Improved filtering device of flow cell of flow cell method dissolution instrument and method for measuring dissolution rate of ibuprofen suspension

Abstract

The invention discloses an improved filtering device of a flow cell of a flow cell method dissolution instrument and a method for measuring the dissolution rate of an ibuprofen suspension. The filtering device is sequentially composed of a screen, a glass fiber membrane, a polycarbonate membrane and a screen. The polycarbonate film has outstanding impact toughness, transparency and dimensional stability, is high in pressure resistance and wide in chemical compatibility, and can be used for an extrusion process of lipidosome. According to the flow pool dissolution method, the polycarbonate film can prevent a flow path on the filter film cover from being blocked, most of the blocking problems are solved, the good pressure resistance of the polycarbonate film can assist drugs, especially drugs with multiple auxiliary materials and high viscosity, to be subjected to dissolution rate testing smoothly by adopting the flow pool dissolution rate method, and the applicability of the novel dissolution method of the flow pool dissolution method is improved.

Description

Technical Field

[0001] The invention belongs to the field of instruments and methods related to drug detection, and specifically relates to an improved filtering device of a flow cell dissolution instrument and a method for determining the dissolution rate of an ibuprofen suspension. Background Art

[0002] The flow-through dissolution apparatus is an experimental device widely used in drug development and quality control. It simulates the environmental conditions that drugs may encounter in the body by precisely controlling the flow rate, temperature and medium conditions, and evaluates the dissolution characteristics of drugs. As a new drug dissolution test method, this technology has the advantages of maintaining trough conditions, simulating the in vivo environment, being applicable to a variety of dosage forms, and having good biological relevance compared to traditional dissolution methods such as the paddle method and the basket method. It is especially suitable for the dissolution test of poorly soluble drugs, controlled-release dosage forms, and special dosage forms such as suspensions, soft capsules, implants, microspheres, and liposomes. However, in the use of the flow-through dissolution apparatus, the control of the system pressure is crucial. When the system pressure of the flow-through dissolution apparatus is too high, a series of problems such as instrument pressure relief, pump stoppage, and inaccurate flow rate may occur, resulting in experimental failure.

[0003] Ibuprofen suspension is a commonly used nonsteroidal anti-inflammatory drug (NSAID), mainly used to relieve mild to moderate pain and fever caused by the common cold or influenza in children. As a BCS Class II drug, ibuprofen is a low-solubility, high-permeability drug, and its absorption is limited by dissolution. In ibuprofen suspension, ibuprofen is dispersed in the medium in the form of microparticles.

[0004] At present, the implementation standards of ibuprofen suspension in China are multiple ministerial and bureau standards, which basically do not include dissolution test items. A study used the paddle method and phosphate buffer (pH 7.2) to determine the dissolution behavior of ibuprofen suspension. The British and American Pharmacopoeia also used the paddle method to determine the dissolution of ibuprofen suspension, but the mechanical stirring method of the traditional paddle method is quite different from the gastrointestinal dissolution environment in vivo. Summary of the invention

[0005] The purpose of the present invention is to provide an improved filtering device of a flow cell dissolution apparatus and a method for determining the dissolution rate of an ibuprofen suspension.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] A filtering device for a flow cell dissolution apparatus, which is composed of a screen, a glass fiber membrane, a polycarbonate membrane, and a screen in sequence;

[0008] The pore size of the glass fiber membrane is 2.4-3.0 μm, preferably 2.7 μm;

[0009] The pore size of the polycarbonate membrane is 9.0-11.0 μm, preferably 10.0 μm.

[0010] A flow cell dissolution apparatus flow cell, comprising the above-mentioned filtering device;

[0011] The filtering device is located at the top of the flow cell and is composed of a screen, a glass fiber membrane, a polycarbonate membrane, and a screen from bottom to top along the direction of the liquid flow;

[0012] Glass beads are added to the bottom of the circulation pool;

[0013] The glass beads have different particle sizes; the large glass beads act as a one-way valve to prevent backflow; the small glass beads disperse the sample and change the flow pattern of the dissolution medium from turbulent flow to laminar flow.

[0014] A flow cell dissolution apparatus comprising the above-mentioned filtering device and / or flow cell;

[0015] The flow cell dissolution apparatus also includes components such as a medium bottle, a pump and a sample collector.

[0016] One or more of the above-mentioned filtration device, circulation cell and flow cell dissolution apparatus can be used to determine the dissolution rate of ibuprofen suspension.

[0017] The method for determining the dissolution rate of ibuprofen suspension comprises the following steps:

[0018] Using the above-mentioned flow cell dissolution apparatus, the test sample is placed above the glass beads in the flow cell; the pump is turned on to pump in the dissolution medium, and after a certain period of time, a sample is taken for chromatographic analysis to obtain the dissolution rate of the ibuprofen suspension;

[0019] The sample is preferably injected using a syringe to spread the test sample on top of the glass beads;

[0020] The flow rate of the pump is controlled to be 8-16 mL min -1 ;

[0021] The dissolution medium is a phosphate buffer with a pH value of 7.1 to 7.3;

[0022] The pH value is preferably 7.2;

[0023] The conditions of the chromatographic analysis are: methanol-acetonitrile-water-phosphoric acid (65:10:25:0.03) as the mobile phase; the flow rate is 1.2 mL per minute; the detection wavelength is 220 nm; the column temperature is 30° C.; and the injection volume is 10 μL.

[0024] Compared with the prior art, the present invention has the following advantages and effects:

[0025] 1. Establishing a suitable in vitro dissolution method is one of the important indicators for evaluating the intrinsic quality of oral preparations. This application creatively uses a flow-through dissolution apparatus to determine the solubility of ibuprofen suspension. Ibuprofen suspension is used as a medicine for children. In order to improve drug compliance, the drug prescription contains a large amount of pharmaceutical excipients such as sugar, flavors, pigments, suspending agents, and the sample is viscous. When the method was established, it was found that when the dissolution of ibuprofen suspension was determined by a flow-through dissolution apparatus, filter blockage, excessive system pressure, and instrument pressure relief were prone to occur. After scheme design and comparative studies, it was found that polycarbonate membranes can effectively improve this situation.

[0026] 2. The polycarbonate membrane has outstanding impact toughness, transparency and dimensional stability, strong pressure resistance and wide chemical compatibility, and can be used in the extrusion process of liposomes. In the flow cell dissolution method of the present application, the polycarbonate membrane can prevent clogging of the flow path on the filter membrane cover, solving most of the clogging problems. Its good pressure resistance can assist drugs, especially drugs with high viscosity and high excipients, to smoothly carry out dissolution testing using the flow cell dissolution method, increasing the applicability of the new dissolution method of the flow cell dissolution method. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a schematic diagram of the composition of the filtering device; wherein, 111-filter screen (lower cover), 112-glass fiber membrane, 113-polycarbonate membrane, 114-filter screen (upper cover), and the arrow indicates the direction of liquid flow.

[0028] Figure 2 It is a schematic diagram of the composition of the circulation pool; wherein, 11 is a filtering device, and 12 is glass beads.

[0029] Figure 3 Schematic diagram of the composition of the flow cell dissolution apparatus; wherein, 1-circulation cell, 2-medium bottle, 3-pump, 4-sample collector.

[0030] Figure 4 The dissolution curves of samples from various companies are shown in Figure 2. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0032] Example 1

[0033] A filtering device for a flow cell dissolution apparatus, such as Figure 1 As shown, it is composed of a filter screen (lower cover) 111, a glass fiber membrane 112, a polycarbonate membrane 113, and a filter screen (upper cover) 114 in sequence.

[0034] A flow cell dissolution apparatus flow cell, such as Figure 2 As shown, it contains the above-mentioned filtering device 11;

[0035] The filtering device is located at the top of the flow cell, and is composed of a filter screen (lower cover) 111, a glass fiber membrane 112, a polycarbonate membrane 113, and a filter screen (upper cover) 114 from bottom to top along the direction of the liquid flow;

[0036] Glass beads 12 of different particle sizes are added to the bottom of the circulation pool.

[0037] A flow cell dissolution apparatus, such as Figure 3 As shown, it contains the above-mentioned flow cell 1;

[0038] The flow cell dissolution apparatus further comprises components such as a medium bottle 2, a pump 3 and a sample collector 4.

[0039] Example 2

[0040] The method for determining the dissolution rate of ibuprofen suspension comprises the following steps:

[0041] (1) Using the flow cell dissolution apparatus described in Example 1, spread the test sample (sample volume of about 5 mL) on top of the glass beads;

[0042] The test samples were ibuprofen suspensions from various manufacturers, including manufacturer A, batch number 210118032 (original localized product); manufacturer B, batch number 20200401-3; manufacturer C, batch number 230108; manufacturer D, batch number 210113024; manufacturer E, batch number 201042; manufacturer F, batch number 210209LB;

[0043] Ibuprofen reference substance was purchased from China Food and Drug Inspection Institute, batch number 100179-202308, purity 99.9%;

[0044] Preparation of reference stock solution: Take an appropriate amount of ibuprofen reference substance, accurately weigh it, dissolve it in methanol and dilute it to make a solution containing 0.22 mg of ibuprofen per 1 mL.

[0045] Preparation of reference solution: Accurately measure 1 mL of reference stock solution, place in a 10 mL volumetric flask, dilute to the mark with dissolution medium, and shake well.

[0046] Preparation of test solution: Centrifuge the dissolution test solution at 4000 rpm for 10 min and take the supernatant.

[0047] (2) Turn on the pump, use pH 7.2 phosphate buffer as the dissolution medium, set the sampling time to 5, 10, 15, 20, 30, 45, and 60 min, and the sampling volume to 1 mL. After sampling, perform chromatographic analysis to obtain the solubility of the ibuprofen suspension;

[0048] Chromatographic conditions: Chromatographic column: Agilent ZORBAX SB-C18 (150mm×4.6mm, 4μm); methanol-acetonitrile-water-phosphoric acid (65:10:25:0.03) as the mobile phase; flow rate: 1.2mL per minute; detection wavelength: 220nm; column temperature: 30℃; injection volume: 10μL.

[0049] Calculate the cumulative dissolution amount at each dissolution point and draw a dissolution curve with the average cumulative dissolution amount at each dissolution point ( Figure 4 ).

[0050] After comparison, the dissolution of enterprise F was the fastest, with the cumulative dissolution reaching more than 85% at the 10-minute sampling point, the cumulative dissolution of enterprises A, B, and C reached more than 85% at the 30-minute sampling point, the cumulative dissolution of enterprise E reached more than 85% at the 60-minute sampling point, and the cumulative dissolution of enterprise D at the 60-minute sampling point still did not reach 85%. See Table 1 for specific data:

[0051] Table 1 Dissolution results of samples from various companies

[0052]

[0053] Comparative Example

[0054] Based on the method of Example 2, the test parameters were changed and the samples from various manufacturers were tested to obtain the results in Table 2:

[0055] Table 2 Dissolution results of Example 2 and Comparative Examples

[0056]

[0057] It can be seen from Table 2 that when the polycarbonate membrane was not used, the sample volume of 1mL, 5mL, and 10mL and the flow rate of 8mL / min were respectively adopted, and the pressure relief test of the sample system of some enterprises failed (Comparative Examples 1, 2, and 3);

[0058] Using a polycarbonate membrane, a 5 mL sample volume and a flow rate of 8 mL / min, no pressure relief occurred in samples from all manufacturers, the problem of excessive system pressure was solved, and the experiment was feasible (Example 2). The cumulative dissolution amount of samples from manufacturer A (original research and localization) at the 30-min sampling point reached more than 85%;

[0059] Using a polycarbonate membrane, a 5 mL sample volume and a flow rate of 16 mL / min, no pressure relief occurred in samples from all manufacturers, the problem of excessive system pressure was solved, and the experiment was feasible (Comparative Example 4). The cumulative dissolution amount of the sample from manufacturer A (original research and localization) at the 15-min sampling point was more than 85%. Compared with the embodiment, the sample dissolved faster under this condition. Considering that the embodiment has a stronger distinguishing power in the comparison of dissolution behaviors of different manufacturers, and the sampling point of the United States Pharmacopoeia ibuprofen suspension dissolution test (paddle method) is 60 min, the flow rate setting of the embodiment is more reasonable;

[0060] Using a polycarbonate membrane, with a sample volume of 10 mL and a flow rate of 8 mL / min, a sample from one manufacturer failed the system pressure relief test (Comparative Example 5). When the sample volume was 10 mL, only about 0.5 cm of space was left above the 22.6 mm standard flow cell after the sample was loaded, and the sample was overloaded. At this time, the amount of filtration auxiliary material required for the filtration device was further increased compared with the example, which exceeded the ability of the polycarbonate membrane to relieve blockage and reduce system pressure. Try to change the sample loading method, use a sandwich sample loading method (half glass beads + sample + the other half glass beads), and add absorbent cotton in front of the filter membrane to block the auxiliary material. At this time, a sample from one manufacturer failed the system pressure relief test (Comparative Example 6), and the system pressure was still too high, which exceeded the ability of the polycarbonate membrane to relieve blockage and reduce system pressure.

[0061] Since the recommended dosage of ibuprofen suspension is 4 to 10 mL per dose, the difference between the sample volume of 1 mL and the actual usage is large, and the small sample volume is not representative enough, the sample volume of 1 mL was not investigated after adding the polycarbonate membrane;

[0062] In summary, from the perspectives of feasibility, discrimination, and representativeness of sample quantity, the embodiment is the best solution, and comparative example 4 is also acceptable.

[0063] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A filtering device for a flow cell dissolution apparatus, characterized in that: The device is composed of a screen, a glass fiber membrane, a polycarbonate membrane and a screen in sequence.

2. The filtering device according to claim 1, characterized in that: The pore size of the glass fiber membrane is 2.4-3.0 μm.

3. The filtering device according to claim 1, characterized in that: The pore size of the polycarbonate membrane is 9.0-11.0 μm.

4. A flow cell dissolution apparatus, characterized in that A filter device comprising the filter device according to any one of claims 1 to 3.

5. The flow cell dissolution apparatus according to claim 4, characterized in that: The filtering device is located at the top of the circulation pool, and is composed of a screen, a glass fiber membrane, a polycarbonate membrane and a screen in sequence from bottom to top along the direction of the liquid flow.

6. The flow cell dissolution apparatus according to claim 4, characterized in that: Glass beads were added to the bottom of the flow cell.

7. The flow cell dissolution apparatus according to claim 6, characterized in that: The glass beads have different particle sizes.

8. A flow cell dissolution apparatus, characterized in that: A filter comprising the filtration device according to any one of claims 1 to 3 and / or the flow cell according to any one of claims 4 to 7.

9. The flow cell dissolution apparatus according to claim 8, characterized in that: The flow cell dissolution apparatus also includes a medium bottle, a pump and a sample collector.

10. Use of one or more of the filtration device according to any one of claims 1 to 3, the flow cell according to any one of claims 4 to 7, and the flow cell dissolution apparatus according to claim 8 or 9 in the determination of the dissolution rate of ibuprofen suspension.

11. A method for determining the dissolution rate of ibuprofen suspension, characterized in that The following steps are involved: Using the flow cell dissolution apparatus described in claim 8 or 9, the test sample is placed above the glass beads in the flow cell; the pump is turned on to pump in the dissolution medium, and after a certain period of time, a sample is taken for chromatographic analysis to obtain the dissolution rate of the ibuprofen suspension.

12. The assay method according to claim 11, characterized in that: The sample casting method is to spread the test sample flat on the glass beads.

13. The assay method according to claim 11, characterized in that: The flow rate of the pump is controlled to be 8-16 mL min -1 .

14. The assay method according to claim 11, characterized in that: The dissolution medium is a phosphate buffer with a pH value of 7.1 to 7.3.

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