Preparation process of solid medicinal composite hard sheet

Abstract

The invention relates to the technical field of medicinal hard sheet preparation, and discloses a solid medicinal composite hard sheet preparation process, which comprises three core steps of preheating thermal refining treatment, pulse electromagnetic field sequence arrangement and instantaneous cooling shaping, and introduces a rotary partition preparation technology and a field homogenizing treatment technology for batch production. According to the invention, through the step-by-step cooperation of three technical elements, the problem that the structure is unstable after particles are arranged in the traditional directional arrangement technology is solved, the stability and durability of the tablet structure are realized, the consistency among batches in batch production is ensured, the accuracy and repeatability of particle arrangement are improved, and the production efficiency is improved. And finally, the solid medicinal composite hard tablet with better mechanical strength uniformity, drug release consistency and longer storage stable period is prepared.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of medicinal hard tablets, and more specifically, to a preparation process of solid medicinal composite hard tablets. Background Art

[0002] Solid pharmaceutical composite hard tablets, as an important drug dosage form, play a key role in drug delivery systems. The traditional preparation process mainly uses simple tableting technology, which has obvious limitations in the preparation of complex functional tablets.

[0003] In recent years, the rotating electromagnetic field-assisted directional alignment technology has shown advantages in improving the mechanical strength of tablets and controlling drug release. However, it faces two key technical problems in practical applications: first, the particles are structurally unstable after directional alignment and are prone to displacement or loosening during subsequent processing, resulting in performance fluctuations in the final product; second, in a batch production environment, uneven electromagnetic field distribution and asynchronous cooling lead to differences between batches of products, affecting product quality consistency. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a process for preparing a solid medicinal composite hard tablet.

[0005] The present invention provides a process for preparing a solid medicinal composite hard tablet, comprising the following steps: Step 1: Preheating and tempering treatment: preheat the active ingredient and excipient mixture at 40-60°C, and apply mechanical vibration to enhance the plasticity of the excipient particles and their responsiveness to the electromagnetic field; Step 2: Pulsed electromagnetic field sequence arrangement: the preheated mixture is placed in the electromagnetic field action area, and an electromagnetic field sequence composed of pulses of different frequencies, intensities and durations is applied to achieve high-precision directional arrangement of particles; Step 3: Instant cooling and shaping. When the particles reach the ideal arrangement state, the cooling medium is introduced from multiple directions at the same time to quickly reduce the particle temperature to below the glass transition temperature of the auxiliary material and fix the arrangement structure of the particles; Step 4: Final tableting, testing and packaging.

[0006] Preferably: the preheating and tempering treatment includes: Raw material preparation: weigh and mix the active ingredients and excipients according to the predetermined formula to obtain a uniform powder mixture; Determination of preheating temperature: Determine the preheating temperature according to the glass transition temperature of the auxiliary material, and the preheating temperature is between the glass transition temperature minus 15°C and minus 5°C; Dynamic preheating operation: mechanical vibration is applied to the powder mixture while increasing the temperature; Maintain uniform temperature: When the target temperature is reached, maintain it for 15-30 minutes, while controlling the relative humidity of the environment within the range of 30-40%.

[0007] Preferably, the powder mixture is subjected to mechanical vibration at a frequency of 10-30 Hz while being heated at a rate of 0.5-2° C. / min.

[0008] Preferably: the pulse electromagnetic field sequence arrangement includes: Pulse sequence parameters were determined as follows: the basic field strength range was 0.2-1.0 Tesla, the pulse frequency was 1-10 Hz, and trapezoidal or sine waves were used; Sample introduction: transfer the preheated and tempered mixture to the electromagnetic field action area within 30 seconds; Pulse sequence execution: applying a pulsed electromagnetic field to the mixture, the execution time is 45-90 seconds; Arrangement state monitoring: Observe the changes in the particle arrangement state through a real-time optical monitoring system to determine the time point when the preset arrangement state is reached.

[0009] Preferably: instant cooling and shaping includes: Cooling system preparation: configure cooling medium delivery device and temperature monitoring system outside the electromagnetic field action area; Trigger condition determination: the time point at which the preset arrangement state is reached is set as the cooling trigger condition; Multi-zone cooling execution: cooling medium is introduced from the top, bottom, left and right of the sample at the same time, and the cooling rate is controlled at 15-30℃ / second; Temperature reduction and stabilization: When the sample temperature drops to 20-25°C, reduce the cooling rate, slowly cool to room temperature and keep for 5-10 minutes.

[0010] Preferably: it also includes a batch production step, and the batch production step includes rotary partition preparation and field equalization treatment.

[0011] Preferably: the rotary partition preparation includes: Unit division: Divide the production line into 4-8 independent preparation units; Peak-shifted start-up execution: Each preparation unit starts in sequence at a time interval of 30-60 seconds; Unit timing control: The relative timing and parameters of the three core steps of preheating and tempering, electromagnetic field arrangement and instantaneous cooling within each unit remain consistent.

[0012] Preferably: the averaging process includes: Field intensity distribution measurement: Conduct three-dimensional field intensity distribution measurement in the production area to form a field intensity contour map; Physical shielding application: Apply physical shielding layer to areas with excessive field strength; Field strength compensation implementation: adding local compensation coils to areas with weaker field strength; Dynamic field intensity regulation: The current parameters of the compensation coil are adjusted through the real-time monitoring system to maintain the stability of the field intensity distribution.

[0013] Preferably, the pulse sequence combination is a three-stage sequence of low frequency and low intensity, high frequency and medium intensity, and low frequency and high intensity.

[0014] Preferably, the cooling medium is liquid nitrogen or cooling air.

[0015] The beneficial effects of the present invention are as follows: the present invention realizes the following specific technical effects by combining the three technical elements of preheating and tempering, pulse electromagnetic field sequence arrangement and instantaneous cooling and shaping with the rotary partition preparation technology and the uniform field treatment technology: Improved structural stability: By implementing instant cooling at the precise moment when the particles reach the ideal arrangement state, the arrangement structure is fixed.

[0016] Improved uniformity of mechanical strength: The pulsed electromagnetic field sequence arrangement technology achieves orderly arrangement of particles and improves the uniformity of the overall structure of the tablet.

[0017] Improved drug release consistency: The ordered particle arrangement structure and uniform internal pore distribution make the drug release behavior more controllable and consistent.

[0018] Batch consistency guarantee: Rotary partition preparation technology and uniform field processing technology effectively solve the problems of electromagnetic field uniformity and cooling synchronization in batch production, ensuring high consistency between product batches.

[0019] Extended storage stability: Structurally stable tablets have an increased ability to resist environmental changes (temperature, humidity fluctuations) during storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a comparison of the structural retention rate after the mechanical vibration test in the present invention; Figure 2 is the compressive strength test result in different directions in the present invention (N); Figure 3 It is a comparison of similarity factors of drug release curves of different batches in the present invention; Figure 4 The percentage of drug release at each time point and the RSD between batches in the present invention are compared; Figure 5 It is a comparison of batch consistency test results in the present invention; Figure 6 This is the change of each quality index in the accelerated stability test (40°C, 75%RH) for 6 months in the present invention. DETAILED DESCRIPTION

[0021] The subject matter described herein will now be discussed with reference to example implementations. It should be understood that the discussion of these implementations is only to enable those skilled in the art to better understand and implement the subject matter described herein, and the functions and arrangements of the elements discussed may be changed without departing from the scope of protection of the present specification. Various examples may omit, replace, or add various processes or components as needed. In addition, the features described in some examples may also be combined in other examples.

[0022] At least one embodiment of the present invention discloses a process for preparing a solid pharmaceutical composite hard tablet, comprising the following specific steps: Step 1: Preheating and tempering The purpose of this step is to enhance the plasticity of the auxiliary material particles and their responsiveness to the electromagnetic field, thus creating favorable conditions for the subsequent directional arrangement of the particles.

[0023] Specific operations include: Raw material preparation: Weigh and mix the active ingredients of the drug and excipients according to the predetermined formula to obtain a uniform powder mixture.

[0024] Preheating temperature determination: According to the physical and chemical properties of each component in the prescription, the preheating temperature range is determined to be 40-60°C. The specific temperature is determined according to the glass transition temperature (Tg) of the excipients, usually controlled between Tg-15°C and Tg-5°C to ensure that the particles have sufficient plasticity without melting deformation.

[0025] Dynamic preheating operation: The powder mixture is placed in a preheating device, and mechanical vibration (frequency 10-30Hz) is applied to the powder mixture during the preheating process, while the temperature is increased (the heating rate is controlled at 0.5-2℃ / min). This operation promotes uniform heat conduction between powder particles and prevents local overheating or uneven temperature distribution.

[0026] Even temperature maintenance: When the target temperature is reached, maintain it for 15-30 minutes to allow the temperature distribution inside the particles to reach an equilibrium state. At the same time, control the relative humidity of the environment within the range of 30-40% to avoid excessive dryness leading to static electricity accumulation or excessive humidity leading to particle agglomeration.

[0027] Step 2: Pulsed electromagnetic field sequence arrangement This step is the core link of this embodiment, and aims to achieve high-precision directional arrangement of auxiliary material particles through a pulsed electromagnetic field sequence.

[0028] Specific operations include: Determination of pulse sequence parameters: Determine the parameters of the pulsed electromagnetic field sequence according to the physical properties of the particles to be processed (such as size, shape, density, etc.) and the target arrangement structure (such as layered, columnar or grid arrangement, etc.). Different from the traditional constant electromagnetic field, this step uses a time-varying pulsed electromagnetic field, which specifically includes: Determination of basic field strength: According to the response characteristics of the auxiliary materials to the electromagnetic field, the basic field strength range is determined to be 0.2-1.0 T (Tesla).

[0029] Pulse frequency selection: The pulse frequency is usually in the range of 1-10 Hz, and the specific frequency is determined according to the response characteristics of the particles.

[0030] Pulse waveform application: Use trapezoidal wave or sine wave instead of traditional square wave to reduce the interference of sudden changes in field strength on particle arrangement.

[0031] Sequence combination: Pulses of different frequencies, intensities, and durations are combined into sequences in a specific order, such as the three-stage sequence of “low frequency and low intensity → high frequency and medium intensity → low frequency and high intensity”, to achieve a progressive and precise arrangement of particles.

[0032] Sample introduction: The preheated and tempered powder mixture is quickly placed (transfer time does not exceed 30 seconds) into the electromagnetic field action area to ensure that the particles remain in the preheated state.

[0033] Pulse sequence execution: According to the preset pulse sequence parameters, the electromagnetic field generation system is started to apply the pulsed electromagnetic field to the powder mixture. The execution time of the entire pulse sequence is usually 45-90 seconds, depending on the prescription and the target arrangement structure.

[0034] Alignment state monitoring: During the pulse sequence execution, the changes in the particle alignment state are observed through a real-time optical monitoring system. When the predetermined alignment state is reached (judged by the optical scattering pattern or transmission image), the system marks it as the "ideal alignment state" as the trigger time point for the next instantaneous cooling.

[0035] in: The excipient is hydroxypropyl methylcellulose (HPMC) K100M, which is a high viscosity grade cellulose ether derivative whose chemical structure is based on a cellulose backbone with some hydroxyl groups replaced by methyl and hydroxypropyl groups.

[0036] In the present invention, HPMC K100M is treated in one of two ways to enhance its magnetic responsiveness: The first type: needle-shaped processing: HPMC K100M is processed into needle-shaped particles with a length-to-diameter ratio of about 5:1 by using directional grinding and screening technology to enhance shape anisotropy.

[0037] Second: doping technology: The uniform dispersion of ultrafine magnetic iron oxide (Fe3O4) nanoparticles (particle size <50nm) can be used; The doping ratio is usually controlled in the range of 0.1-0.5%, which is enough to provide magnetic responsiveness without affecting drug safety; Surface modification: Improve the surface properties of particles and enhance the dispersibility of particles in the mixture through treatment with surfactants such as silane coupling agents.

[0038] 1. Magnetic anisotropy and magnetic moment alignment The directional arrangement of magnetic particles in an external magnetic field is based on the principle of magnetic anisotropy. When a material with magnetic anisotropy is placed in a magnetic field, its magnetic moment will be aligned along the direction of the magnetic field to minimize the magnetic energy of the material. For non-spherical particles (such as needle-shaped or flake-shaped), due to shape anisotropy, the particles will align along their long axis with the direction of the external magnetic field. In polymer materials such as HPMCK100M, although they do not have ferromagnetism themselves, they can show magnetic responsiveness after processing and doping. These magnetic responsiveness mainly come from two aspects: Shape anisotropy: Needle-shaped HPMC K100M particles will produce a demagnetization effect in a magnetic field, causing the long axis of the particles to tend to be parallel to the direction of the external magnetic field. Doping with trace magnetic materials: HPMC can be doped with very small amounts of ferrite or other magnetic auxiliary materials to enhance its magnetic responsiveness 2. Theoretical basis of waveform design The physical effects of different waveforms vary significantly: Trapezoidal wave: The field intensity gradient process provides smooth transition and reduces particle "overshoot" phenomenon Sine wave: provides a continuously changing force field, which is conducive to the fine arrangement of particles Square wave: sudden change in field strength causes particles to respond violently, which can easily lead to unstable arrangement The present invention adopts a combination of trapezoidal waves and sine waves, which is based on the principle of minimum entropy production in non-equilibrium thermodynamics - under the condition of achieving the same arrangement effect, the entropy increase produced by the gently changing field intensity is minimal, and the system is more likely to reach an ordered state.

[0039] Step 3: Instant cooling and shaping This step is designed to fix the structure of the particles at the moment they reach a preset ideal arrangement state through a precisely controlled instantaneous cooling process, thereby preventing loosening or rearrangement during subsequent processing.

[0040] Specific operations include: Cooling system preparation: A fast-response cooling system is configured around the electromagnetic field action area, including a cooling medium delivery device and a temperature monitoring system. The cooling medium can be liquid nitrogen or cooling air, depending on the required cooling rate.

[0041] Determine the trigger condition: Set the "ideal arrangement state" time point marked in the previous step as the cooling trigger condition to ensure that the cooling process is started at the moment when the particle arrangement reaches the optimal state.

[0042] Multi-zone cooling execution: When the trigger condition is met, the cooling system simultaneously introduces cooling medium from multiple directions of the sample (up, down, left, and right) to form a uniform cooling wave front, avoiding the problem of uneven temperature gradient that may be caused by unidirectional cooling. The cooling rate is controlled at 15-30℃ / second to ensure rapid fixation of the particle structure without generating excessive internal stress.

[0043] Temperature reduction stabilization: When the sample temperature drops to 20-25°C (lower than the glass transition temperature of the excipient), reduce the cooling rate, slowly cool to room temperature, and keep for 5-10 minutes to ensure that the structure is completely stable.

[0044] Step 4: Subsequent processing After the structure is fixed, the material is tableted, tested and packaged.

[0045] In order to solve the problems of electromagnetic field uniformity and cooling synchronization in a mass production environment, this embodiment adopts the following method: Rotary partition preparation The large-scale production is divided into multiple independently operated small-scale continuous preparation units, and each unit independently completes the entire process of preheating and tempering, electromagnetic field arrangement and cooling and shaping.

[0046] Specific implementation includes: Unit division: According to the production scale and equipment characteristics, the production line is divided into multiple (usually 4-8) independent preparation units, each unit is equipped with complete preheating and tempering, electromagnetic field arrangement and instantaneous cooling and shaping equipment.

[0047] Peak-shifted start-up execution: Each preparation unit starts up in turn at a preset time interval (usually 30-60 seconds), forming a peak-shifted operation mode. This peak-shifted start-up method prevents all units from entering high-energy consumption stages (such as preheating high temperature maintenance or electromagnetic field peak output) at the same time, reduces the system peak load, and ensures that each unit operates under optimal conditions.

[0048] Unit timing control: Although the start-up time of each unit is different, the relative timing and parameters of the three core steps within each unit (preheating and tempering, electromagnetic field arrangement, and instantaneous cooling) remain consistent to ensure uniform product quality.

[0049] Average field processing This technology solves the problem of uneven electromagnetic field distribution at different locations in mass production, ensuring that the electromagnetic environment of each preparation unit is consistent.

[0050] Specific implementation includes: Field strength distribution measurement: After the mass production equipment is installed, use a high-precision magnetic field detector to measure the three-dimensional field strength distribution of the entire production area, form a field strength contour map, and determine the area of ​​uneven field strength.

[0051] Physical shielding application: For areas where the field strength is too high, a physical shielding layer made of specific materials (such as high magnetic permeability alloy) is applied to weaken the local field strength.

[0052] Implementation of field strength compensation: For areas with weak field strength, local compensation coils are added to increase local field strength and achieve uniform distribution of overall field strength.

[0053] Dynamic field intensity regulation: During the production process, the actual field intensity in each area is continuously monitored through the real-time field intensity monitoring system, and the current parameters of the compensation coil are adjusted through the feedback control system to maintain the stability of the field intensity distribution.

[0054] This embodiment achieves the following effects through the step-by-step coordination of three technical elements: preheating and tempering, pulse electromagnetic field sequence arrangement, and instantaneous cooling and shaping, combined with rotary partition preparation and field averaging: Improved structural stability: By implementing instantaneous cooling at the precise moment when the particles reach the ideal arrangement state, the fixed effect of the arrangement structure is achieved. Tests show that the internal structure retention rate of the solid pharmaceutical composite hard tablets prepared by this process reaches more than 95% after undergoing a standard mechanical vibration test (20Hz, amplitude 2mm, lasting 30 minutes), while the structure retention rate of the samples prepared by the traditional process is only 70-80%.

[0055] Improved uniformity of mechanical strength: The pulsed electromagnetic field sequence arrangement technology achieves orderly arrangement of particles and improves the uniformity of the overall structure of the tablet. The compressive strength test shows that the compressive strength deviation of tablets prepared by this process in different directions is less than ±7%, while the directional deviation of tablets prepared by traditional processes is usually within the range of ±15-20%.

[0056] Improved drug release consistency: The ordered particle arrangement structure and uniform internal pore distribution make the drug release behavior more controllable and consistent. The dissolution test shows that the drug release curve similarity between different batches of tablets prepared by this process is greater than 85%, while the traditional process is usually 70-75%.

[0057] Batch consistency guarantee: Rotary partition preparation technology and uniform field treatment technology effectively solve the problems of electromagnetic field uniformity and cooling synchronization in batch production, ensuring high consistency between product batches. Batch production tests show that the inter-batch coefficient of variation (RSD) of key quality attributes (such as content uniformity, dissolution, mechanical strength, etc.) of tablets prepared by this process is reduced by about 40%.

[0058] Extended storage stability: Structurally stable tablets have an enhanced ability to resist environmental changes (temperature and humidity fluctuations) during storage. Accelerated stability tests (40°C, 75%RH, 6 months) showed that the key quality attributes of tablets prepared by this process did not change by more than 5% of the initial value during storage, while samples prepared by traditional processes usually changed within the range of 10-15%.

[0059] The experimental results show that the drug release curves of the solid pharmaceutical composite hard tablets prepared in this embodiment show higher consistency among different batches. The value is 91.1, which is significantly higher than 72.9 of the traditional process. The relative standard deviation (RSD) between batches is generally less than 3%, meeting the pharmacopoeia's requirements for highly uniform preparations.

[0060] In order to verify the above technical effects, the following experiments and tests are used to prove the technical advantages of the present invention through objective data. The following experiments are conducted for each technical effect.

[0061] 1. Structural stability test 1. Purpose of the experiment The structure retention rate of the solid pharmaceutical composite hard tablet prepared by the process of the present invention after mechanical vibration was verified and compared with the samples prepared by the traditional process.

[0062] 2. Experimental methods Sample preparation: Experimental group: solid medicinal composite hard tablets were prepared by the process of "preheating and tempering - pulse electromagnetic field sequence arrangement - instantaneous cooling and shaping" of the present invention, with a total of 3 batches, 20 tablets in each batch.

[0063] Control group: The solid pharmaceutical composite hard tablets were prepared by the traditional electromagnetic field assisted directional alignment process (without preheating and tempering and instantaneous cooling and shaping steps), with a total of 3 batches, 20 tablets in each batch.

[0064] Vibration test: The sample was placed on a standard vibration table and the vibration parameters were set to: frequency 20 Hz, amplitude 2 mm.

[0065] Vibrate continuously for 30 minutes, the experimental temperature is controlled at 25±2℃, and the relative humidity is 45±5%.

[0066] Structural analysis: Before vibration: Use X-ray computed tomography (Micro-CT) to perform a three-dimensional structural scan of the sample to obtain initial structural data.

[0067] After vibration: The same sample was scanned again using Micro-CT to obtain structural data after vibration.

[0068] The structural changes before and after vibration were compared by image analysis software, and the structural retention rate was calculated.

[0069] Calculation method: Structural retention rate (%) = (number of particles that retain the original arrangement after vibration / total number of particles before vibration) × 100%.

[0070] 3. Experimental results The experimental results show that the solid pharmaceutical composite hard tablet prepared by the process of the present invention has significantly higher structural stability. Figure 1 As shown: Figure 1 : Comparison of structure retention after mechanical vibration test.

[0071] It can be seen from the experimental results that after the standard mechanical vibration test, the sample prepared by the process of the present invention has an average structural retention rate of 96.4%, which is significantly higher than the 76.5% of the traditional process, an average increase of 19.9 percentage points. At the same time, the relative standard deviation (RSD) of the structural retention rate of the samples prepared by the process of the present invention is only 0.72%, which is much lower than the 3.47% of the traditional process, indicating that the process of the present invention has better batch consistency.

[0072] 2. Mechanical strength uniformity test 1. Purpose of the experiment The uniformity of the compressive strength of the solid pharmaceutical composite hard tablet prepared by the process of the present invention in different directions was evaluated to verify the isotropic characteristics of its mechanical properties.

[0073] 2. Experimental methods Sample preparation: Experimental group: solid medicinal composite hard tablets prepared by the process of the present invention, 3 batches in total, 30 tablets in each batch.

[0074] Control group: solid pharmaceutical composite hard tablets prepared by traditional technology, 3 batches in total, 30 tablets in each batch.

[0075] Compressive strength test: The compressive strength of the samples was tested using a standard tablet hardness tester (Erweka TBH-425).

[0076] Test direction: Each batch of samples is tested in three orthogonal directions (X, Y, and Z axes), with 10 pieces in each direction.

[0077] Test conditions: The pressure increase rate is 10 N / s until the tablet breaks, and the pressure value at the time of breaking is recorded.

[0078] Data Analysis: Calculate the average compressive strength of each batch of samples in three directions.

[0079] Evaluate directional deviation: Calculate the maximum relative deviation of the compressive strength of a single sample in three directions.

[0080] Deviation calculation formula: Directional deviation (%) = [(maximum compressive strength - minimum compressive strength) / average compressive strength] × 100% 3. Experimental results The experimental results show that the mechanical strength of the solid pharmaceutical composite hard tablet prepared by the process of the present invention shows better uniformity in different directions. Figure 2 As shown: Figure 2 : Compressive strength test results in different directions (N).

[0081] It can be seen from the experimental results that the average deviation of the compressive strength of the solid pharmaceutical composite hard tablets prepared by the process of the present invention in different directions is 6.8%, which is much lower than 29.9% of the traditional process, indicating that the process of the present invention significantly improves the uniformity of the mechanical strength of the tablets, making them have better isotropic characteristics. At the same time, the standard deviation of the compressive strength of the samples prepared by the process of the present invention in each direction is generally smaller than that of the traditional process, indicating that the consistency within the batch has also been improved.

[0082] 3. Drug Release Consistency Test 1. Purpose of the experiment The consistency of drug release behavior of solid pharmaceutical composite hard tablets prepared by the process of the present invention between different batches was evaluated to verify the reliability and predictability of their controlled release performance.

[0083] 2. Experimental methods Sample preparation: Experimental group: solid pharmaceutical composite hard tablets containing acetaminophen (APAP) prepared by the process of the present invention, 5 batches in total, 100 tablets in each batch.

[0084] Control group: solid pharmaceutical composite hard tablets containing the same active ingredients and content prepared by traditional technology, a total of 5 batches, each batch of 100 tablets.

[0085] Sample specifications: diameter 10mm, thickness 4mm, APAP content 500mg / piece.

[0086] Dissolution Test: Test method: According to the second method (paddle method) of the dissolution test method of the Chinese Pharmacopoeia (2020 edition).

[0087] Dissolution medium: pH 6.8 phosphate buffer, 900 ml.

[0088] Rotation speed: 75rpm.

[0089] Temperature: 37±0.5℃.

[0090] Sampling time points: 0.5h, 1h, 2h, 4h, 6h, 8h, 12h.

[0091] Detection method: UV spectrophotometry, the measurement wavelength is 243nm.

[0092] Twelve pieces were randomly selected from each batch for testing.

[0093] Data Analysis: The cumulative release percentage at each time point was calculated.

[0094] Batch-to-batch similarity evaluation: Calculate the similarity factor of drug release curves between batches ( ).

[0095] Factor calculation formula:

[0096] Where n is the number of sampling time points, and are the cumulative release percentages of the reference preparation and the test preparation at time point t, respectively.

[0097] Batch-to-batch consistency: The inter-batch relative standard deviation (RSD) of the release rate at each time point was calculated.

[0098] 3. Experimental results The experimental results show that the solid pharmaceutical composite hard tablets prepared by the process of the present invention show significantly higher consistency of drug release between different batches. Figure 3 and Figure 4 As shown: Figure 3 : Similarity factor of drug release curves of different batches ( )contrast.

[0099] Figure 4 : Comparison of drug release percentage at each time point and RSD between batches.

[0100] It can be seen from the experimental results that the similarity of drug release curves of solid pharmaceutical composite hard tablets prepared by the process of the present invention between different batches is significantly improved. The value reached 91.2, which is much higher than 72.8 of the traditional process. At the same time, the average inter-batch RSD of the drug release percentage of the samples prepared by the process of the present invention at each time point was only 1.9%, which was significantly lower than 6.5% of the traditional process. This shows that the process of the present invention can significantly improve the batch-to-batch consistency of drug release and provide a more reliable guarantee for the safety and effectiveness of clinical medication.

[0101] 4. Batch consistency test 1. Purpose of the experiment The batch consistency performance of the process of the present invention in a mass production environment is comprehensively evaluated, and the effects of the rotary partition preparation technology and the uniform field treatment technology in ensuring the consistency of product quality are verified.

[0102] 2. Experimental methods Sample preparation: The rotary partition preparation technology is adopted, 6 independent preparation units are set up, and 10 batches of solid medicinal composite hard tablets are continuously produced by the process of the present invention, each batch of 5000 tablets.

[0103] The conventional batch production process was used to continuously produce 10 batches of solid pharmaceutical composite hard tablets of the same specifications, with 5,000 tablets in each batch.

[0104] Record the electromagnetic field intensity distribution and temperature change curve of each preparation unit during the production process.

[0105] Quality Index Testing: A comprehensive quality assessment was conducted on samples produced by both processes to test the following key quality attributes: Weight variation: Randomly select 20 tablets from each batch and measure the single tablet weight and intra-batch variation.

[0106] Content uniformity: According to the content uniformity determination method of the "Chinese Pharmacopoeia" (2020 edition), the drug content uniformity of each batch of samples was determined.

[0107] Dissolution consistency: According to the above dissolution test method, the dissolution rate and intra-batch variation of each batch of samples at the specified time point were determined.

[0108] Hardness consistency: Randomly select 20 pieces from each batch and measure the compressive strength and intra-batch variation.

[0109] Batch-to-batch variation assessment: The inter-batch relative standard deviation (RSD) of each quality index was calculated.

[0110] The differences between the two processes in terms of batch-to-batch consistency were compared and analyzed.

[0111] Analysis of variance (ANOVA) was used to evaluate the significance of the impact of batch factors on each quality index.

[0112] 3. Experimental results The experimental results show that the rotary partition preparation technology and field treatment technology used in the process of the present invention significantly improve the batch consistency in a mass production environment. Figure 5 As shown: Figure 5 : Comparison of batch consistency test results.

[0113] The results of variance analysis showed that batch factors had a significant effect on the quality indicators of the traditional process (p<0.01), but had no significant effect on the quality indicators of the process of the present invention (p>0.05), which proved that the process of the present invention can effectively eliminate the influence of batch differences.

[0114] In addition, the real-time monitoring data of the electromagnetic field intensity distribution showed that after the field averaging technology was used, the field intensity distribution deviation in the six preparation units was reduced to ±3.2%, while the field intensity distribution deviation was as high as ±15.7% when the technology was not used. Through the process optimization of the present invention, the average RSD of various quality indicators between batches was reduced by 64.0%, indicating that the rotary partition preparation technology and the field averaging technology can significantly improve the product consistency in a batch production environment.

[0115] 5. Storage stability test 1. Purpose of the experiment The storage stability of the solid pharmaceutical composite hard tablet prepared by the process of the present invention under accelerated test conditions was evaluated to verify the influence of its structural fixation effect on the long-term storage performance.

[0116] 2. Experimental methods Sample preparation: Experimental group: solid medicinal composite hard tablets prepared by the process of the present invention, 3 batches in total, 100 tablets in each batch.

[0117] Control group: solid pharmaceutical composite hard tablets prepared by traditional technology, 3 batches in total, 100 tablets in each batch.

[0118] The sample specifications and prescription ratios remain consistent.

[0119] Accelerated stability test: Test conditions: Accelerated test conditions were set according to ICH guideline Q1A (R2), temperature 40 ± 2 ° C, relative humidity 75 ± 5%.

[0120] Storage container: Place the sample in a high-density polyethylene bottle and seal it.

[0121] Testing time points: 0, 1, 3, and 6 months.

[0122] At each time point, 20 tablets were randomly selected from each batch for testing.

[0123] Quality indicator evaluation: The following quality indicators were tested at each detection time point: Appearance changes: Visually inspect surface finish, color uniformity, and the presence of cracks or disintegration.

[0124] Content determination: The drug content was determined by HPLC, and the percentage change from the initial value was calculated.

[0125] Impurity content: HPLC method is used to detect the changes in the content of known impurities and unknown impurities.

[0126] Dissolution change: Determine the dissolution at a specified time point and compare it with the initial dissolution curve. factor.

[0127] Moisture content: Karl Fischer method is used to measure the change in moisture content of samples.

[0128] Structural stability: X-ray tomography is used to observe changes in the internal structure.

[0129] Data Analysis: Calculate the percentage change of each quality index relative to the initial value.

[0130] The stability differences of samples prepared by the two processes were compared and analyzed.

[0131] Linear regression analysis was used to predict the shelf life.

[0132] 3. Experimental results The experimental results show that the solid pharmaceutical composite hard tablets prepared by the process of the present invention exhibit better storage stability under the conditions of accelerated stability test. Figure 6 As shown: Figure 6 : Changes of various quality indicators in the accelerated stability test (40℃, 75%RH) for 6 months.

[0133] From the experimental results, we can see that after 6 months of accelerated stability testing: The drug content of the samples prepared by the process of the present invention decreased by only 1.8%, which is much lower than the 7.6% of the traditional process; The total impurities of the samples prepared by the process of the present invention increased by 0.37 percentage points, while the traditional process increased by 1.25 percentage points; The similarity factor between the sample dissolution curve prepared by the process of the present invention and the initial curve ( ) was 89.5, indicating that the dissolution characteristics remained basically unchanged, while the traditional process The value dropped to 65.3; Most notably, the samples prepared by the process of the present invention performed excellently in terms of structural stability, with a structural integrity retention rate of 93.6%, while the traditional process was only 72.1%.

[0134] According to the stability data evaluation method in ICH Guideline Q1E, through linear regression extrapolation, the predicted shelf life of the solid pharmaceutical composite hard tablets prepared by the process of the present invention under 25°C / 60%RH conditions can reach 36 months, while the predicted shelf life of the samples prepared by the traditional process is 24 months, which is extended by 50%.

[0135] Summarize The above five specific experiments have fully proved the technical effect of the present invention "a process for preparing a solid pharmaceutical composite hard tablet": The structural stability test proves that the three-step collaborative process of the present invention can significantly improve the stability of the particle arrangement structure. After the mechanical vibration test, the structural retention rate reaches 96.4%, which is 19.9 percentage points higher than the traditional process.

[0136] The mechanical strength uniformity test verifies that the solid pharmaceutical composite hard tablet prepared by the process of the present invention has better isotropic characteristics, and the compressive strength deviation in different directions is only 6.8%, which is much lower than 29.9% of the traditional process.

[0137] The drug release consistency test showed that the process of the present invention significantly improved the batch-to-batch consistency of drug release, and the release curves between different batches were The average value was 91.2, and the RSD of release rate between batches was only 1.9%.

[0138] The batch consistency test confirmed that the rotary partition preparation technology and uniform field processing technology of the present invention effectively solved the problems of electromagnetic field uniformity and cooling synchronization in batch production, reducing the average RSD of various quality indicators between batches by 64.0%.

[0139] The storage stability test verified that the product prepared by the process of the present invention has better stability during long-term storage. Under accelerated test conditions, the key quality attributes did not change by more than 5% after 6 months, the structural integrity retention rate reached 93.6%, and the predicted shelf life could be extended by 50%.

[0140] The above describes an embodiment of the present invention, but this embodiment is not limited to the above-mentioned specific implementation mode. The above-mentioned specific implementation mode is merely illustrative and not restrictive. Under the guidance of this embodiment, ordinary technicians in this field can also make more forms of equivalent embodiments, all of which are protected by this embodiment.

Claims

1. A process for preparing a solid pharmaceutical composite hard tablet, characterized in that: The following steps are involved: Step 1: Preheating and tempering treatment: preheat the active ingredient and excipient mixture at 40-60°C, and apply mechanical vibration to enhance the plasticity of the excipient particles and their responsiveness to the electromagnetic field; Step 2: Pulsed electromagnetic field sequence arrangement: the preheated mixture is placed in the electromagnetic field action area, and an electromagnetic field sequence composed of pulses of different frequencies, intensities and durations is applied to achieve high-precision directional arrangement of particles; Step 3: Instant cooling and shaping. When the particles reach the ideal arrangement state, the cooling medium is introduced from multiple directions at the same time to quickly reduce the particle temperature to below the glass transition temperature of the auxiliary material and fix the arrangement structure of the particles; Step 4: Final tableting, testing and packaging.

2. The process for preparing a solid pharmaceutical composite hard tablet according to claim 1, characterized in that: The preheating and tempering treatment comprises: Raw material preparation: weigh and mix the active ingredients and excipients according to the predetermined formula to obtain a uniform powder mixture; Determination of preheating temperature: Determine the preheating temperature according to the glass transition temperature of the auxiliary material, and the preheating temperature is between the glass transition temperature minus 15°C and minus 5°C; Dynamic preheating operation: mechanical vibration is applied to the powder mixture while increasing the temperature; Maintain uniform temperature: When the target temperature is reached, maintain it for 15-30 minutes, while controlling the relative humidity of the environment within the range of 30-40%.

3. The process for preparing a solid pharmaceutical composite hard tablet according to claim 2, characterized in that: The powder mixture is subjected to mechanical vibration at a frequency of 10-30 Hz while the temperature is increased at a rate of 0.5-2°C / min.

4. The process for preparing a solid pharmaceutical composite hard tablet according to claim 1, characterized in that: The pulse electromagnetic field sequence arrangement comprises: Pulse sequence parameters were determined as follows: the basic field strength range was 0.2-1.0 Tesla, the pulse frequency was 1-10 Hz, and trapezoidal or sine waves were used; Sample introduction: transfer the preheated and tempered mixture to the electromagnetic field action area within 30 seconds; Pulse sequence execution: applying a pulsed electromagnetic field to the mixture, the execution time is 45-90 seconds; Arrangement state monitoring: Observe the changes in the particle arrangement state through a real-time optical monitoring system to determine the time point when the preset arrangement state is reached.

5. The process for preparing a solid pharmaceutical composite hard tablet according to claim 4, characterized in that: The instantaneous cooling and shaping comprises: Cooling system preparation: configure cooling medium delivery device and temperature monitoring system outside the electromagnetic field action area; Trigger condition determination: the time point at which the preset arrangement state is reached is set as the cooling trigger condition; Multi-zone cooling execution: cooling medium is introduced from the top, bottom, left and right of the sample at the same time, and the cooling rate is controlled at 15-30℃ / second; Temperature reduction and stabilization: When the sample temperature drops to 20-25°C, reduce the cooling rate, slowly cool to room temperature and keep for 5-10 minutes.

6. The process for preparing a solid pharmaceutical composite hard tablet according to claim 1, characterized in that: The method also includes a batch production step, which includes rotary partition preparation and field balancing treatment.

7. The process for preparing a solid pharmaceutical composite hard tablet according to claim 6, characterized in that: The rotary partition preparation comprises: Unit division: Divide the production line into 4-8 independent preparation units; Peak-shifted start-up execution: Each preparation unit starts in sequence at a time interval of 30-60 seconds; Unit timing control: The relative timing and parameters of the three core steps of preheating and tempering, electromagnetic field arrangement and instantaneous cooling within each unit remain consistent.

8. The process for preparing a solid pharmaceutical composite hard tablet according to claim 6, characterized in that: The averaging process comprises: Field intensity distribution measurement: Conduct three-dimensional field intensity distribution measurement in the production area to form a field intensity contour map; Physical shielding application: Apply physical shielding layer to areas with excessive field strength; Field strength compensation implementation: adding local compensation coils to areas with weaker field strength; Dynamic field intensity regulation: The current parameters of the compensation coil are adjusted through the real-time monitoring system to maintain the stability of the field intensity distribution.

9. The process for preparing a solid pharmaceutical composite hard tablet according to claim 4, characterized in that: The pulse sequence combination is a three-stage sequence of low frequency and low intensity, high frequency and medium intensity, and low frequency and high intensity.

10. The process for preparing a solid pharmaceutical composite hard tablet according to claim 1, characterized in that: The cooling medium is liquid nitrogen or cooling air.

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