Method for detecting granularity of chemical raw material medicine

Abstract

The invention relates to the technical field of pharmacy, and discloses a chemical bulk drug particle size detection method which comprises the following steps: S1, preparing an ibuprofen saturated aqueous solution containing polysorbate 80 as a dispersion medium; s2, mixing a raw material medicine with the dispersion medium, and dispersing the medicine through stirring and ultrasonic treatment; and S3, measuring the particle size of the treated sample by using a laser particle size analyzer. The method disclosed by the invention is suitable for measuring the granularity of various raw material medicines, is particularly suitable for the medicine raw materials which are sensitive to the granularity and are easy to gather, and provides a reliable quality control means for the medicine preparation.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, in particular to a method for detecting the particle size of chemical raw materials. Background Art

[0002] In the process of drug development and production, the determination of particle size is one of the key parameters to ensure the quality and performance of drugs. The particle size of drug raw materials affects their dissolution rate, bioavailability and stability. Therefore, accurate measurement of the particle size of chemical raw materials is of great significance for drug manufacturing and quality control.

[0003] Traditional particle size determination methods usually rely on a single physical dispersion method to prepare samples. When dealing with some chemical APIs that are difficult to disperse or easy to aggregate, it may not be possible to achieve a uniform and stable dispersion effect, resulting in inconsistent and low repeatability results. In addition, a single dispersion method may cause partial dissolution of the API in some cases, which will further affect the accuracy of particle size determination.

[0004] In pharmaceutical preparations, some APIs have particularly high solubility or are prone to particle size changes due to dissolution during the preparation process, which places higher demands on particle size determination. The lack of effective methods to control the dissolution of APIs may result in the inability to obtain accurate particle size data. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for detecting the particle size of chemical raw materials, which can more effectively process and control the dispersion and dissolution of raw materials, thereby improving the accuracy and repeatability of particle size determination. By improving the sample processing method and optimizing the conditions for particle size determination, the true particle size distribution of the sample can be measured, and the particle size of the raw materials can be accurately controlled, meeting the strict requirements for quality control in modern drug production.

[0006] To achieve the above objectives, the present invention is implemented by the following technical scheme: A method for detecting the particle size of chemical raw materials, comprising the following steps:

[0007] S1, preparing a saturated aqueous solution of ibuprofen containing polysorbate 80 as a dispersion medium;

[0008] S2, mixing the API with the dispersion medium, and dispersing the drug by stirring and ultrasonic treatment;

[0009] S3. Use a laser particle size analyzer to measure the particle size of the treated samples.

[0010] Preferably, the preparation of the dispersion medium comprises:

[0011] S11, weigh 3 g of polysorbate 802 and place it in a stirring container;

[0012] S12, add 4500-5500 mL of purified water and stir for 3-7 minutes;

[0013] S13, weigh 4-6g of ibuprofen sample and add it to the stirring container, and continue stirring for 40-80min;

[0014] S14. Filter through a 0.45 μm filter membrane to obtain a saturated aqueous solution of ibuprofen containing 0.04%-0.06% polysorbate 80.

[0015] Preferably, the step of mixing the bulk drug with the dispersion medium comprises:

[0016] S21. Add 0.8-1.2 g of API to a beaker containing 140-210 mL of dispersion medium;

[0017] S22, turn on the stirring device and set the speed to 150-850 rpm;

[0018] S23, ultrasonic power 280-520W, frequency 35-45KHZ for 100-300s.

[0019] Preferably, the particle size determination step further comprises:

[0020] S31. Turn on the instrument according to the particle size analyzer operating procedures and stabilize it for 20-40 minutes;

[0021] S32, adjust the pump speed to 1800-2200rpm / min;

[0022] S33, add 450-550 mL of dispersion medium to the EV beaker;

[0023] S34, adding the sample until the turbidity is within the light-shielding range of 8%-20%;

[0024] S35. Measure within 1 minute after the shading degree stabilizes.

[0025] Preferably, the particle size analyzer is a Malvern laser particle size analyzer.

[0026] Preferably, in the particle size determination step, the refractive index of the dispersion medium is set to 1.32-1.34, and the refractive index of the bulk drug particles is set to 1.42-1.45.

[0027] Preferably, in the particle size determination step, the absorption rate of the bulk drug particles is set to 0.08-0.12.

[0028] Preferably, in the particle size determination step, each sample is automatically measured twice and the average value is taken as the determination result.

[0029] Preferably, in the particle size determination step, the measurement time of the sample and the background is 15-25 s.

[0030] Preferably, in the particle size determination step, the determination is started after a delay of 20-40 seconds after the drug substance and the dispersion medium are mixed.

[0031] The present invention provides a method for detecting the particle size of chemical raw materials. It has the following beneficial effects:

[0032] 1. The present invention uses polysorbate 80 as a cosolvent to minimize the dissolution of the API through its highly saturated solution state, which not only avoids further changes in particle size but also improves the accuracy and repeatability of measurement.

[0033] 2. The present invention effectively improves the dispersibility of drug raw materials and ensures the consistency of measurement results by combining stirring and ultrasonic treatment technology.

[0034] 3. The method of the present invention is suitable for the particle size determination of various raw materials, especially those that are sensitive to particle size and easy to aggregate, and provides a reliable quality control method for pharmaceutical preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 It is a schematic diagram of the method flow of the present invention. DETAILED DESCRIPTION

[0036] The following will be combined with the drawings in the specification of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] Please see attached Figure 1 The present invention provides a method for detecting the particle size of chemical raw materials, which can accurately measure the particle size distribution of raw materials, and is particularly suitable for raw materials that need to accurately control the particle size to ensure efficacy and stability. By using a specific dispersion medium and combining stirring and ultrasonic processing technology, the present invention effectively improves the accuracy and repeatability of particle size determination.

[0038] Specifically, the method comprises the following steps:

[0039] Step 1: Preparation of dispersion medium

[0040] The preparation of dispersion medium is a preliminary and key step of the present invention, and the purpose is to form a medium that can effectively disperse the bulk drug particles and reduce their self-solubility. First, 2-3g of polysorbate 80 is weighed and placed in a stirring container. Subsequently, 4500-5500mL of purified water is added and stirred for 3-7min to ensure that polysorbate 80 is completely dissolved. Next, 4-6g of ibuprofen sample is added, and stirring is continued for 40-80min to fully saturate ibuprofen. Finally, a saturated aqueous solution of ibuprofen containing 0.04%-0.06% polysorbate 80 is obtained by filtering through a 0.45μm filter membrane. This step ensures the uniformity and stability of the dispersion medium and provides a good basis for subsequent particle size detection.

[0041] Step 2: Mixing and processing of API and dispersion medium

[0042] In the prepared dispersion medium, add 0.8-1.2g of the API to a beaker containing 140-210mL of dispersion medium. Use a stirring device and set the speed at 150-850rpm / min to ensure that the drug particles are fully dispersed. Subsequently, the mixture is ultrasonically treated for 100-300s using an ultrasonic power of 280-520W and a frequency of 35-45KHZ. The key to this step is to use the cavitation effect and microjet generated by ultrasound to further break up the aggregated drug particles, thereby obtaining a more uniform particle distribution.

[0043] Step 3: Particle size determination

[0044] Before using the Malvern laser particle size analyzer for particle size measurement, you need to preheat and stabilize the instrument for 20-40 minutes according to the operating procedures. Add the prepared dispersion medium to the EV beaker, set the pump speed at 1800-2200rpm / min, start the SOP and check the parameter settings, and complete the system light alignment, background measurement and other steps in accordance with the instrument operating procedures. When "Add sample until turbidity is within the range" appears, add the sample to the sample pool until the shading is stable in the range of 8%-20%. Click "Measure sample" within 1 minute, and the instrument will start automatic measurement. The measurement results are obtained by taking two readings for each sample and taking the average value to increase the reliability of the results.

[0045] The method of the present invention utilizes polysorbate 80 as a cosolvent, and reduces the dissolution of the bulk drug to the greatest extent through its highly saturated solution state, which not only avoids further changes in particle size, but also improves the accuracy and repeatability of measurement. In addition, in combination with stirring and ultrasonic treatment technology, the dispersibility of the drug raw material is effectively improved, ensuring the consistency of the measurement result. This method is applicable to the particle size determination of various bulk drugs, and is particularly suitable for those drug raw materials that are sensitive to particle size and easily aggregated, and provides a reliable quality control means for pharmaceutical preparations.

[0046] Five embodiments are provided below to illustrate in detail the specific operation of the method for detecting the particle size of chemical raw materials according to the present invention.

[0047] Embodiment 1:

[0048] Step 1: Prepare the dispersion medium

[0049] Weigh 2.5 g of polysorbate 80 and place it in a stirring container; add 5000 mL of purified water and stir for 5 minutes; add 5 g of ibuprofen sample and continue stirring for 60 minutes; filter through a 0.45 μm filter membrane to obtain a saturated aqueous solution of ibuprofen containing 0.05% polysorbate 80.

[0050] Step 2: Mixing and Processing

[0051] Add 1 g of API to a beaker containing 150 mL of dispersion medium; turn on the stirring device and set the speed to 200 rpm; use ultrasonic power of 300 W and frequency of 40 KHZ for 120 s.

[0052] Step 3: Particle size determination

[0053] Use Malvern laser particle size analyzer, preheat and stabilize for 30 minutes; adjust the pump speed to 2000rpm / min; add 500mL dispersion medium to the EV beaker; ensure that the sample turbidity is within the shading range of 8%-20%; delay the measurement for 30 seconds after the sample is added; set the refractive index of the dispersion medium to 1.33, the refractive index of the raw material particles to 1.43, and the absorbance to 0.1; the measurement time is 20 seconds, and each sample is read twice and the average value is taken.

[0054] Embodiment 2:

[0055] Step 1: Prepare the dispersion medium

[0056] Weigh 3 g of polysorbate 80 and place it in a stirring container; add 5500 mL of purified water and stir for 7 minutes; add 6 g of ibuprofen sample and continue stirring for 80 minutes; filter through a 0.45 μm filter membrane to obtain a saturated aqueous solution of ibuprofen containing 0.06% polysorbate 80.

[0057] Step 2: Mixing and Processing

[0058] Add 1.2 g of API to a beaker containing 210 mL of dispersion medium; turn on the stirring device and set the speed to 850 rpm; use ultrasonic power of 520 W and frequency of 45 KHZ for 300 s.

[0059] Step 3: Particle size determination

[0060] Use Malvern laser particle size analyzer, preheat and stabilize for 40 minutes; adjust the pump speed to 2200rpm / min; add 550mL dispersion medium to the EV beaker; ensure that the sample turbidity is within the shading range of 8%-20%; delay the measurement for 35 seconds after the sample is added; set the refractive index of the dispersion medium to 1.34, the refractive index of the raw material particles to 1.45, and the absorbance to 0.12; the measurement time is 25 seconds, and each sample is read twice and the average value is taken.

[0061] Embodiment 3:

[0062] Step 1: Prepare the dispersion medium

[0063] Weigh 2 g of polysorbate 80 and place it in a stirring container; add 4500 mL of purified water and stir for 3 minutes; add 4 g of ibuprofen sample and continue stirring for 40 minutes; filter through a 0.45 μm filter membrane to obtain a saturated aqueous solution of ibuprofen containing 0.04% polysorbate 80.

[0064] Step 2: Mixing and Processing

[0065] Add 0.8 g of API to a beaker containing 140 mL of dispersion medium; turn on the stirring device and set the speed to 150 rpm; use ultrasonic power of 280 W and frequency of 35 kHz for 100 s.

[0066] Step 3: Particle size determination

[0067] Use Malvern laser particle size analyzer, preheat and stabilize for 20 minutes; adjust the pump speed to 1800rpm / min; add 450mL dispersion medium to the EV beaker; ensure that the sample turbidity is within the shading range of 8%-20%; delay the measurement for 20 seconds after the sample is added; set the refractive index of the dispersion medium to 1.32, the refractive index of the raw material particles to 1.42, and the absorbance to 0.08; the measurement time is 15 seconds, and each sample is read twice and the average value is taken.

[0068] Embodiment 4:

[0069] Step 1: Prepare the dispersion medium

[0070] Weigh 2.8 g of polysorbate 80 and place it in a stirring container; add 5200 mL of purified water and stir for 6 minutes; add 5.5 g of ibuprofen sample and continue stirring for 70 minutes; filter through a 0.45 μm filter membrane to obtain a saturated aqueous solution of ibuprofen containing 0.055% polysorbate 80.

[0071] Step 2: Mixing and Processing

[0072] Add 1 g of API to a beaker containing 180 mL of dispersion medium; turn on the stirring device and set the speed to 500 rpm; use ultrasonic power of 400 W and frequency of 42.5 KHZ for 210 s.

[0073] Step 3: Particle size determination

[0074] Use Malvern laser particle size analyzer, preheat and stabilize for 35 minutes; adjust the pump speed to 2000rpm / min; add 500mL dispersion medium to the EV beaker; ensure that the sample turbidity is within the shading range of 8%-20%; delay the measurement for 25 seconds after the sample is added; set the refractive index of the dispersion medium to 1.34, the refractive index of the raw material particles to 1.44, and the absorbance to 0.1; the measurement time is 20 seconds, and each sample is read twice and the average value is taken.

[0075] Embodiment 5:

[0076] Step 1: Prepare the dispersion medium

[0077] Weigh 3 g of polysorbate 80 and place it in a stirring container; add 5400 mL of purified water and stir for 4 minutes; add 6 g of ibuprofen sample and continue stirring for 60 minutes; filter through a 0.45 μm filter membrane to obtain a saturated aqueous solution of ibuprofen containing 0.06% polysorbate 80.

[0078] Step 2: Mixing and Processing

[0079] Add 1.1 g of API to a beaker containing 195 mL of dispersion medium; turn on the stirring device and set the speed to 775 rpm; use ultrasonic power of 450 W and frequency of 40 kHz for 255 s.

[0080] Step 3: Particle size determination

[0081] Use Malvern laser particle size analyzer, preheat and stabilize for 30 minutes; adjust the pump speed to 2100rpm / min; add 525mL dispersion medium to the EV beaker; ensure that the sample turbidity is within the shading range of 8%-20%; delay 40s for measurement after sample addition; set the refractive index of the dispersion medium to 1.33, the refractive index of the raw material particles to 1.42, and the absorbance to 0.12; the measurement time is 25s, and each sample is read twice and the average value is taken.

[0082] Test experiment:

[0083] The purpose is to verify and compare the effectiveness and repeatability of the particle size detection method for chemical raw materials under different embodiments.

[0084] Experimental procedures

[0085] 1. Preparation of dispersion medium: Prepare dispersion medium according to the specific formulation of each example.

[0086] 2. Sample preparation: According to the instructions of each example, accurately weigh the API and add it into the corresponding dispersion medium in the specified proportion.

[0087] 3. Stirring and ultrasonic treatment: Stir and ultrasonicate each sample, making sure to follow the speed, ultrasonic power and treatment time specified in each example.

[0088] 4. Particle size determination: The same Malvern laser particle size analyzer was used to measure the particle size of all samples, ensuring that the equipment was preheated and stabilized before each measurement.

[0089] 5. Data recording: Perform two independent measurements on each sample and record the particle size distribution data each time.

[0090] Experimental setup

[0091] Instrument: Malvern laser particle size analyzer.

[0092] Dispersion medium volume: adjusted for each example, ranging from 450-550 mL.

[0093] Sample weight: adjusted for each example, ranging from 0.8 to 1.2 g.

[0094] Stirring speed: Each example is set separately, ranging from 150-850 rpm.

[0095] Ultrasonic power and time: according to the setting of the embodiment, the power is 280-520W, and the time is 100-300s.

[0096] Measuring time: 15-25s.

[0097] Refractive index and absorptivity settings: adjusted according to the embodiment.

[0098] The test data is shown in the following table:

[0099]

[0100] Based on the experimental data in the above table, the following is the conclusion of the particle size detection method of chemical raw materials for five embodiments:

[0101] Granularity consistency and repeatability:

[0102] All examples showed good repeatability, among which the measurement result of Example 4 had the lowest standard deviation (0.07 μm), indicating that it had the highest precision in the experimental operation.

[0103] Example 3 and Example 1 also showed good particle size consistency, with average particle sizes of 10.1 μm and 10.35 μm, respectively, and standard deviations of 0.14 μm and 0.21 μm, respectively.

[0104] The measurement results of Example 5 show a maximum particle size (average particle size 10.45 μm) and a standard deviation of 0.21 μm, indicating that it still maintains good repeatability within a higher measurement range.

[0105] Influence of operating parameters:

[0106] It can be observed from the settings of each embodiment that higher ultrasonic power and longer treatment time (such as 520 W and 300 s in Example 2) are helpful to achieve a more uniform particle size distribution, but also require a higher pump speed (2200 rpm / min) to maintain the accuracy of the measurement.

[0107] Based on the above analysis, it can be concluded that the provided chemical raw material drug particle size detection method not only has high repeatability and accuracy, but also the flexibility of its operating parameters enables it to adapt to different experimental requirements. Through careful parameter setting and strict operation control, this method can be effectively used in the quality control of chemical raw materials and the development of new drugs. In addition, this test verifies the feasibility of different embodiments in actual operation, and provides valuable reference data and experience for future applications.

[0108] Comparative experiment 1:

[0109] To evaluate the effect of stirring alone versus ultrasonic treatment alone on the dispersion of chemical APIs, and the effect of these two methods on the accuracy and repeatability of particle size determination results.

[0110] Experimental setup

[0111] Comparative Example 1: Only stirring

[0112] Preparation of dispersion medium: As in Example 1, a saturated aqueous solution of ibuprofen containing 0.05% polysorbate 80 was prepared.

[0113] Sample preparation: Add 1 g of API to a beaker containing 150 mL of dispersion medium. Turn on the stirring device, set the speed to 200 rpm, and continue stirring for 120 s without using ultrasound.

[0114] Particle size determination: The particle size determination was performed using the same Malvern laser particle size analyzer as in Example 1. The remaining measurement parameters were the same as in Example 1 (such as pump speed, light shielding, measurement time, etc.).

[0115] Comparative Example 2: Ultrasound only

[0116] Preparation of dispersion medium: same as in Example 1.

[0117] Sample treatment: Add 1g of API to a beaker containing 150mL of dispersion medium. Do not turn on the stirring device and directly apply ultrasonic treatment, setting the power to 300W, the frequency to 40KHZ, and the duration to 120s.

[0118] Particle size determination: Particle size determination was performed using the same setup as in Example 1.

[0119] The experimental test data are shown in the following table:

[0120] Experimental treatment Determination of 1 particle size (μm) Determination 2 Particle size (μm) Average particle size (μm) Standard deviation(μm) Just stir 12 12.4 12.2 0.28 Ultrasound only 9.7 9.5 9.6 0.14

[0121] Based on the experimental data in the above table, the following conclusions are drawn:

[0122] Comparative experiments showed that using ultrasound alone to treat the API samples resulted in a smaller average particle size and lower standard deviation than using only stirring. This suggests that ultrasound treatment is more effective in particle dispersibility and can better break up aggregates, thereby achieving a more uniform particle size distribution.

[0123] However, although stirring alone can achieve a certain dispersion of particles in some cases, the consistency and repeatability of the results are not as good as those of ultrasonic treatment, and the particle size is usually larger and the dispersion is poorer.

[0124] The dual treatment method combining stirring and ultrasound used in Example 1 combines the advantages of the two technologies and can effectively improve the accuracy and consistency of the particle size determination of the API. By using stirring and ultrasound at the same time, not only can the macroscopic flow generated by stirring be used to help the particles to be initially dispersed, but the microscopic impact force of ultrasound can also be used to further refine the particle distribution, especially in breaking up stubborn particles.

[0125] In addition, the dual processing method shows higher processing efficiency when processing drug materials with higher viscosity or tendency to aggregate quickly, which can significantly reduce processing time and increase yield.

[0126] Comparative experiment 2:

[0127] To evaluate the role of a cosolvent (polysorbate 80) in the dispersion of the API, especially its effect on preventing dissolution and particle size change of the API, and to clarify the effectiveness of the cosolvent by comparing it with the absence of a cosolvent.

[0128] Comparative Example 3:

[0129] In the step 1 of preparing the dispersion medium, the cosolvent polysorbate 80 is not used. The other steps are the same as in Example 1.

[0130] The test data is shown in the following table:

[0131] Experimental conditions Determination of 1 particle size (μm) Determination 2 Particle size (μm) Average particle size (μm) Standard deviation(μm) Use Polysorbate 80 10.2 10.5 10.35 0.21 No co-solvents are used 12.5 12.7 12.6 0.14

[0132] Based on the experimental data in the above table, the following conclusions are drawn:

[0133] The sample using polysorbate 80 as a cosolvent showed a smaller average particle size (10.35 μm), which was significantly smaller and more consistent compared to the sample without a cosolvent (average particle size 12.6 μm).

[0134] Although the standard deviations of the samples with and without cosolvents were similar, the particle size of the samples without cosolvents was larger overall, indicating that in the absence of polysorbate 80, more dissolution or aggregation of the API occurred, affecting the uniformity of the particle size.

[0135] This experiment highlights the importance of using appropriate cosolvents in particle size testing of chemical APIs. The use of cosolvents such as polysorbate 80 can significantly improve the reliability and consistency of particle size determination, which is critical to ensuring the quality and stability of drug formulations.

[0136] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for detecting particle size of chemical raw materials, characterized in that: The following steps are involved: S1, preparing a saturated aqueous solution of ibuprofen containing polysorbate 80 as a dispersion medium; S2, mixing the API with the dispersion medium, and dispersing the drug by stirring and ultrasonic treatment; S3. Use a laser particle size analyzer to measure the particle size of the treated samples.

2. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: The preparation of the dispersion medium comprises: S11, weigh 3 g of polysorbate 802 and place it in a stirring container; S12, add 4500-5500 mL of purified water and stir for 3-7 minutes; S13, weigh 4-6g of ibuprofen sample and add it to the stirring container, and continue stirring for 40-80min; S14. Filter through a 0.45 μm filter membrane to obtain a saturated aqueous solution of ibuprofen containing 0.04%-0.06% polysorbate 80.

3. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: The step of mixing the bulk drug with the dispersion medium comprises: S21. Add 0.8-1.2 g of API to a beaker containing 140-210 mL of dispersion medium; S22, turn on the stirring device and set the speed to 150-850 rpm; S23, ultrasonic power 280-520W, frequency 35-45KHz for 100-300s.

4. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: The particle size determination step further comprises: S31. Turn on the instrument according to the operating procedures of the laser particle size analyzer and stabilize it for 20-40 minutes; S32, adjust the pump speed to 1800-2200rpm / min; S33, add 450-550 mL of dispersion medium to the EV beaker; S34, adding the sample until the turbidity is within the shading range of 8%-20%; S35. Measure within 1 minute after the shading degree stabilizes.

5. A method for detecting particle size of chemical raw materials according to claim 4, characterized in that: The particle size analyzer is a Malvern laser particle size analyzer.

6. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: In the particle size determination step, the refractive index of the dispersion medium is set to 1.32-1.34, and the refractive index of the bulk drug particles is set to 1.42-1.

45.

7. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: In the particle size determination step, the absorption rate of the bulk drug particles is set to 0.08-0.

12.

8. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: In the particle size determination step, each sample is automatically measured twice and the average value is taken as the measurement result.

9. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: In the particle size determination step, the measurement time of the sample and the background is 15-25s.

10. A method for detecting particle size of chemical raw materials according to claim 1, characterized in that: In the particle size determination step, after the raw material drug and the dispersion medium are mixed, the determination is started after a delay of 20-40 seconds.

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