, and detecting the granularity distribution of the nanocrystals by a Markov laser granularity meter to be: d (D) 10 0.3μm，D 50 0.9μm，D 90 2.0 μm. The methanol was not detected by gas chromatography.
Example 2
Paliperidone palmitate 10g was dissolved in 100mL of methanol to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 35 ℃ and the temperature of a nozzle to be 40 ℃; introducing carbon dioxide at a flow rate of 1L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 15MPa. Opening a high-pressure metering pump, and setting the methanol solution of paliperidone palmitateAnd the sample rate is 30mL/min, the paliperidone palmitate solution is sprayed into the crystallization kettle through a nozzle at the top of the crystallization kettle by a high-pressure metering pump, and after the paliperidone palmitate methanol solution is completely added, the high-pressure metering pump is closed, and carbon dioxide is continuously introduced for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, collecting and obtaining 8.0g of white paliperidone palmitate nanocrystals, and detecting the particle size distribution by a Markov laser particle sizer: d (D) 10 0.6μm，D 50 1.4μm，D 90 4.4 μm. The methanol was not detected by gas chromatography.
Example 3
Paliperidone palmitate 10g was dissolved in 1000mL of methanol to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 55 ℃ and setting the temperature of a nozzle to be 55 ℃; introducing carbon dioxide at a flow rate of 2L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 30MPa. Opening a high-pressure metering pump, setting the sampling rate of the paliperidone palmitate methanol solution to be 30mL/min, spraying the paliperidone palmitate solution into the crystallization kettle through a nozzle at the top of the crystallization kettle by the high-pressure metering pump, and after the paliperidone palmitate methanol solution is completely added, closing the high-pressure metering pump, and continuously introducing carbon dioxide for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, collecting and obtaining 8.8g of white paliperidone palmitate nanocrystals, and detecting the particle size distribution by a Markov laser particle sizer: d (D) 10 0.5μm，D 50 1.0μm，D 90 3.5 μm. The methanol was not detected by gas chromatography.
Example 4
Paliperidone palmitate 10g was dissolved in 500mL methanol to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 45 ℃ and setting the temperature of a nozzle to be 45 ℃; introducing carbon dioxide at a flow rate of 2L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 20MPa. Opening a high-pressure metering pump, setting the sampling rate of the paliperidone palmitate methanol solution to be 60mL/min, spraying the paliperidone palmitate solution into the crystallization kettle through a nozzle at the top of the crystallization kettle by the high-pressure metering pump, and after the paliperidone palmitate methanol solution is completely addedThe high-pressure metering pump is closed, and carbon dioxide is continuously introduced for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, collecting and obtaining 8.6g of white paliperidone palmitate nanocrystals, and detecting the particle size distribution by a Markov laser particle sizer: d (D) 10 0.4μm，D 50 1.1μm，D 90 3.0 μm. The methanol was not detected by gas chromatography.
Example 5
Paliperidone palmitate 10g was dissolved in 500mL acetone to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 45 ℃ and setting the temperature of a nozzle to be 45 ℃; introducing carbon dioxide at a flow rate of 2L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 20MPa. Opening a high-pressure metering pump, setting the sampling rate of the paliperidone palmitate methanol solution to be 60mL/min, spraying the paliperidone palmitate solution into the crystallization kettle through a nozzle at the top of the crystallization kettle by the high-pressure metering pump, and after the paliperidone palmitate acetone solution is completely added, closing the high-pressure metering pump, and continuously introducing carbon dioxide for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, collecting and obtaining 8.7g of white paliperidone palmitate nanocrystals, and detecting the particle size distribution by a Markov laser particle sizer: d (D) 10 0.4μm，D 50 1.2μm，D 90 3.4 μm. The acetone was not detected by gas chromatography.
Example 6
Paliperidone palmitate 10g was dissolved in 500mL acetone to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 35 ℃ and the temperature of a nozzle to be 40 ℃; introducing carbon dioxide at a flow rate of 2L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 10MPa. Opening a high-pressure metering pump, setting the sampling rate of the paliperidone palmitate methanol solution to be 30mL/min, spraying the paliperidone palmitate solution into the crystallization kettle through a nozzle at the top of the crystallization kettle by the high-pressure metering pump, and after the paliperidone palmitate acetone solution is completely added, closing the high-pressure metering pump, and continuously introducing carbon dioxide for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, and collecting 8.8g of white paliperidine palmitateThe particle size distribution of the methylphenol nanocrystals was measured by a malvern laser particle sizer: d (D) 10 0.3μm，D 50 1.0μm，D 90 2.5 μm. The acetone was not detected by gas chromatography.
Example 7
Paliperidone palmitate 10g was dissolved in 500mL ethanol to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 45 ℃ and setting the temperature of a nozzle to be 45 ℃; introducing carbon dioxide at a flow rate of 1L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 20MPa. Opening a high-pressure metering pump, setting the sampling rate of the paliperidone palmitate methanol solution to be 30mL/min, spraying the paliperidone palmitate solution into the crystallization kettle through a nozzle at the top of the crystallization kettle by the high-pressure metering pump, and after the paliperidone palmitate ethanol solution is completely added, closing the high-pressure metering pump, and continuously introducing carbon dioxide for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, collecting and obtaining 8.7g of white paliperidone palmitate nanocrystals, and detecting the particle size distribution by a Markov laser particle sizer: d (D) 10 0.3μm，D 50 1.0μm，D 90 2.5μm。
Example 8
Paliperidone palmitate 10g was dissolved in 1000mL ethanol to give a paliperidone palmitate solution. Opening a supercritical crystallization device, setting the temperature of a crystallization kettle to be 50 ℃ and setting the temperature of a nozzle to be 50 ℃; introducing carbon dioxide at a flow rate of 2L/min, and regulating a back pressure valve to maintain the pressure of the crystallization kettle at 20MPa. Opening a high-pressure metering pump, setting the sampling rate of the paliperidone palmitate methanol solution to be 60mL/min, spraying the paliperidone palmitate solution into the crystallization kettle through a nozzle at the top of the crystallization kettle by the high-pressure metering pump, and after the paliperidone palmitate ethanol solution is completely added, closing the high-pressure metering pump, and continuously introducing carbon dioxide for 30min. Stopping introducing carbon dioxide, opening an exhaust valve to release pressure to normal pressure, opening a crystallization kettle, collecting and obtaining 8.6g of white paliperidone palmitate nanocrystals, and detecting the particle size distribution by a Markov laser particle sizer: d (D) 10 0.4μm，D 50 1.1μm，D 90 2.9μm。
Example 9
80mL of water for injection is added into a container made of stainless steel, 0.20g of citric acid, 0.20g of disodium hydrogen phosphate, 0.11g of sodium hydroxide and 40001.20g of polyvinyl alcohol are sequentially added, and the mixture is fully stirred and mixed until the mixture is completely dissolved, so as to obtain an auxiliary material mixed solution. 8.0g of paliperidone palmitate nanocrystals prepared in examples 1-8 were added to the above adjuvant mixture and thoroughly mixed, respectively, to obtain 8 uniformly dispersed paliperidone palmitate nanocrystal suspensions. Canning into a syringe to prepare the paliperidone palmitate nanocrystalline suspension injection with the specification of 100 mg/mL.
Example 10
80mL of water for injection is added into a container made of stainless steel, 0.28g of citric acid, 0.28g of disodium hydrogen phosphate, 0.15g of sodium hydroxide and 40001.68g of polyvinyl alcohol are sequentially added, and the mixture is fully stirred and mixed until the mixture is completely dissolved, so as to obtain an auxiliary material mixed solution. 8.0g of paliperidone palmitate nanocrystals prepared in examples 1-8 were added to the above adjuvant mixture and thoroughly mixed, respectively, to obtain 8 uniformly dispersed paliperidone palmitate nanocrystal suspensions. Canning into a syringe to prepare the paliperidone palmitate nanocrystalline suspension injection with the specification of 100 mg/mL.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. A method for preparing paliperidone palmitate nanocrystals, comprising the steps of:
and dissolving paliperidone palmitate in an organic solvent, and performing carbon dioxide supercritical crystallization on the paliperidone palmitate solution to obtain paliperidone palmitate nanocrystals.
2. The method of preparing of claim 1, wherein the paliperidone palmitate solution has a concentration of 10-100 g/mL;
the organic solvent comprises one or more of methanol, ethanol and acetone.
3. The method according to claim 1, wherein the supercritical carbon dioxide crystallization specifically comprises: introducing carbon dioxide into a crystallization kettle, spraying paliperidone palmitate solution into the crystallization kettle through a nozzle positioned at the top of the crystallization kettle, and performing supercritical carbon dioxide crystallization.
4. The process according to claim 3, wherein the crystallization kettle is at a temperature of 35 to 55℃and a pressure of 10 to 30MPa.
5. A method of manufacture according to claim 3, wherein the temperature of the nozzle is 40-45 ℃.
6. The method of claim 3, wherein the continuous carbon dioxide introduction time is 30 to 60 minutes after the paliperidone palmitate solution is stopped being injected.
7. The method of preparing of claim 3 or 6, wherein the flow rate ratio of paliperidone palmitate solution to carbon dioxide is 15 to 60:1.
8. paliperidone palmitate nanocrystals prepared by the preparation method of any one of claims 1 to 7, having a particle size distribution range of: d (D) 10 Is 0.3-0.6 mu m, D 50 Is 0.9-1.4 mu m, D 90 2.0-4.4 μm.
9. The paliperidone palmitate nanocrystalline suspension injection is characterized by comprising the following components in parts by weight: the paliperidone palmitate nanocrystal of claim 8, 100 parts, 2.5-3.5 parts of citric acid, 2.5-3.5 parts of disodium hydrogen phosphate, 1.4-1.9 parts of sodium hydroxide, 15-21 parts of polyvinyl alcohol and 1000-1100 parts of water for injection.
10. The method for preparing paliperidone palmitate nanocrystalline suspension injection as defined in claim 9, comprising the steps of:
mixing citric acid, disodium hydrogen phosphate, sodium hydroxide, polyvinyl alcohol and water for injection to obtain an auxiliary material mixed solution;
and mixing the auxiliary material mixed solution with paliperidone palmitate nanocrystals to obtain paliperidone palmitate nanocrystal suspension injection.
CN202310279892.2A 2023-03-20 2023-03-20 Paliperidone palmitate nanocrystals and preparation method thereof, paliperidone palmitate nanocrystal suspension injection and preparation method thereof Pending CN116444516A (en)

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