A method for evaluating co-processed crystal excipients for preventing machine pluggage during tablet compression
By evaluating the crystallinity, thermal stability, and particle size distribution of co-processed crystalline excipients, the problem of machine blockage caused by co-processed excipients during tableting was solved, achieving efficient production forecasting and improved production efficiency.
Patent Information
- Application Number
- CN202310432618.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-04-20
- Publication Date
- 2026-01-06
- Estimated Expiration
- 2043-04-20
AI Technical Summary
Existing technologies often result in machine blockage due to the handling of excipients during tableting, leading to low production efficiency. Furthermore, there is a lack of effective prediction methods, requiring multiple trials and adjustments to the excipients to resolve the blockage problem.
The crystallinity, thermal stability, particle shape, and particle size distribution of the co-processed crystalline excipients were measured and evaluated using equipment such as X-ray diffraction, differential scanning calorimetry, and particle size and shape analyzer. The vector angle cosine method was used to determine whether the excipients would cause blockage, ensuring that the correlation coefficient was not less than 0.90.
Accurately predicting whether co-processing auxiliary materials will cause blockage of the core push rod reduces pre-production testing, improves production efficiency, and reduces time, manpower, and material consumption.
Smart Images
Figure CN116794248B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical formulation technology. More specifically, it relates to a method for evaluating co-processed crystal excipients to prevent machine blockage during tableting. Background Technology
[0002] Pharmaceutical excipients are an indispensable and crucial component of pharmaceutical formulations. They not only determine the specific route of administration but also influence drug stability, efficacy, and formulation quality. In formulation design and manufacturing, multiple excipients are often used simultaneously to meet the process requirements of the formulation. Therefore, companies have developed premixed and co-processed excipients that can improve formulation quality, increase production efficiency, and facilitate excipient management. Premixed excipients refer to mixed excipients made by simply mixing two or more pharmaceutical excipients. Co-processed excipients are mixed excipients obtained by processing two or more pharmaceutical excipients through specific physical processes, such as spray drying, hot melting, freeze drying, melt extrusion, co-crystallization, and granulation, to achieve specific functions. Because co-processed excipients undergo specific physical processing, their particle state changes, resulting in synergistic effects such as enhanced compressibility and reduced hygroscopicity, leading to better physical and mechanical properties of the product and making it more suitable for the preparation of solid dosage forms.
[0003] However, in practical applications, co-processed excipients still suffer from poor flowability and sticking issues during tableting. Furthermore, in chip packaging production, the poor performance of co-processed excipients frequently leads to blockages in the die pusher rods. Once a die pusher rod blockage occurs, not only does it require disassembling the tablet press for cleaning, halting tableting, but it also necessitates the re-preparation of co-processed excipients to improve tableting conditions and production continuity. This situation not only increases the consumption of time, manpower, financial resources, and materials but also severely restricts production continuity and significantly impacts production efficiency.
[0004] Currently, the common method for confirming whether co-processed excipients will cause sticking or clogging of the tablet core pusher rod is small-scale production. This involves first preparing the co-processed excipients, then performing a small-scale tableting test to observe whether sticking or clogging of the pusher rod occurs. If sticking or clogging persists, the co-processed excipients must be prepared again until this phenomenon disappears. The biggest problem with this method is that the results cannot be predicted before tableting. Furthermore, when modifying the preparation method of the co-processed excipients or changing the excipient type or source, there is a lack of clear direction and objectives. Companies often try different types, manufacturers, or models of excipients multiple times, but this may not necessarily improve the pusher rod clogging issue. Moreover, once the excipients are determined, changing suppliers, even with identical ingredient lists, often results in sticking and clogging of the pusher rod, making it difficult to switch suppliers and severely limiting production.
[0005] Therefore, there is an urgent need to provide a co-processing crystal excipient evaluation method to prevent machine blockage during tableting, so as to reduce pre-production testing work, reduce the consumption of time, manpower and material resources, and provide simple and quick conditions for production. Summary of the Invention
[0006] The technical problem to be solved by this invention is to overcome the shortcomings and deficiencies of existing excipient selection, which lacks directionality, requires multiple tests, and is time-consuming and labor-intensive. This invention provides a co-processing crystal excipient evaluation method to prevent machine blockage during tableting, thereby reducing pre-production testing work, reducing the consumption of time, manpower and material resources, and providing simple and quick conditions for production.
[0007] The above-mentioned objective of this invention is achieved through the following technical solution:
[0008] A method for evaluating co-processed crystal excipients to prevent machine blockage during tableting includes the following steps:
[0009] S1. According to the formulation of the co-processed crystal excipient, the co-processed crystal excipient is stirred and mixed evenly to obtain a premixed excipient, and the co-processed crystal excipient is prepared according to the drug specification process.
[0010] S2. Determine the crystallinity of the co-treated crystalline excipients and premixed excipients. Based on the peak position 2θ and relative intensity value I / I0 data of the co-treated crystalline excipients and premixed excipients, peaks with relative intensity I / I0 ≥ 20% are identified as common peaks. Obtain the number of common peaks and their relative intensities. List the peak positions and relative intensities of the common peaks and evaluate their similarity using the cosine similarity method. The correlation coefficient should not be lower than 0.90.
[0011] S3. The thermal stability of the co-processed crystal additives and premixed additives was measured, and the position and number of thermal peaks were analyzed and compared. The position and number of the endothermic and exothermic peaks were basically the same.
[0012] S4. The particle size distribution of the co-treated crystal additives was measured to obtain particle size data, d. 10 d 50 , where d 10 Not less than 30μm;
[0013] S5. Determine the particle shape of the co-treated crystal excipients to obtain particle shape data, including sphericity, symmetry, and concavity / convexity. When d 50 When the diameter is less than 100 μm, the sphericity, aspect ratio, and roughness of the co-processed crystal auxiliary material should be no less than 0.90, 0.90, and 0.98, respectively. 50 For particles larger than 100 μm, the particle shape does not affect the particle size.
[0014] Furthermore, in step S2, the crystallinity is determined using an X-ray diffractometer.
[0015] Furthermore, in step S2, the parameters of the X-ray diffractometer are set as follows: Cu target, Ka line, voltage 10-40kV, current 10-40mA, step size 0.02°-1°, scanning speed 0.1-10° / min, and scanning range 2°-90°.
[0016] Furthermore, in step S3, the thermal stability performance is measured using a differential scanning calorimeter.
[0017] Furthermore, in step S3, the parameters of the differential scanning calorimeter are set as follows: heating from room temperature to 100-400°C at a heating rate of 1-20°C / min.
[0018] Furthermore, in step S4, the particle size distribution is determined using a particle size and shape analyzer or a laser particle size analyzer.
[0019] Furthermore, in step S4, if a particle size and shape analyzer is used, the parameters of the particle size and shape analyzer are set to: X-jet or X-fall mode. When using X-jet mode, the dispersion pressure is between 5 and 50 kPa, and the apparent coverage area is not higher than 0.2%.
[0020] Further, in step S4, if a laser particle size analyzer is used, the parameters of the laser particle size analyzer are set as follows: using general mode, shading degree 0.2% to 10.0%, and dispersion pressure 1.0 to 10 bar.
[0021] Furthermore, in step S5, the particle shape is measured using a particle size analyzer.
[0022] Further, in step S5, the parameters of the particle size and shape analyzer are set to: X-jet or X-fall mode, with the dispersion pressure between 10 and 50 kPa and the apparent coverage area not exceeding 0.2% when using X-jet mode.
[0023] The present invention has the following beneficial effects:
[0024] This invention provides a method for evaluating co-processed crystal additives to prevent machine blockage during tableting. By comparing and evaluating indicators such as crystallinity, thermal stability, particle shape, and particle size distribution of co-processed or premixed crystal additives, this method can accurately predict and easily determine whether the co-processed additives used will cause blockage of the die core push rod. This directly avoids push rod blockage during die-packing production, thereby reducing time, manpower, and material consumption, providing simple and quick conditions for production, and offering high accuracy. It can significantly improve the production efficiency of die-packing and is very suitable for large-scale industrial production. Attached Figure Description
[0025] Figure 1 The DVS spectra are for the co-processed crystal additives and premixed crystal additives in Examples 1-3.
[0026] Figure 2 The DVS spectra are from Examples 4-5. Detailed Implementation
[0027] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.
[0028] This application uses the same excipient formulation and component source as the known original drug to premix the excipients to obtain the premixed excipients. The excipient formulations in each embodiment or comparative formulation are also the same. The differences are in the manufacturers, batches, specifications, etc. of each component, as well as the different processing technology, in order to obtain the same drug quality as the original drug under the condition of lower cost.
[0029] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.
[0030] Example 1: An evaluation method for co-processed crystal excipients to prevent machine blockage during tableting (No. T01)
[0031] The evaluation method for co-processed crystal excipients to prevent machine blockage during tableting specifically includes the following steps:
[0032] S1. Based on the formulation of the co-processing crystal auxiliary material, a premixed auxiliary material is prepared by a simple physical mixing method (simply stirring and mixing), and co-processing crystal auxiliary material a is prepared according to the predetermined process.
[0033] S2. Take appropriate amounts of co-treated crystal excipient a and premixed excipient, place them on a sample holder, compact them, and use a powder X-ray diffractometer (PXRD) to determine the crystallinity of co-treated crystal excipient a and premixed excipient. The parameters of the X-ray diffractometer (PXRD) are set as follows: Cu target, Ka line, voltage 30kV, current 30mA, step size 0.02°, scanning speed 1° / min, and scanning range 2°~90°. The peak positions (2θ) and relative intensity values (I / I0) obtained by PXRD detection are used. Peaks with a relative intensity (I / I0) ≥ 20% are considered common peaks, and the number and relative intensity of common peaks are obtained. The peak positions and relative intensities of the common peaks in PXRD are listed, and the similarity is evaluated by the cosine similarity method. The results are shown in Table 1.
[0034] S3. Take appropriate amounts of co-treated crystal additive a and premixed additive, place them in a covered crucible, and use a differential scanning calorimeter (DSC) with parameters set to a heating rate of 5℃ / min, heating from 25℃ to 350℃. Analyze the thermal stability of co-treated crystal additive a and premixed additive. The endothermic and exothermic peaks of co-treated crystal additive a should be basically consistent with the peak positions and number of peaks of the premixed additive. See [link to results]. Figure 1 Compared with Table 1;
[0035] S4. Take an appropriate amount of co-treated crystal excipient a and use a particle size analyzer to determine the particle size distribution of co-treated crystal excipient a. The parameters are set to X-jet mode, the dispersion pressure is 10 kPa, and the apparent coverage area is not higher than 0.2%. The results are shown in Table 1.
[0036] S5. Take an appropriate amount of co-treated crystal excipient a and use a particle size and shape analyzer to determine the particle shape of co-treated crystal excipient a. The parameters of the particle size and shape analyzer are set to X-jet mode, the dispersion pressure is 10 kPa, and the apparent coverage area is not higher than 0.2%. The results are shown in Table 1.
[0037] Example 2: An evaluation method for co-processed crystal excipients to prevent machine blockage during tableting (No. T02)
[0038] The evaluation method for co-processed crystal excipients to prevent machine blockage during tableting specifically includes the following steps:
[0039] S1. Based on the formulation of the co-processing crystal auxiliary material, a premixed auxiliary material is prepared by a simple physical mixing method (simply stirring and mixing), and co-processing crystal auxiliary material b is prepared according to the predetermined process.
[0040] S2. Take appropriate amounts of co-treated crystal excipient b and premixed excipient, place them on a sample holder, compact them, and use a powder X-ray diffractometer (PXRD) to determine the crystallinity of co-treated crystal excipient b and premixed excipient. The parameters of the X-ray diffractometer (PXRD) are set as follows: Cu target, Ka line, voltage 40kV, current 40mA, step size 0.02°, scanning speed 2° / min, and scanning range 2°~90°. The peak positions (2θ) and relative intensity values (I / I0) obtained by PXRD detection are used. Peaks with a relative intensity (I / I0) ≥ 20% are considered common peaks, and the number and relative intensity of common peaks are obtained. The peak positions and relative intensities of the common peaks in PXRD are listed, and the similarity is evaluated by the cosine similarity method. The results are shown in Table 1.
[0041] S3. Take appropriate amounts of co-treated crystal additive b and premixed additive, place them in a covered crucible, and use a differential scanning calorimeter (DSC) with parameters set to a heating rate of 10℃ / min to heat from room temperature to 300℃. Analyze the thermal stability of co-treated crystal additive b and premixed additive. The endothermic and exothermic peaks of co-treated crystal additive b should be basically consistent with the peak positions and number of peaks of the premixed additive. See [link to results]. Figure 1 Compared with Table 1;
[0042] S4. Take an appropriate amount of co-treated crystal excipient b and use a laser particle size analyzer to determine the particle size distribution of co-treated crystal excipient b. Use the general mode, 5.0% light shading, and 10 bar dispersion pressure. The results are shown in Table 1.
[0043] S5. Take an appropriate amount of co-treated crystal excipient b and use a particle size and shape analyzer to determine the particle shape of co-treated crystal excipient b. The parameters of the particle size and shape analyzer are set to X-jet mode, the dispersion pressure is 10 kPa, and the apparent coverage area is not higher than 0.2%. The results are shown in Table 1.
[0044] Example 3: An evaluation method for co-processed crystal excipients to prevent machine blockage during tableting (No. T03)
[0045] The evaluation method for co-processed crystal excipients to prevent machine blockage during tableting specifically includes the following steps:
[0046] S1. Based on the formulation of the co-processing crystal auxiliary material, a premixed auxiliary material is prepared by a simple physical mixing method (simply stirring and mixing), and the co-processing crystal auxiliary material c is prepared according to the predetermined process.
[0047] S2. Take appropriate amounts of co-treated crystal excipient c and premixed excipient, place them on a sample holder, compact them, and use a powder X-ray diffractometer (PXRD) to determine the crystallinity of co-treated crystal excipient c and premixed excipient. The parameters of the X-ray diffractometer (PXRD) are set as follows: Cu target, Ka line, voltage 20kV, current 20mA, step size 0.02°, scanning speed 0.5° / min, and scanning range 2°~90°. The peak positions (2θ) and relative intensity values (I / I0) obtained by PXRD detection are used. Peaks with a relative intensity (I / I0) ≥ 20% are considered common peaks, and the number and relative intensity of common peaks are obtained. The peak positions and relative intensities of the common peaks in PXRD are listed, and the similarity is evaluated by the cosine similarity method. The results are shown in Table 1.
[0048] S3. Take appropriate amounts of co-treated crystal additive c and premixed additive, place them in a covered crucible, and use a differential scanning calorimeter (DSC) with parameters set to a heating rate of 5℃ / min to heat from room temperature to 250℃. Analyze the thermal stability of the co-treated crystal additive c and the premixed additive. The endothermic and exothermic peaks of the co-treated crystal additive c should be basically consistent with the peak positions and number of the premixed additive in the DSC acquisition results. See [link to results]. Figure 1 Compared with Table 1;
[0049] S4. Take an appropriate amount of co-treated crystal excipient c and use a laser particle size analyzer to determine the particle size distribution of co-treated crystal excipient c. Use the general mode, 8.0% light shading, and 8 bar dispersion pressure. The results are shown in Table 1.
[0050] S5. Take an appropriate amount of co-treated crystal excipient c and use a particle size and shape analyzer to determine the particle shape of co-treated crystal excipient c. The parameters of the particle size and shape analyzer are set to X-fall mode, and the apparent coverage area is not higher than 0.2%. The results are shown in Table 1.
[0051] The co-processed crystal excipients of Examples 1 to 3 (numbered T01 to T03) were pressed into tablets and compared with the predicted results. The results are shown in Table 1.
[0052] Table 1. Test data and tableting results for Examples 1-3
[0053]
[0054]
[0055] As can be seen from the table, the evaluation method of this invention can accurately predict whether the co-processed crystal additives will cause blockage of the tablet core push rod during the tableting process.
[0056] Example 4: An evaluation method for co-processed crystal excipients to prevent machine blockage during tableting (No. T04)
[0057] The co-treated crystal additive d was evaluated and measured according to the method in Example 1. The DVS measurement results are shown in the figure below. Figure 2 The results are shown in Table 2.
[0058] Example 5: An evaluation method for co-processed crystal excipients to prevent machine blockage during tableting (No. T05)
[0059] The co-treated crystal additive e was evaluated and measured according to the method in Example 1. The DVS measurement results are shown in the figure below. Figure 2 The results are shown in Table 2.
[0060] The co-processed crystal excipients from Examples 4-5 were pressed into tablets, and the results were compared with the predicted results. The results are shown in Table 2.
[0061] Table 2. Test data and tableting results for Examples 4-5
[0062]
[0063]
[0064] As can be seen from the table, the evaluation method of this invention can accurately predict whether the co-processed crystal additives will cause blockage of the tablet core push rod during the tableting process.
[0065] Comparative Example 1: An Evaluation Method for Co-processed Crystal Additives (Y1)
[0066] The evaluation method for co-processed crystal additives specifically includes the following steps:
[0067] S1. Take an appropriate amount of co-treated crystal excipient f and use a laser particle size analyzer to determine the particle size distribution of co-treated crystal excipient f. Use the general mode, 8.0% shading, and 8 bar dispersion pressure. The results are shown in Table 3.
[0068] S2. Take an appropriate amount of co-treated crystal auxiliary material f and place it in a weighing bottle that has been dried to a very heavy weight at 105℃. Dry it at 105℃ to a constant weight. The moisture content of the co-treated crystal auxiliary material f is determined by the weight loss and the amount of sample taken. The results are shown in Table 3.
[0069] S3. Take an appropriate amount of co-treated crystal auxiliary material f, spray it with gold using an ion sputtering instrument, observe it under a field emission electron microscope, and use an energy dispersive spectroscopy instrument to detect the binder-specific elements in the formula and examine whether its surface distribution is uniform. The results are shown in Table 3.
[0070] The prediction of whether the co-processed crystal additives will clog the plunger rod is based on the particle size, moisture content, binder concentration, and binder distribution. The results are shown in Table 3.
[0071] Comparative Example 2: An Evaluation Method for Co-processed Crystal Additives (No. Y2)
[0072] The evaluation method for co-processed crystal additives specifically includes the following steps:
[0073] The co-treated crystal excipient g was evaluated and measured according to the method of Comparative Example 1, and the results are shown in Table 3.
[0074] Comparative Example 3: An Evaluation Method for Co-processed Crystal Additives (Y3)
[0075] The evaluation method for co-processed crystal additives specifically includes the following steps: the co-processed crystal additive h is evaluated and measured with reference to the method of Comparative Example 1, and the results are shown in Table 3.
[0076] The co-processed crystal excipients of Comparative Examples 1 to 3 (numbered Y1 to Y3) were pressed into tablets and compared with the predicted results. The results are shown in Table 3.
[0077] Table 3. Comparative Examples 1-3: Test Data and Tableting Results
[0078]
[0079] As shown in the table, the average particle size of the three comparative samples ranges from 82.98 μm to 257 μm, indicating that the sample particles are large and have good flowability. Meanwhile, d 10 The data for all samples are relatively large, especially for Y3, indicating that there is little fine powder and no problem of excessive fine powder causing blockage. The moisture content of the three batches of samples is basically the same, all around 1%, which is low and should not cause blockage. The binder concentration of the three samples is consistent. Electron microscopy energy dispersive spectroscopy analysis showed that the binder distribution of the three batches of samples is uniform, and there is no problem of uneven binder causing blockage. In summary, the evaluation and analysis concluded that none of the three batches of samples will block the column pusher.
[0080] However, during the actual tablet compression process, it was found that only Y2 of the three batches of samples did not experience clogging, while the other two batches showed clogging, especially sample Y3, which was significantly inconsistent with existing understanding of the causes of clogging. Furthermore, the method of Example 1 of this invention was used to predict the effects on samples Y1 to Y3, and the prediction results were basically consistent with the actual results.
[0081] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A method for evaluating co-processed crystalline excipients for preventing machine pluggage during tableting, characterized by, Specifically comprising the following steps: S1, according to the formula of the co-processed crystal adjuvant, the co-processed crystal adjuvant is stirred and mixed uniformly to obtain a premixed adjuvant, and the co-processed crystal adjuvant is prepared according to the specified process of the drug; S2, the crystallinity of the co-processed crystal adjuvant and the premixed adjuvant is determined, and the number and relative intensity of the common peaks are obtained according to the peak position 2θ and relative intensity value I / I0 data of the co-processed crystal adjuvant and the premixed adjuvant, the peak with relative intensity I / I0≥20% is the common peak, the similarity evaluation is carried out, and the correlation coefficient should not be less than 0.90; S3, the thermal stability of the co-processed crystal adjuvant and the premixed adjuvant is determined, and the position and number of the thermal peaks are analyzed and compared, and the position and number of the peaks are basically consistent; S4, the particle size distribution of the co-processed crystal excipient is measured to obtain particle size data, wherein d 10 not less than 30 pm; S5. Measure the particle shape of the co-processed crystal additive to obtain particle shape data. When d 50 When the diameter is less than 100 μm, the sphericity, aspect ratio, and roughness of the co-processed crystal auxiliary material should be no less than 0.90, 0.90, and 0.98, respectively. 50 For particles larger than 100 μm, the particle shape does not affect the particle size.
2. The evaluation method according to claim 1, characterized by, In step S2, the crystallinity is determined by X-ray diffractometer.
3. The evaluation method according to claim 2, characterized by, In step S2, the parameters of the X-ray diffractometer are set as follows: Cu target, Ka line, voltage 10-40 kV, current 10-40 mA, step length 0.02-1°, scanning speed 0.1-10° / min, scanning range 2-90°.
4. The evaluation method according to claim 1, characterized by, In step S3, the thermal stability is determined by differential scanning calorimeter.
5. The evaluation method according to claim 4, characterized by, In step S3, the parameters of the differential scanning calorimeter are set as follows: heating rate 1-20℃ / min, from room temperature to 100-400℃.
6. The evaluation method according to claim 1, characterized by, In step S4, the particle size distribution is determined by particle size and shape analyzer or laser particle size analyzer.
7. The evaluation method according to claim 6, characterized by, In step S4, the parameters of the particle size and shape analyzer are set as follows: X-jet or X-fall mode, when using X-jet mode, dispersion pressure is 5-50 kpa, and apparent coverage area is not higher than 0.2%.
8. The evaluation method according to claim 6, characterized by, In step S4, the parameters of the laser particle size analyzer are set as follows: general mode is used, light shielding degree is 0.2%-10.0%, and dispersion gas pressure is 1.0-10 bar.
9. The evaluation method according to claim 1, characterized by, In step S5, the particle shape is determined by particle size and shape analyzer.
10. The evaluation method according to claim 9, wherein In step S5, the parameters of the particle size and shape analyzer are set as X-jet or X-fall mode, when using X-jet mode, dispersion pressure is 5-50 kpa, and apparent coverage area is not higher than 0.2%.