A microscale holding device for simulating production conditions

Abstract

The utility model relates to a kind of holding devices of micro analog production condition, including stirring drive system, nested container and temperature control system;The nested container includes outer bottle, material test piece, inner bottle and rotor;The material test piece is made of material directly contacted by solution under simulated production condition, and is arranged in the outer bottle;The inner bottle can be put into outer bottle, and its bottle mouth is lower than the bottle mouth of the outer bottle;The rotor can be put into the inner bottle;The nested container can be set in the water bath kettle of the temperature control system to carry out temperature control;The water bath kettle is set on the stirring drive system, and the rotor can rotate in the inner bottle under the control of the stirring drive system.The utility model reduces sample consumption and avoids pollution risk.

Description

Technical Field

[0001] This utility model relates to a miniature holding device, and more particularly to a miniature holding device that simulates production conditions. Background Technology

[0002] In the field of pharmaceutical formulation industrialization, solid dispersion production typically employs 1L-level stirring and temperature-controlled holding devices, requiring 200-500mL sample volumes, which are unsuitable for small quantities or expensive compounds. Traditional devices suffer from high sample consumption and significant solvent evaporation, and are also unsuitable for probing conditions before actual production. Therefore, a holding device with small volume requirements that can simulate production conditions is needed. Utility Model Content

[0003] To address the aforementioned problems, this utility model provides a device for maintaining micro-simulated production conditions, comprising a stirring drive system, a nested container, and a temperature control system. The nested container includes an outer bottle, a material test piece, an inner bottle, and a rotor. The material test piece is made of materials (all existing materials) that are in direct contact with the solution under the simulated production conditions and is disposed inside the outer bottle. The inner bottle can be placed inside the outer bottle, with its opening lower than the opening of the outer bottle. The rotor can be placed inside the inner bottle. The nested container can be placed in a water bath of the temperature control system for temperature control. The water bath is mounted on the stirring drive system, and the rotor can rotate within the inner bottle under the control of the stirring drive system.

[0004] In some implementations, the outer bottle has a cap.

[0005] In some implementations, the lid has a gasket.

[0006] In some embodiments, the nested container further includes accessories; the accessories include a sealing film for sealing the outer bottle; the accessories also include aluminum foil for wrapping the outer bottle.

[0007] In some implementations, the rotor is a structure with a core of a strong magnetic material (such as a neodymium iron boron magnet) and an outer shell of PTFE (polytetrafluoroethylene).

[0008] In some implementations, the outer bottle has a volume of 80-20 mL, and the inner bottle has a volume of 8-2 mL.

[0009] In some implementations, a gas filling system is also included for filling the outer bottle with an inert gas (e.g., nitrogen).

[0010] In some embodiments, the water bath has holes for inserting the outer bottle. Further, the number of holes is at least one, for example, 2, 4, 5, 6, 7, 8, 9, 10, etc.

[0011] In some implementations, the material test piece is in sheet form and placed at the bottom of the outer bottle, on which the inner bottle can stand upright.

[0012] In some embodiments, the material test specimen is 316L stainless steel; both the outer bottle and the inner bottle are glass bottles. The outer / inner bottle is amber glass or transparent glass.

[0013] The holding device provided by this utility model reduces sample consumption and avoids the risk of contamination, specifically as follows: 1) Can be used for trace samples: Reduces the sample volume required by traditional methods from ≥200 mL to a minimum of 25 mL, reducing material consumption by 87.5%.

[0014] 2) Pollution risk is close to zero: Non-contact drive between PTFE stir bar and 316L stainless steel sheet avoids the introduction of metal / plastic contaminants.

[0015] 3) The evaporation rate of the solution is greatly reduced: The combination of the cap, gasket and sealing film greatly reduces the evaporation rate of the solution inside the outer bottle.

[0016] 4) Simulation of all parameters of key production conditions: synchronous integration of four key parameters: temperature (temperature control accuracy ±0.5℃), shear force (50-2000rpm), 316L metal contact, and inert environment (e.g., nitrogen protection).

[0017] 5) Moving quality control forward: It allows for better prediction of potential production problems during the R&D stage. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the structure of the device for maintaining micro-simulated production conditions in Example 1. Detailed Implementation

[0019] To make the above-mentioned objects, features, and advantages of this utility model more apparent and understandable, the specific embodiments of this utility model will be described in detail below with reference to the accompanying drawings. Many specific details are set forth in the following description to provide a full understanding of this utility model. However, this utility model can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of this utility model. Therefore, this utility model is not limited to the specific embodiments disclosed below.

[0020] In the description of this utility model, it should be understood that if terms such as "center", "longitudinal", "transverse", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", "axial", "radial", "circumferential", etc. appear, these terms indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this utility model and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this utility model.

[0021] In the description of this utility model, the term "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0022] In this utility model, unless otherwise explicitly specified and limited, the terms "installed," "equipped with," "set up," "connected," "joined," "fixed," etc., should be interpreted broadly. For example, "connection" can be a fixed connection, a detachable connection, or an integral part; it can be a direct connection or an indirect connection through an intermediate medium; it can be the internal communication of two components or the interaction between two components, unless otherwise explicitly limited. Those skilled in the art can understand the specific meaning of the above terms in this utility model according to the specific circumstances.

[0023] In this utility model, unless otherwise explicitly specified and limited, the use of descriptions such as "above" or "below" the second feature indicates that the first and second features are in direct contact, or indirect contact via an intermediate medium. Furthermore, "above," "on top of," and "over" the second feature can mean that the first feature is directly above or diagonally above the second feature, or simply that the first feature is at a higher horizontal level than the second feature. Similarly, "below," "below," and "under" the second feature can mean that the first feature is directly below or diagonally below the second feature, or simply that the first feature is at a lower horizontal level than the second feature.

[0024] It should be noted that if an element is referred to as being "fixed to" or "set on" another element, it can be directly on the other element or there may be an intervening element. If an element is considered to be "connected to" another element, it can be directly connected to the other element or there may be an intervening element. If so, the terms "vertical," "horizontal," "upper," "lower," "left," "right," and similar expressions used in this invention are for illustrative purposes only and do not represent the only possible implementation.

[0025] In this article, "and / or" means that both can exist together, or one of them can exist. For example, A and / or B means that it can be A and B, or it can be A, or it can be B.

[0026] Example 1 like Figure 1 As shown, the device for maintaining micro-simulated production conditions includes a stirring drive system 1 (e.g., a magnetic stirrer), a nested container, a temperature control system 11 (e.g., a circulating programmable temperature-controlled water bath device), and an aeration system.

[0027] The nested container includes an outer bottle 4, a material test piece 3, an inner bottle 8, a rotor 9, and accessories. The material test piece 3 is made of materials (all existing materials) that will be in direct contact with the solution under simulated production conditions and is placed inside the outer bottle 4. The outer bottle 4 has a cap 5 with a gasket. The inner bottle 8 can be placed inside the outer bottle 4, with its opening lower than the opening of the outer bottle 4. The rotor 9 can be placed inside the inner bottle 8. The nested container can be placed in a water bath 2 of a temperature control system 11 for temperature control. The water bath 2 is mounted on a stirring drive system 1, and the rotor 9 can rotate within the inner bottle 8 under the control of the stirring drive system 1.

[0028] The accessories include sealing film 6 and aluminum foil 7. Sealing film 6 is used to seal the outer bottle 4; aluminum foil 7 is used to wrap the outer bottle 4. The rotor 9 is a structure with a core of a strong magnetic material (such as neodymium iron boron magnet) and an outer shell of PTFE (polytetrafluoroethylene), abbreviated as PTEE stirrer. The outer bottle 4 has a volume of 40mL, and the inner bottle 8 has a volume of 4mL.

[0029] The filling system is used to fill the outer bottle with an inert gas (such as nitrogen).

[0030] The water bath 2 has holes for inserting the outer bottle 4. The number of holes is at least one, for example, 2, 4, 5, 6, 7, 8, 9, 10, etc.

[0031] The material test piece 3 is in sheet form and is made of 316L stainless steel (i.e., a 316L stainless steel sheet). It is placed at the bottom of the outer bottle 4, and the inner bottle 8 can stand on it. Both the outer bottle 4 and the inner bottle 8 are brown glass bottles or transparent glass bottles.

[0032] A 4 mL inner bottle (containing a PTFE stir bar) is nested inside a 40 mL outer bottle (containing a 316L stainless steel sheet) to maintain a certain liquid level difference to ensure solution exchange, thus physically isolating the PTFE stir bar from the 316L stainless steel sheet.

[0033] An external magnetic stirrer drives the PTFE stir bar inside the bottle (speed adjustable from 50-2000 rpm), which avoids the contamination problems caused by the built-in stirring drive system.

[0034] For the nitrogen-protected sealing system: introduce nitrogen at a certain flow rate for 30 seconds, quickly tighten the cap, and seal with a sealing film, using a double seal of gasket + sealing film.

[0035] Use brown or clear glass bottles, wrapped in aluminum foil to protect them from light.

[0036] Place it in a custom-made 40 mL water bath mold and connect it to a circulating program temperature-controlled water bath device (temperature control accuracy ±0.5℃).

[0037] The specific implementation steps are as follows: 1. Pretreatment: Place a 316L stainless steel sheet in a 40mL outer bottle and a PTFE stir bar of appropriate size in a 4mL inner bottle.

[0038] 2. Assembly: The inner bottle is placed vertically into the outer bottle and placed on a 316L stainless steel sheet.

[0039] 3. Sample addition: Pour the solution of the raw material drug to be tested or the solid dispersion solution into the outer bottle until the liquid level is higher than the mouth of the inner bottle.

[0040] 4. Inerting: Introduce nitrogen gas at a certain flow rate for 30 seconds and then seal.

[0041] 5. Temperature control: Heat the water bath to the target temperature.

[0042] 6. Stirring: Start the magnetic stirrer, and the PTFE stir bar will rotate and stir in the inner bottle.

[0043] 7. Monitoring: Take samples regularly for testing and observe physical stability.

[0044] Example 2 The material test piece is fixed to the bottom inner surface of the outer bottle, and the rest is the same as in Example 1.

[0045] Control Experiment Example 1: Large-volume holding device Experimental steps: Accurately weigh 20 g of API (active pharmaceutical ingredient) into a 2 L glass bottle, add 160 g of MeOH (methanol) and 1070 g of DCM (dichloromethane) as the starting material solution. Transfer 300 mL of the prepared solution to a 500 mL jacketed bottle, add a 1 cm x 1 cm x 0.2 cm stainless steel sheet and a stir bar of appropriate size, purge with nitrogen gas, and quickly stopper the bottle with a glass stopper. Seal the bottle with parafilm, wrap it with aluminum foil to protect it from light, and connect it to a 15°C programmable temperature water bath. Simultaneously stir with a magnetic stirrer at 200 rpm. Take photos of the appearance daily and take samples for analysis at different time points. After each sampling, purge with nitrogen gas again, quickly stopper the bottle, and seal it with parafilm.

[0046] Table 1. Experimental Results As shown in Table 1, the safe maintenance time of the solid dispersion solution is 5 days. No significant physicochemical changes were found within 5 days. Therefore, the time from solution preparation to production must be controlled within 5 days.

[0047] Experimental Example 1: Assessment of Low-Temperature Safety Maintenance Time of Active Pharmaceutical Ingredient Solution Experimental steps: The water bath mold designed for 40 ml glass bottles is connected to a programmable temperature water bath device set to 8℃±1°, and simultaneously stirred at a speed of 150 rpm by a magnetic stirrer.

[0048] Weigh 6 g of API, 81.5 g of DCM, 32.5 g of MeOH, and 1 g of water into a 200 mL glass bottle and mix thoroughly to obtain the initial API solution. Then transfer this solution to separate 40 mL glass bottles (approximately 28 mL of solution per bottle). Next, place a 1 cm x 1 cm x 0.2 cm stainless steel sheet and a 4 mL glass bottle (inner bottle) containing a suitable stirrer into each 40 mL glass bottle (outer bottle). Fill each 40 mL glass bottle with nitrogen gas and quickly cap it. Seal with Parafilm and wrap with aluminum foil to prevent light exposure.

[0049] All samples were then transferred to a water bath mold connected to a programmable temperature-controlled water bath device and stirred at 150 rpm using a magnetic stirrer at 8℃±0.5°C. Samples were taken at different time points, and their appearance was recorded. The samples were then appropriately diluted for high-performance liquid chromatography (HPLC) analysis. After each sampling, nitrogen gas was added to ensure that the remaining samples remained in a nitrogen atmosphere protected from light, and the mixture was stirred at 150 rpm and 8℃±0.5°C.

[0050] Key data verification: Table 2. Experimental Results As shown in Table 2, the safe maintenance time of API solution at 8°C is 1 day, and obvious precipitation was found after 5 days, indicating that low temperature control of production poses a significant risk.

[0051] Experimental Example 2: Assessment of the Safety Maintenance Time of PVP K30 Solid Dispersion Solution The water bath mold designed for 40 ml glass bottles is connected to a programmable temperature water bath device set to 30℃±1°, and simultaneously stirred at a speed of 150 rpm by a magnetic stirrer.

[0052] Weigh 4.2 g of API, 1.8 g of PVP K30 (polyvinylpyrrolidone K30), 67.2 g of DCM, and 26.8 g of MeOH into a 200 mL glass bottle and mix thoroughly to prepare the initial API solution. Then transfer this solution separately into 40 mL glass bottles (approximately 28 mL of solution per bottle). Next, add a 1 cm x 1 cm x 0.2 cm stainless steel sheet and a 4 mL glass bottle containing a suitable stirrer to each 40 mL bottle. Fill each 40 mL bottle with nitrogen gas and quickly seal it (top cap). Seal with Parafilm and wrap with aluminum foil to prevent light exposure.

[0053] All samples were then transferred to a water bath mold connected to a programmable temperature-controlled water bath device and stirred at 150 rpm using a magnetic stirrer at 30℃±0.5°C. Samples were taken at different time points, and their appearance was recorded. The samples were then appropriately diluted for high-performance liquid chromatography (HPLC) analysis. After each sampling, the remaining samples were kept in a nitrogen atmosphere protected from light and stirred at 150 rpm and 30℃±0.5°C.

[0054] Table 3. Experimental Results As shown in Table 3, the safe maintenance time of the solid dispersion solution is 14 days. No significant physicochemical changes were found within 14 days. Therefore, the time from solution preparation to production must be controlled within 14 days.

[0055] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0056] The embodiments described above are merely illustrative of several implementations of this utility model, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this utility model, and these all fall within the protection scope of this utility model. Therefore, the protection scope of this utility model patent should be determined by the appended claims.

Claims

1. A device for maintaining miniature simulated production conditions, characterized in that, The system includes a stirring drive system, a nested container, and a temperature control system. The nested container comprises an outer bottle, a material test piece, an inner bottle, and a rotor. The material test piece is made of a material that will be in direct contact with the solution under simulated production conditions and is placed inside the outer bottle. The inner bottle can be placed inside the outer bottle, with its opening lower than that of the outer bottle. The material test piece is sheet-shaped and placed at the bottom of the outer bottle, on which the inner bottle can stand upright. The material test piece is made of 316L stainless steel. Both the outer and inner bottles are glass bottles. The rotor can be placed inside the inner bottle. The nested container can be placed in a water bath within the temperature control system for temperature control. The water bath has holes for inserting the outer bottle. The water bath is mounted on the stirring drive system, and the rotor can rotate within the inner bottle under the control of the stirring drive system. The stirring drive system is a magnetic stirrer. The rotor has a structure with a core of strongly magnetic material and an outer shell of PTFE.

2. The holding device as claimed in claim 1, characterized in that, The outer bottle has a cap.

3. The holding device as claimed in claim 2, characterized in that, The lid has a gasket.

4. The holding device according to any one of claims 1 to 3, characterized in that, The nested container also includes accessories; the accessories include sealing film for sealing the outer bottle; the accessories also include aluminum foil for wrapping the outer bottle.

5. The holding device as claimed in claim 1, characterized in that, The outer bottle has a volume of 80-20 mL, and the inner bottle has a volume of 8-2 mL.

6. The holding device as claimed in claim 1, characterized in that, It also includes an inflation system for filling the outer bottle with inert gas.

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