A method for gradient iron release of ferrous fumarate and sodium ferric EDTA

Abstract

The application discloses a gradient iron release method of ferrous fumarate and EDTA iron sodium, belongs to the field of oral iron preparation and drug controlled release, and aims at solving the problems of excessive release in the stomach section, insufficient iron supply in the intestine section and batch curve deviation caused by release difference of two iron sources in the gastrointestinal pH environment. The F group and E group iron release units with different pore fluxes and film layer structures are constructed, the pH single group curve of the batch sequence is obtained, the mixing ratio is determined according to the element iron equivalent weight under the constraints of the proportion window and the cross-pH release, and the finished product is retested, so that the technical effects of limiting the iron release in the stomach section, maintaining the iron supply in the intestine section, reducing the pH disturbance and the influence of single group batch difference are achieved.

Description

Technical Field

[0001] This invention relates to the field of oral iron preparation and controlled release of drugs, and particularly to a method for gradient iron release from ferrous fumarate and EDTA iron sodium. Background Technology

[0002] Oral iron supplements typically utilize inorganic iron salts, organic acid iron salts, or chelated iron sources to provide elemental iron. Ferrous fumarate exhibits specific dissolution and valence state changes in acidic media, while sodium EDTA exhibits different dissociation and iron release behaviors depending on its complexation state and media conditions. When two iron sources are used together, the formulation structure, particle size, carrier pores, and coating layer all affect the order of release across the gastrointestinal environment.

[0003] Existing conventional mixing methods typically involve directly mixing two iron sources according to the nominal dosage in the prescription, making it difficult to adjust the mixing ratio using the release characteristics of individual groups in each batch. This may result in premature release of elemental iron in the gastric segment, followed by insufficient follow-up release after entering the near-neutral intestinal segment. At the same time, changes in particle size, elemental iron content, membrane flux, and environmental pH may cause deviations between the predicted curve and the finished product curve, leading to a decrease in release consistency between different production batches.

[0004] Therefore, there is a need for a gradient iron release method using ferrous fumarate and EDTA iron sodium that can overcome the shortcomings of the existing technology. Summary of the Invention

[0005] One objective of this invention is to propose a gradient iron release method using ferrous fumarate and EDTA iron-sodium mixtures. Addressing the problem in existing technologies where ordinary mixing of two iron sources makes it difficult to simultaneously control the peak release in the stomach segment, continuous iron supply in the intestinal segment, and batch-to-batch release consistency, this invention proposes a method that first characterizes and classifies the two iron sources by particle size and elemental iron content. Then, it constructs F-group iron release units with internal microenvironment regulation and non-pH-dependent blocking membranes, and E-group iron release units with an internal blocking layer and an external enterocoating layer. Next, it obtains sequential pH release curves for both groups and batches, and, under predetermined proportional windows and constraints on the stomach segment, intestinal segment, endpoint, and switching rate, selects the mixing ratio by weighting based on elemental iron equivalent. This invention provides the technical advantages of identifying infeasible batches before physical mixing, verifying and predicting the overall curve at the finished product stage, and reducing the impact of pH disturbances and batch-to-batch differences on the overall iron release curve.

[0006] This invention provides a gradient iron release method using ferrous fumarate and EDTA iron sodium, comprising: S1, determining the particle size distribution and elemental iron content of ferrous fumarate and EDTA iron sodium from the same production batch and performing particle size classification to obtain two iron source fractions measured in elemental iron equivalent; S2, preparing F-group iron release units with a first pore flux parameter, a microenvironmental conditioning component within the carrier pores, and a non-pH-dependent barrier membrane using the ferrous fumarate fraction; S3, preparing E-group iron release units with a second pore flux parameter, an inner barrier layer, and an outer enteric coating layer using the EDTA iron sodium fraction; S4, sequentially classifying the two iron release units from acidic to near-neutral conditions. In the pH release test, the cumulative elemental iron release curves of group F and group E are obtained by normalizing the release amount according to the total elemental iron content; S5, within the predetermined iron source ratio window, the elemental iron equivalent fraction of group F is used as the decision factor to weight the two cumulative elemental iron release curves by elemental iron equivalent to obtain the candidate total release curve, and feasible elemental iron equivalent fractions of group F are screened according to the upper limit of cumulative release in the stomach segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the difference in release rate before and after pH switching; S6, the approved mixing ratio is determined according to the feasible elemental iron equivalent fractions of group F, and the two groups of iron release units are mixed according to the approved mixing ratio to prepare a multi-unit oral formulation.

[0007] Optionally, S1 includes: taking representative samples from the batch for ferrous fumarate and sodium ferric ethylenediaminetetraacetate respectively, obtaining volume distribution particle size data using the same particle size determination method, and obtaining elemental iron content data using an elemental iron determination method that can distinguish between ferrous iron and total iron. Based on the volume distribution particle size data of each iron source, the corresponding particle size classification boundary is set, and the particle size range, mass and elemental iron content of each particle size are recorded. The elemental iron equivalent of each particle size is calculated based on the mass and elemental iron content. The particle size range, elemental iron content, and elemental iron equivalent are associated with the production batch identifier to form a batch attribute record for steps S2, S3, and S5.

[0008] Optionally, S2 includes: loading the ferrous fumarate fraction into a pharmaceutical porous carrier with interconnected internal channels, and setting microenvironment-regulating components screened by iron valence state retention ability, complexation stability and outward migration quality in the internal channels; The first pore flux parameter is determined based on the liquid permeation rate per unit time of the porous carrier under a specified pressure difference and a specified temperature. A pH-independent blocking membrane is formed on the outside of the loaded pharmaceutical porous carrier. The first pore flux parameter, the amount of iron per unit element of the microenvironment regulating component, and the dry membrane mass per unit area of ​​the pH-independent blocking membrane are determined together based on the upper limit of cumulative release in the target gastric segment and the continued release requirements after being transferred to a near-neutral medium. Furthermore, the screening of the microenvironment regulation components includes: preparing a carrier sample containing candidate microenvironment regulation components and a control sample without candidate microenvironment regulation components, and then contacting the two types of samples sequentially with the acidic medium and the near-neutral medium. In each medium stage, the proportion of divalent iron in the carrier to the total iron in the carrier and the proportion of soluble iron complexes in the carrier were determined for both types of samples. The mass of candidate microenvironment regulation components that migrated to the outside of the carrier in the carrier sample containing candidate microenvironment regulation components was also determined. Calculate the difference in the proportion of divalent iron and the difference in the proportion of soluble iron complexes between the carrier sample containing the candidate microenvironment regulation components and the control sample. Candidate microenvironment conditioning components are selected based on the following conditions: the proportions of ferrous iron and soluble iron complexes are within their respective predetermined stability ranges; the difference between the proportions of ferrous iron and soluble iron complexes is not less than the corresponding predetermined lower limit of improvement; and the migration quality does not exceed the predetermined upper limit of migration. The amount of iron per unit element required to achieve the predetermined stability range and the predetermined lower limit of improvement is used as the amount of microenvironment conditioning component used in step S2.

[0009] Optionally, S3 includes: loading the sodium iron ethylenediaminetetraacetate fractionated material into a pharmaceutical porous carrier, and determining the second pore flux parameter based on the liquid permeation rate per unit time of the pharmaceutical porous carrier under a specified pressure difference and a specified temperature; An inner blocking layer and an outer enteric coating layer are sequentially formed on the outside of the loaded pharmaceutical porous carrier. The dry film mass per unit area of ​​the inner blocking layer is determined according to the target release time after the outer enteric coating layer is opened. The dry film mass per unit area of ​​the outer enteric coating layer and the dissolution pH boundary are determined according to the gastric segment closure requirements and the near-neutral medium opening requirements.

[0010] Optionally, S4 includes: placing the current batch of F group iron-releasing units and the current batch of E group iron-releasing units in an acidic medium with a pH of 1.2, sampling at the gastric segment test time point, transferring to a near-neutral medium with a pH of 6.8, and sampling at multiple intestinal segment test time points; The amount of iron released in each sample was measured and normalized according to the total amount of iron in the corresponding test unit to obtain the cumulative iron release ratio at each time point. Using the last two adjacent sampling points before pH switching and the first two adjacent sampling points after pH switching as point pairs, the cumulative difference in the elemental iron release ratio of each point pair is divided by the corresponding sampling time interval to obtain the release rate before switching and the release rate after switching. The absolute value of the difference between the two release rates is taken as the difference in release rates before and after pH switching in step S5.

[0011] Optionally, S5 includes: setting multiple candidate values ​​for the iron equivalent fraction of F group elements within the predetermined iron source ratio window; For each candidate value, the product of the cumulative iron release ratio of group F at each time point and the candidate value is added to the product of the cumulative iron release ratio of group E at each time point and the difference obtained by subtracting the candidate value, to obtain the corresponding candidate total release curve. The candidate total release curves are sequentially judged to meet the constraints of the upper limit of cumulative release in the stomach segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the difference in release rate before and after pH switching. Candidate values ​​that simultaneously meet all constraints are formed into a feasible score set, and the approved mixing ratio is determined based on the feasible score set. Furthermore, the upper limit of cumulative release in the stomach segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the release rate difference before and after pH switching are all constrained by the same preset target curve specification. Calculate the absolute value of the cumulative elemental iron release ratio difference between each candidate total release curve and the preset target curve at each test time point, add the absolute values ​​at all test time points to obtain the cumulative deviation, and record the peak value of the absolute value at each test time point; When the feasible score set includes multiple candidate values, the candidate values ​​are first sorted in ascending order according to the cumulative deviation. If the cumulative deviations are the same, they are sorted in ascending order according to the peak value of the absolute value. If both the cumulative deviation and the peak value of the absolute value are the same, they are sorted in ascending order according to the iron equivalent score of the F group element. The candidate value with the first ranking is selected as the iron equivalent score of the F group element. The iron equivalent fraction of the F group elements, the corresponding approved mixing ratio, the cumulative iron release curve of the F group elements in the current batch, the cumulative iron release curve of the E group elements in the current batch, the corresponding candidate total release curve, and the feasibility judgment result are all written into the batch mixing record. Furthermore, pH perturbation verification is also included: for each perturbation condition that changes the residence time in the acidic medium and changes the pH value of the near-neutral medium after transfer, release tests are conducted on the iron release units of the F group and the iron release units of the E group in the same batch, respectively, to obtain the cumulative elemental iron release curves of the F group and the cumulative elemental iron release curves of the E group under the corresponding perturbation conditions. According to the approved mixing ratio, the two cumulative elemental iron release curves under each disturbance condition are weighted by elemental iron equivalent to obtain the predicted total disturbance release curve. The finished product prepared according to the approved mixing ratio is then subjected to a release test under the corresponding disturbance condition to obtain the total disturbance release curve of the finished product. The predicted total release curve of disturbance and the total release curve of finished product disturbance are compared with the candidate total release curve corresponding to the approved mixing ratio at time points. When all differences are within the pH disturbance deviation range given by the preset target curve specification, the approved mixing ratio is retained. When any difference exceeds the pH perturbation deviation range, S5 is re-executed with the cumulative elemental iron release curves of group F and group E under each perturbation condition as input, and the pH perturbation deviation range under all perturbation conditions is used as an additional constraint. If no feasible iron equivalent fraction of group F elements is found after re-execution, the production batch is intercepted. If a feasible iron equivalent fraction of group F elements is found, a new iron equivalent fraction of group F elements is determined according to the sorting rule of claim 9 and the approved mixing ratio is updated. The finished product is prepared again according to the updated approved mixing ratio and the pH perturbation verification is repeated. If all the differences in the repeated verification are within the pH perturbation deviation range, the updated approved mixing ratio is retained and the finished product is released; otherwise, the production batch is intercepted.

[0012] Optionally, S6 includes: when the set of feasible scores is empty, forming a no-solution exception record and intercepting the production batch; When the set of feasible fractions is not empty, the approved mixing ratio is converted into the mass ratio of the iron-releasing units of the current batch F group to the iron-releasing units of the current batch E group. The elemental iron content of the current batch recorded in step S1 is used for the conversion. After being mixed according to the stated mass ratio, the mixture is filled into capsules or compressed into tablets to maintain the integrity of the F group iron-releasing units and the E group iron-releasing units; The obtained finished product is subjected to a sequential pH release test in step S4. The cumulative elemental iron release ratio of the finished product is compared with the candidate total release curve corresponding to the approved mixing ratio at time points. When the difference at each time point is within the predetermined deviation range of the finished product curve and the cumulative elemental iron release ratio of the finished product meets all the constraints of step S5, a gradient total iron release curve confirmed by the finished product retest is obtained and the multi-unit oral formulation is released. Otherwise, an abnormal release record of the finished product is formed and the multi-unit oral formulation is blocked.

[0013] The beneficial effects of this invention are: 1. The F-group iron release unit uses controlled pore flux, carrier internal pore microenvironment regulation components and non-pH-dependent blocking membrane, while the E-group iron release unit uses pore flux, internal blocking layer and external enterocoating layer. The division of labor between the two types of structures limits the early release of iron from the stomach and provides a structural basis for continuous iron supply after entering a near-neutral medium.

[0014] 2. The cumulative elemental iron release curves of F and E groups in the same production batch are weighted according to elemental iron equivalent, and the approved mixing ratio is screened under the common constraints of the upper limit of the gastric segment, the lower limit of the intestinal segment, the endpoint range, and the difference in pH switching rate, so that the mixing control can respond to changes in batch particle size, elemental iron content, and single group release curve.

[0015] 3. The lack of feasible solutions for interception, point-by-point retesting of the finished product curve, and recalculation and retesting under pH disturbance conditions form a closed chain from single-group determination and proportion approval to finished product release, which helps to reduce the deviation between the predicted total curve and the finished product total curve and improve the traceability of the batch release process. Attached Figure Description

[0016] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings: Figure 1 This is a flowchart of the iron release method of ferrous fumarate and EDTA iron sodium gradient in this invention.

[0017] Figure 2 This is a flowchart of the S5 ratio screening and optimization step of the present invention. Detailed Implementation

[0018] The present invention will now be described in further detail with reference to the accompanying drawings. These drawings are simplified schematic diagrams, illustrating only the basic structure of the invention, and therefore only show the components relevant to the invention.

[0019] refer to Figures 1-2 A gradient iron release method using ferrous fumarate and EDTA iron sodium, comprising: S1, determining the particle size distribution and elemental iron content of ferrous fumarate and EDTA iron sodium from the same production batch and performing particle size classification to obtain two iron source fractions measured in elemental iron equivalent; S2, preparing F-group iron release units with a first pore flux parameter, a microenvironmental conditioning component in the carrier pore channel, and a non-pH-dependent barrier membrane using the ferrous fumarate fraction; S3, preparing E-group iron release units with a second pore flux parameter, an inner barrier layer, and an outer enteric coating layer using the EDTA iron sodium fraction; S4, performing sequential pH release from acidic to near-neutral pH on the two iron release units. S5. In the release experiment, the cumulative elemental iron release curves of group F and group E were obtained by normalizing the release amount according to the total elemental iron content; S6. Within the predetermined iron source ratio window, the elemental iron equivalent fraction of group F was used as the decision factor to weight the two cumulative elemental iron release curves by elemental iron equivalent to obtain the candidate total release curve, and feasible elemental iron equivalent fractions of group F were screened according to the upper limit of cumulative release in the stomach segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the difference in release rate before and after pH switching; S7. The approved mixing ratio was determined according to the feasible elemental iron equivalent fractions of group F, and the two groups of iron release units were mixed according to the approved mixing ratio to prepare a multi-unit oral formulation.

[0020] In this specific embodiment, S1 includes: In this specific implementation method, ferrous fumarate and sodium ferric ethylenediaminetetraacetate from the same production batch are used as a group of materials to be evaluated. The production batch identification is recorded in the raw material receiving record, sampling record, and subsequent unit preparation record. The sampler takes samples at no less than ten equal mass sampling points along the upper, middle, and lower depths of the packaging container of each raw material. After merging the samples from each point, the samples are cross-reduced to obtain a representative sample of no less than 500g within the batch. Of this, 100g is used for particle size determination, 20g is used for elemental iron content determination, and the remaining samples are sealed and reserved for grading verification. If the packaging identification, appearance, or moisture test result of any sampling point is inconsistent with the other sampling points in the same batch, the point is individually numbered and the sample merging is suspended until the retest confirms that it belongs to the same batch before it is included in the representative sample. Particle size was determined using the same laser diffractometer calibrated with standard microspheres. Ferrous fumarate and sodium EDTA were both dispersed in anhydrous ethanol for 60 seconds at 2000 r / min, and measured three times consecutively. The instrument output the volume fraction of each particle size range and the 10%, 50%, and 90% volume quantiles. If the relative standard deviation of the three 50% volume quantiles was not greater than 3%, the arithmetic mean of the three volume distributions was taken. Otherwise, the particle size was re-dispersed and measured. If the second measurement still did not meet the requirements, a particle size detection anomaly record was generated and the raw material was intercepted. In this specific embodiment, ferrous fumarate was divided into three particle sizes: not greater than 75 μm, greater than 75 μm and not greater than 150 μm, and greater than 150 μm. Sodium EDTA was divided into three particle sizes: not greater than 106 μm, greater than 106 μm and not greater than 180 μm, and greater than 180 μm. The classification boundaries, along with the instrument number, dispersion conditions, and particle size method version, were written into the batch attribute record. For elemental iron detection, representative samples and fractional samples were accurately weighed, digested, and brought to a final volume. The total iron mass was determined by inductively coupled plasma atomic emission spectrometry (ICP-AES), while the ferrous iron mass was determined by o-phenanthroline spectrophotometry under an inert atmosphere. Five-point calibration curves were established for both methods using certified iron standard solutions, with a correlation coefficient not less than 0.999. The elemental iron mass fraction of the samples was determined according to the formula... Calculate, where Indicates iron source group The The mass fraction of iron in the particle size distribution is a dimensionless value. This indicates the converted mass of elemental iron in the digestion solution, in mg. This indicates the mass of the graded samples taken in this test, in mg. This indicates the iron source group classification index. The unit is not applicable; use F or E. It originates from the S1 batch attribute record. This indicates the particle size discrete index of the corresponding iron source. The unit is not applicable and can be 1 to 3. It is derived from the locked three-level particle size classification record. Three parallel measurements are performed for each particle size. If the relative standard deviation of the total iron results of the three measurements is not greater than 2%, the average value is taken. If it exceeds 2%, the samples are resampled and measured, and the original test data is retained. The grading equipment is configured with screens according to the aforementioned boundaries and the sieving is completed in a closed, low-humidity environment. The net mass of each particle size is weighed separately. The material mass recovery rate before and after sieving should be between 98.0% and 102.0%. The elemental iron equivalent of each particle size is determined according to the formula... Calculate, where Indicates iron source group The The elemental iron equivalent contained in the particle size, in grams. This indicates the net mass of the particle size, in grams. This represents the mass fraction of iron, a dimensionless value. and The objects, values, units, inapplicable situations, and data sources are all directly derived from the complete explanation in the previous section; the difference between the sum of the elemental iron equivalents of all particle sizes of the same iron source and the elemental iron equivalents of the representative sample before classification converted by total mass shall not exceed 2.0%. If this condition is not met, check the sieve residues, equipment residues, and weighing records and recalculate. Batch attribute records use batch identifier, iron source group, and particle size sequence number as a joint index. Fields include particle size range, volume fraction, net mass of each grade, total iron mass fraction, divalent iron mass fraction, elemental iron equivalent, sampling date, instrument number, detection method version, and status mark. After the record is written, it is reviewed by a second inspector using the original spectrum and weighing sheet. Only particle sizes that meet the aforementioned criteria in terms of mass recovery rate, parallel determination precision, and elemental iron equivalent balance are marked as usable for preparation. The preparation scheduling module allocates qualified particle sizes of ferrous fumarate to S2 according to their elemental iron equivalent, and allocates qualified particle sizes of sodium ferric ethylenediaminetetraacetate to S3 according to their elemental iron equivalent, based on the batch attribute records. The particle size mass and elemental iron equivalent mapping of the two iron sources are simultaneously transferred to S5 and S6. This forms a graded material ledger for the two iron sources with the same production batch as the primary key and the elemental iron equivalent of the particle size as the measurement standard. This ledger serves as a common data source for subsequent carrier loading, single-group release curve normalization, and approved mixing ratio mass conversion. To directly obtain elemental iron content data that can distinguish between ferrous iron and total iron, this step utilizes elemental iron determination methods that can differentiate between ferrous iron and total iron. The total iron method uses a completely digested solution as the analyte, while the ferrous iron method involves adding a colorimetric reagent within 2 minutes of sampling and correcting the absorbance with a blank matrix. The mass of ferrous iron in the same sample must not exceed the mass of total iron; if this occurs, it is considered an analytical anomaly, and a new calibration curve must be prepared. Abnormal values ​​are not recorded in the classification log. The screening of particle size boundaries uses the three-dimensional average volume distribution as input. First, the volume fraction on both sides of each candidate boundary is calculated. Then, filtering is performed according to the thresholds that the volume fraction of each particle size is not less than 15%, the 50% volume fraction diameter of adjacent particle sizes does not overlap, and the mass recovery rate after screening can reach 98.0% to 102.0%. When multiple candidate boundaries meet the thresholds at the same time, they are sorted in descending order by the difference in iron mass fraction of adjacent particle sizes and in ascending order by the deviation of the standard specification of the screen. The boundary with the first ranking is selected and the unselected boundaries and the reasons for their elimination are saved, so that the boundary setting has clear screening and ranking rules. The matching of samples, test results, and grading results uses a three-item consistency threshold: production batch identifier, iron source group, and sampling bottle barcode. Only when all three items are completely consistent can the records be merged. If any item is inconsistent, the record is set to a pending verification status. Verification personnel confirm the attribution through the raw material release form and the electronic balance timestamp. If it cannot be confirmed, the production use right of the result is deleted, but an audit copy is retained, thereby avoiding mismatch of elemental iron content between different batches or different iron sources. The batch attribute record provides S6 with the elemental iron content source field required for the mass conversion of the F group and E group iron-releasing units in the current batch, and S6 obtains the measurement mass ratio accordingly; in the finished product stage, after mixing according to the measurement mass ratio, it is filled into capsules or pressed into tablets to maintain the integrity of the F group and E group iron-releasing units. This step reserves fields for formulation form, measurement mass ratio version and unit integrity verification status in the record, so that subsequent formulation records can be traced back to the graded materials and elemental iron content of this step; The single-group curve version returned by S4 is written to the release curve association field of the batch attribute record. After the sequential pH release test of the obtained product in step S4 is performed in S6, the product test number, the F group and E group batches used, and the approved mixing ratio version are written back to this field. If the unit batch used in the product test is inconsistent with the batch registered in this step, the system refuses to generate a release record and prompts for re-verification of the feeding chain. After all testing and grading records have been reviewed, the record management module locks the current version according to the production batch identifier and generates a verification value. Only when the verification values ​​are consistent and all particle size statuses are usable for preparation will the two iron source grading materials be released. The release objects include the F group grading material list, the E group grading material list and a common elemental iron equivalent summary, which are respectively used for S2, S3 and subsequent ratio screening and finished product retesting.

[0021] In this specific embodiment, S2 includes: The preparation module reads the graded ferrous fumarate material marked as suitable for preparation from S1, and selects pharmaceutical porous microcrystalline cellulose pellets with particle sizes ranging from 0.60 mm to 0.85 mm and interconnected pores as carriers. Before loading, 30 pellets are randomly selected from each carrier batch, and the distribution of interconnected pore throats is measured using capillary flow pore size analysis after complete wetting with the wetting liquid, and the diameter of the 10th percentile interconnected pore throat is recorded. The 90th percentile volume fraction of the suspension to be loaded is measured by laser diffraction. Vacuum suspension loading is only allowed when the 90th percentile volume fraction of the suspension is not greater than 80% of the diameter of the 10th percentile interconnected pore throat of the carrier. If this condition is not met, the suspension is wet-milled and retested. If the condition is still not met after retesting, the process is repeated. Use a validated larger pore throat carrier or interceptor combination instead of directly using the original particle size suspension; prepare a loading suspension with a solid content of 20% by mixing each particle size of ferrous fumarate that has passed the adaptation verification according to the elemental iron equivalent ratio of the batch; keep it uniform by stirring at 25°C; then evacuate the pellet core to a negative pressure of 70 kPa and maintain it for 3 min; after introducing the loading suspension, release the vacuum and perform rolling adsorption for 10 min; repeat the loading and drying cycle at 40°C until the elemental iron content per gram of carrier reaches the batch prescription value; after each cycle, weigh and extract pellet cores from three positions to determine the elemental iron content; if the relative standard deviation between positions is not greater than 5%, proceed to the next cycle; if it exceeds 5%, extend the rolling adsorption time and resample. After each F-group loading, six pellet cores were randomly selected for cross-sectional elemental surface scanning, and the outer surface rinsing liquid of the same batch of unloaded pellet cores was used as a blank. It was required that continuous iron signals could be detected in the internal region of the six samples at least 10% of the diameter of the pore throat from the outer surface, and the elemental iron mass obtained from the outer surface rinsing after loading should not exceed 5.0% of the input elemental iron mass. If the internal signal was discontinuous or the surface residue exceeded the limit, wet micronization, dispersion stability verification and reloading were performed first. If the requirements were still not met, a particle-pore throat mismatch record was generated and the carrier and suspension combination was intercepted. The first pore flux parameter of the pharmaceutical porous carrier was determined using a constant pressure osmosis apparatus. The test solution was purified water at 37.0℃, the pressure difference was set at 20 kPa, and the unloaded carrier was spread over an area of ​​10.0 cm². 2 The test layer has a uniform thickness, and the volume of liquid permeating through it is recorded within 5 minutes; the first pore flux parameter is calculated according to the formula. Calculate, where This represents the first pore flux parameter of the F-group support, expressed in mL / (cm²). 2 (·min·kPa), This indicates the volume of liquid permeated, in mL. This represents the effective area of ​​the test layer, in cm². 2 , This indicates the test time, in minutes. The pressure difference across the test layer is expressed in kPa; in this specific embodiment, 0.018 mL / (cm²) is selected.2 ·min·kPa) to 0.024mL / (cm 2 The carrier batch with a concentration of (·min·kPa) below this range will result in insufficient release during the near-neutral phase, while the batch with a concentration above this range will not be included in the preparation of the F group. The microenvironment conditioning component was a compound of sodium ascorbate and sodium citrate in a mass ratio of 2:1. Both the screening and control samples were prepared using the same batch of blank pellets, the same batch of ferrous fumarate fractionating material, the same particle size elemental iron equivalent composition, and the same vacuum loading and drying process. The initial elemental iron equivalent of each sample was controlled to be 98% to 102% of the target value. Only the screening samples were introduced with the candidate microenvironment conditioning component during the final vacuum release, while the control samples were introduced with an equal volume of purified water without the component. Before introducing the component, six samples were taken from each group to determine the initial total iron and ferrous iron ratio. The mean difference in initial total iron between the two groups was no greater than 2.0%, the absolute difference in ferrous iron ratio was no greater than 0.03, and the elemental iron loading of each group was consistent. The samples were only compared when the mass balance was between 97.0% and 103.0%. If any value exceeded the limit, the sample pair was discarded and re-prepared using the same iron source and pellet core. Both types of samples were first shaken in a medium at 37.0℃ and pH 1.2 for 120 min, then transferred to a medium at 37.0℃ and pH 6.8 and shaken for 360 min. After each medium stage, the carrier and external medium were separated. The carrier was extracted for 30 min under nitrogen protection with the corresponding fresh medium at a mass-to-volume ratio of 1:20. The extracted solution was obtained by centrifugation at 10000g for 10 min and filtration through a 0.22μm filter membrane. The ferrous iron and total iron were determined by the o-phenanthroline method and inductively coupled plasma atomic emission spectrometry, respectively. The procedure defines the operability of soluble iron complexes as the elemental iron corresponding to the iron-containing chromatographic peaks in the dissolved extract that do not fall within the retention time window of free Fe(II) or Fe(III) in the locked-method version of size exclusion high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry, but are consistent with the retention time windows of the iron ascorbate and ferric citrate reference solutions prepared in the same batch. Five-point iron mass concentration calibration curves are established for free Fe(II), free Fe(III), iron ascorbate, and ferric citrate reference solutions, with correlation coefficients not less than 0.995. The elemental iron mass of the soluble iron complex is calculated and summarized based on the iron-containing peak area through the corresponding calibration curves. Each batch is calculated according to... The blank carrier extract, free iron reference, complexed iron reference, control sample, sample containing components, and spiked sample were injected sequentially. The blank response was no higher than 20% of the lowest calibration point. The recovery rate of the complexed iron spike was between 95% and 105%. The data were valid when the total amount of iron-containing chromatographic peaks converted to the total iron in the same filtrate was between 90% and 110%. Otherwise, the extraction and injection were repeated. The total mass of the migrated sodium ascorbate and sodium citrate in the external medium was determined by high performance liquid chromatography. Three parallels were set up for the control, sample containing components, and external medium. The relative standard deviation of the parallel results was no greater than 5%. Subsequent proportions, improvement differences, and the amount of iron per unit element were all calculated based on this common initial elemental iron baseline. Component-containing samples in the medium stage The proportion of divalent iron is according to the formula The proportion of soluble iron complexes is calculated according to the formula. Calculate, where This represents the proportion of divalent iron to total iron within the carrier, and is a dimensionless value. This indicates the mass of divalent iron within the carrier, expressed in mg. This indicates the total iron mass within the carrier, expressed in mg. This indicates the proportion of soluble iron complexes to total iron within the carrier, and is a dimensionless value. This represents the elemental iron mass contained in the soluble iron complex, calculated and summarized based on the iron peak area of ​​the aforementioned coupled chromatography, the reference solution calibration curve, and the mass recovery threshold. The unit is mg. This indicates the classification index of the medium stage. The unit is not applicable. It refers to the acidic medium stage or the near-neutral medium stage, which is derived from the two-stage test records in this section. The difference in the proportion of ferrous iron and the difference in the proportion of soluble iron complex relative to the control sample are obtained by subtracting the corresponding proportion of the control sample from the corresponding proportion of the sample containing the component. Both differences are dimensionless values. During screening, the proportion of ferrous iron in both media stages must be no less than 0.85, the proportion of soluble iron complexes must be between 0.60 and 0.90, the difference in the proportion of ferrous iron must be no less than 0.10, and the difference in the proportion of soluble iron complexes must be no less than 0.08. Furthermore, the mass of the compound component migrating outside the carrier must not exceed 0.10 times the mass of elemental iron per unit within the carrier. Evaluation was conducted sequentially at four dosage levels: 0.10 mg, 0.14 mg, 0.18 mg, and 0.22 mg of elemental iron per mg. The lowest dosage that simultaneously met all criteria was selected. In this batch, 0.18 mg of elemental iron per mg was determined. The candidate component batch number, the detection values ​​at both stages, the migration mass, the judgment result, and the dosage were recorded in the microenvironment component screening record. If the stability range or improvement limit is not met in any media stage, the candidate dosage must not be used in the F group unit. The screened microenvironment conditioning group was divided into a 10% aqueous solution and introduced into the carrier's internal channels during the final vacuum release process of the ferrous fumarate loading cycle. It was then fluidized and dried at 40°C until the moisture content did not exceed 3.0%. The outer surface of the carrier was subsequently sprayed with a non-pH-dependent barrier membrane consisting of ethyl cellulose and hydroxypropyl methylcellulose at a mass ratio of 9:1. The inlet air temperature was 45°C, the material temperature was 35°C to 38°C, and the atomization pressure was 0.18 MPa. The dry film mass was calculated based on the outer surface area of ​​the pellet core. Before coating, all pellet cores to be coated were equilibrated at 40°C until the difference between two consecutive weighings was no greater than 0.2%. The net mass after deducting the container weight was recorded. After coating curing, the pellet cores were equilibrated and weighed again under the same conditions. The net mass after curing was recorded. The dry film solids mass is obtained by subtracting the net weight before coating and correcting for process sampling, sieving, and equipment residue. Simultaneously, the actual weight of the sprayed liquid is multiplied by the solids content, and then the solids recovered from the exhaust filter bag, spray gun, and container are deducted for independent verification. If the difference between the two results is no greater than 3.0%, the weighing difference correction value is used. Before coating, 100 pellets are randomly selected for triaxial automatic optical imaging. Ellipsoidal surface area values ​​are fitted according to the actual major axis, minor axis, and thickness. The total outer surface area is obtained by multiplying the average surface area of ​​a single pellet by the actual number of pellet cores converted from the batch net weight and the average weight of 100 pellets. The area version is locked when the relative standard deviation of the total outer surface area is no greater than 3.0% after repeating three sets. The dry film mass per unit area is calculated according to the formula... Calculate, where This represents the dry film mass per unit area of ​​the F-group non-pH-dependent blocking membrane, expressed in mg / cm³. 2 , This indicates the dry film solids mass determined according to the aforementioned weighing difference and recovered solids verification rules, in mg. This represents the total outer surface area of ​​the coated pellet core, determined according to the aforementioned three-axis imaging, quantity conversion, and three sets of verification rules, in cm². 2 If any weighing discrepancy or area precision exceeds the limit, the dry film mass per unit area must not be calculated, and re-weighing or sampling and determination are required; this batch uses 8.0 mg / cm³. 2 After the coating weight gain reaches 98% to 102% of the target value, continue curing for 24 hours; The first pore flux parameter, the amount of microenvironment conditioning components, and the dry membrane mass per unit area of ​​the non-pH-dependent barrier membrane were all controlled by the same F group process parameters; the joint screening was fixed with a first pore flux parameter of 0.018 mL / (cm²). 2 ·min·kPa) to 0.024mL / (cm 2 (·min·kPa), step size 0.001mL / (cm) 2 The dosage of the microenvironment conditioning component for iron (·min·kPa) was fixed at the aforementioned minimum effective dosage of 0.18 mg / mg, and the dry membrane mass per unit area of ​​the non-pH-dependent barrier membrane was 7.0 mg / cm³. 2 Up to 9.0 mg / cm2 Step length 0.5 mg / cm 2 All finite candidate combinations are constructed, and the candidate range and step size are locked after the start of this batch of screening. For each combination, six samples are re-prepared and retested in the order specified in S4. Only when both of the following conditions are true, the cumulative elemental iron release ratio in the gastric segment is not higher than 0.25 and the cumulative release ratio in the gastric segment is not lower than 0.75, is the combination written into the joint feasible set of F group. When the joint feasible set of F group contains multiple combinations, it is first sorted in ascending order by the dry membrane mass per unit area of ​​the non-pH-dependent blocking membrane, and then sorted in ascending order by the first pore flux parameter, and the first item is selected. Any change in parameter will invalidate the original combination, and the gastric segment and near-neutral stage must be retested. One improvement cannot offset the failure of another. When the joint feasible set is empty, an F group process infeasible solution record containing all candidate values, two measured results and failure constraints is generated. The F group unit batch is intercepted and stopped from being passed to S4. Repeated trials by unidirectionally increasing membrane mass or pore flux are no longer allowed. After the solidified pellet cores are sieved to remove adhering and broken particles, F-group iron-releasing units are formed. The finished product is sieved to retain a particle size range of 0.65mm to 0.95mm. 100 particles are randomly selected for visual inspection, and six samples are selected to determine the elemental iron content. When the proportion of broken or adhered particles is not higher than 1.0% and the relative standard deviation of the elemental iron content of the six samples is not higher than 5%, the F-group unit batch number, carrier batch number, first pore flux parameter, microenvironment conditioning component dosage, dry film quality, and actual elemental iron content are written into the F-group unit record, and the record and the sample are sent to S4. For the F-group carrier samples, elemental iron content data were obtained using an elemental iron determination method that can distinguish between ferrous iron and total iron. The extract was processed according to the aforementioned nitrogen-protected extraction, centrifugation, and 0.22 μm filtration process, and the matrix response was subtracted using an iron-free blank carrier extract. Soluble iron complexes were strictly identified and quantified using the aforementioned size exclusion high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry, retention time windows of four types of reference solutions, and peak area calibration rules, without directly substituting filtered total iron. In each media stage, the proportion of ferrous iron in the carrier to the total iron in the carrier and the proportion of soluble iron complexes in the carrier were determined for both types of samples. The detection order was blank, control, sample containing components, and spiked sample. Only when all the aforementioned blank, calibration, spiked recovery, and chromatographic total iron mass recovery thresholds were passed could the data be used for screening. Candidate records for microenvironment regulation components are established based on component batch number and unit element iron dosage. The generation rule is to write the two-stage stability results, improvement difference, and migration quality of four dosage levels into the same record, and then construct a qualified candidate set through the conjunctive condition of the entire stability range, two improvement lower limits, and migration upper limits. The unit element iron dosage required to achieve the predetermined stability range and predetermined improvement lower limit is used as the dosage of the microenvironment regulation component used in step S2. When multiple dosages are qualified, the first item is selected in ascending order of unit element iron dosage. Doses eliminated due to migration exceeding the limit cannot be offset by other indicators. The consistency verification algorithm for loading and coating batches uses a four-field joint key: ferrous fumarate grader batch number, carrier batch number, microenvironment conditioning component batch number, and process parameter version. An F-group process task is generated only when all four fields are consistent and the status is "released". The process task executes vacuum loading, component introduction, drying, barrier film spraying, curing, and sieving in sequence. If the measured value of any step exceeds the threshold within the task, the subsequent steps are stopped and a pending status is generated. Abnormal batches are not allowed to be replaced by the test results of another batch. The F-group unit record ultimately includes the iron content per gram of unit element, the first pore flux parameter, the amount of iron microenvironment conditioning component per unit element, the dry membrane mass per unit area, the membrane breakage ratio, and the pre-test results of the gastric segment and near-neutral stage. The record management module generates a unique F-group unit version according to the above fields and locks the original weighing, chromatographic and release data. S4 only receives physical samples and records with a qualified version status, thereby completely transferring the carrier structure, component screening and membrane parameters to the single-group release curve determination.

[0022] In this specific embodiment, S3 includes: The preparation module reads the sodium iron ethylenediaminetetraacetate fractionated material marked as usable for preparation from S1, and selects pharmaceutical porous microcrystalline cellulose pellets with a particle size of 0.60 mm to 0.85 mm that are similar in shape to group F. Before loading, the diameter of the 10% quantile connecting pore throat of the carrier is measured using the same 30-particle sampling and capillary flow pore size analysis method as in S2, and the 90% volume fraction diameter of the undissolved particles in the loading solution is determined. When the loading solution is clarified after stirring at 25°C for 10 min and the mass of undissolved particles is less than 1.0% of the feed mass, it is loaded as a solution, without being limited by the solid particle-pore throat ratio. When the undissolved particles reach or exceed 1.0%, loading is only performed when their 90% volume fraction diameter is not large. Loading is permitted when the diameter of the pore throat reaches 80% of the 10% quantile. If this is not met, the following methods are used in sequence: continued dissolution, wet micronization, or replacement with a carrier with a larger pore throat. If no suitable combination is found after retesting, the mixture is intercepted. Each particle size that has passed the compatibility verification is prepared into a loading solution with a solid content of 18% according to the elemental iron equivalent ratio. After maintaining a negative pressure of 60 kPa for 3 minutes, the solution is introduced into the core pores. After the vacuum is released, the solution is rolled and adsorbed for 10 minutes and then dried at 40°C. This cycle is repeated until the elemental iron loading specified in the batch formula is reached. After each round of loading, samples are taken from three positions on the fluidized bed: top, middle, and bottom. Loading can be stopped if the relative standard deviation of the elemental iron content at the three positions is not greater than 5%. If it exceeds this, the mixture is stirred again and retested. After each E-group loading, six pellet cores are randomly selected for cross-sectional elemental surface scanning, and the elemental iron in the standardized rinsing solution on the outer surface is measured. All six samples must form a continuous iron signal inside the pellet core, and the mass of elemental iron obtained from rinsing the outer surface must not exceed 5.0% of the mass of elemental iron input in this instance. Otherwise, the pellets are returned to the undissolved particle state for further dissolution or wet micronization and reloading. If the retest still does not meet the requirements, an E-group loading mismatch record is generated and the pellets are intercepted. Surface residues must not be covered up by subsequent coating. The second pore flux parameters for the E-group carriers were obtained using the same constant-pressure permeation apparatus, 37.0℃ test solution, 20 kPa pressure difference, and 10.0 cm⁻¹. 2 The test area and 5-minute test time were determined according to the formula. Calculate, where This represents the second pore flux parameter of the E-group support, in mL / (cm²). 2 (·min·kPa), This indicates the volume of liquid permeated, in mL. This represents the effective area of ​​the test layer, in cm². 2 , This indicates the test time, in minutes. The pressure difference across the test layer is expressed in kPa; in this specific embodiment, 0.030 mL / (cm²) is selected. 2 (·min·kPa) to 0.042mL / (cm) 2The carrier batches (·min·kPa) are designed to allow the medium to enter the pores after the outer enteric coating is opened and to be continuously released under the control of the inner barrier layer. After loading, the E-group pellet cores are first sprayed with an inner barrier layer consisting of ethyl cellulose and hydroxypropyl methyl cellulose in a mass ratio of 8:2. The inlet air temperature is 45℃, the material temperature is 35℃ to 38℃, and the atomization pressure is 0.18MPa. Before spraying, all E-group pellet cores are equilibrated at 40℃ until the difference between two consecutive weighings is no greater than 0.2%. After spraying and curing, they are equilibrated and weighed again under the same conditions. The dry film solid mass of the inner barrier layer is obtained by correcting for the difference between the two net mass measurements, including process sampling, sieving, and equipment residue. The actual solid mass of the sprayed liquid is then deducted from the solid mass of the exhaust filter. The bags, spray guns, and containers for recovering solids are independently checked. When the difference between the two results is no greater than 3.0%, the weighing difference correction value is used. Before spraying, 100 particles are randomly selected for triaxial automatic optical imaging. Ellipsoidal surface area values ​​are fitted according to the major axis, minor axis, and thickness. The total outer surface area of ​​group E particles is obtained by multiplying the average surface area of ​​a single particle by the actual number of core particles calculated from the batch net weight and the average weight of 100 particles. The area version is locked when the relative standard deviation of three repeated sets is no greater than 3.0%. The dry film mass per unit area of ​​the inner barrier layer is calculated according to the formula... Calculate, where This indicates the dry film mass per unit area of ​​the inner retardation layer, expressed in mg / cm³. 2 , This represents the mass of the dry film solids in the inner barrier layer, determined according to the aforementioned weight difference before and after coating and the rules for verifying the recovered solids. The unit is mg. This represents the total outer surface area of ​​the E-group pellet cores, determined according to the aforementioned three-axis imaging, quantity conversion, and three sets of verification rules, in cm². 2 If the weighing verification error or area precision exceeds the limit, calculation is not allowed and re-measurement is required; after locking in the second pore flux parameter and the candidate conditions for the enterocoating layer, use 4.0 mg / cm³. 2 Up to 8.0 mg / cm 2 Step length 0.5 mg / cm 2A limited candidate set of inner retardation layers was established. Six parallel samples were prepared for each candidate, using the same medium volume, temperature, rotation speed, total iron determination, and release stock boundary as in S4. In this screening, the moment the test unit was completely immersed in the pH 6.8 medium was defined as the zero point of the enteric coating opening time. The outer layer must be continuously opened within 20 minutes after this zero point; otherwise, the parallel sample was invalid. Sacrificial parallel units corresponding to each candidate were also established, with full recovery performed at 300 minutes and 480 minutes, corresponding to 180 minutes and 360 minutes after the zero point of the opening time, respectively. The mass of released elemental iron was determined by the medium, suspended sediment, and other parameters. The sediment, container, transfer basket, and filter membrane retentates were combined and digested for measurement. Unreleased iron from the complete unit was only used for 95% to 105% overall system equilibration and was not included in the released amount. Interpolation or a fixed S4 ten-point curve was not used as a substitute. The requirement was that the cumulative elemental iron release ratio within 180 minutes after opening should not exceed 0.65, and the cumulative elemental iron release ratio within 360 minutes after opening should not be less than 0.80. The relative standard deviation of the six results should not exceed 10%. Qualified candidates were first sorted in ascending order by the absolute difference between the measured value within 360 minutes after opening and 0.80, then sorted in ascending order by the dry film mass per unit area of ​​the inner barrier layer, and the first item was selected. Therefore, 6.0 mg / cm³ was selected for this batch. 2 It is then cured at 40℃ for 12 hours; when the qualified set is empty, an internal retardation layer containing all candidate values ​​and failure criteria is generated, indicating no feasible solution. The E group batch is intercepted or the candidate set is reconstructed after changing the carrier. 6.0 mg / cm³ must not be directly specified. 2 ; After the inner barrier layer is cured, a hydroxypropyl methylcellulose phthalate enteric coating is sprayed onto it. The test record of the enteric material gives a dissolution pH range of 5.5 to 5.8, a solid content of 12% in the spray solution, and a material temperature maintained at 32℃ to 36℃. The outer layer is equilibrated at 40℃ before and after spraying until the difference between two consecutive weighings is no greater than 0.2%. The net weight of the cured outer layer is subtracted from the net weight of the cured inner barrier layer, and the process sampling, screening, and equipment residues between the two weighings are corrected to obtain the dry film solid weight of the outer enteric coating. Then, the actual weight of the outer layer spray solution is multiplied by 12% of the solid content, and the solids recovered from the exhaust filter bag, spray gun, and container are independently verified. If the difference between the two results is no greater than 3.0%, the weighing difference correction value is used. The unit area of ​​the outer layer uses the total outer surface area of ​​the E-group pellet core of the same batch, sample, and locked version as the formula for the inner barrier layer as a unified nominal benchmark, without changing the area version due to the increased weight of the inner layer. The dry film weight per unit area of ​​the outer enteric coating is calculated according to the formula. Calculate, where This indicates the dry film mass per unit area of ​​the enterolytic layer, expressed in mg / cm³. 2 , This indicates the mass of dry membrane solids in the enterocoating layer, determined according to the aforementioned weight difference before and after the outer layer and the 12% actual solids recovery verification rule, in mg. This represents the total outer surface area of ​​the E-group pellet core, obtained from the aforementioned three-axis imaging, quantity conversion, and three sets of verifications, and locked by the same batch area version, in cm². 2 If the weighing discrepancy exceeds the limit or the area version is inconsistent, calculations must not be performed and re-verification is required; this batch uses 9.0 mg / cm³. 2 This allows the outer layer to remain closed for 120 minutes in a pH 1.2 medium and to continuously open within 20 minutes in a pH 6.8 medium; Gastric segmental atresia and near-neutral opening of the enteric coating were confirmed using a two-segment media integrity test; combined screening used only batches of enteric-coated material with a measured pH boundary of 5.5 to 5.8, and these batches were compared with 8.0 mg / cm³ media. 2 Up to 10.0 mg / cm 2 Step length 0.5 mg / cm 2 The mass of the dry membrane per unit area of ​​the enterolytic layer constitutes a finite candidate set; for each candidate combination, six E group units are randomly prepared, and first kept in pH 1.2 medium for 120 min, requiring no continuous cracks in appearance and the cumulative elemental iron release ratio not higher than 0.05. Then, they are transferred to pH 6.8 medium and the continuous opening time is recorded with staining tracer solution, requiring not more than 20 min. All three criteria must be met simultaneously. When the feasible set of E-group enteric coating contains multiple combinations, it should first be sorted in ascending order by the dry membrane mass per unit area of ​​the outer layer, and then sorted in ascending order by the measured value of the material dissolution pH boundary, and the first item should be selected. Any change in material batch or membrane quality will invalidate the original combination and require a complete two-stage medium test to be performed again. Single adjustment commands in opposite directions should not be used when acidic release exceeds the limit and near-neutral opening is too slow at the same time. When the feasible set is empty, a record of no feasible solution for E-group enteric coating is generated and the E-group unit batch is blocked. After changing the material batch, a new locked candidate set must be established. The second pore flux parameter, the dry film mass per unit area of ​​the inner barrier layer, the dry film mass per unit area of ​​the enteric layer, and the dissolution pH boundary are all written into the E-group process parameter record. Among them, the second pore flux parameter determines the amount of medium entering after the outer layer is opened, the dry film mass of the inner barrier layer is used to maintain the release time within the target range after opening, and the dry film mass of the enteric layer and the material dissolution pH boundary are used to meet the requirements of gastric segment closure and near-neutral medium opening. The parameter record uses the carrier batch number, enteric material batch number, and process version as a joint index. Material must not be fed if the material test value exceeds the dissolution pH boundary. After the outer layer of the E-group unit is cured, sieve out the adhering particles and broken particles, retaining the particle size range of 0.65mm to 1.00mm. Randomly select 100 particles for visual inspection and select six samples to determine the elemental iron content. When the defect ratio is not higher than 1.0%, the relative standard deviation of the elemental iron content is not higher than 5%, and the integrity test of the two media sections is qualified, write the E-group unit batch number, the second pore flux parameter, the quality of the two dry film layers, the pH boundary of the enteric material dissolution, and the actual elemental iron content into the E-group unit record, and send the record and the sample into S4. This step establishes a loading task according to the material relationship described in "S3 includes: loading the ethylenediaminetetraacetic acid iron sodium fractionation material into a pharmaceutical porous carrier". The task reads the particle size range, net weight and elemental iron equivalent of the fractionation material from S1. First, the free fine powder generated during transportation is removed by sieving through a 100-mesh sieve. Then, the fractionation material is weighed and prepared according to the elemental iron equivalent ratio of each particle size. After loading, the surface of the carrier is cleaned with dust-free compressed air to remove the attached powder that has not entered the pores. The sieved material and the attached powder are weighed and included in the loading material balance. When the material balance is between 97.0% and 103.0%, the coating process begins. The uniformity verification of E-group loading was carried out using an elemental iron determination method that can distinguish between ferrous iron and total iron to obtain elemental iron content data. The total iron result was used to calculate the elemental iron content per gram of E-group unit, and the ferrous iron result was used to identify valence state shifts caused by abnormal reduction during loading and drying. Six samples were filtered through a 0.22μm filter membrane and blank matrix subtraction was performed. If the total iron result of any sample exceeded the mean ±10% or the ferrous iron ratio exceeded the upper limit of process confirmation, the sample was returned to the loading or drying process for investigation and was not allowed to proceed to the inner barrier layer spraying. The E-group unit records are matched according to the batch number of the graded material, the batch number of the carrier, the batch number of the inner retardation layer, the batch number of the outer enteric coating layer, and the process version. The task sequence after matching is fixed as pore loading, inner layer spraying and curing, outer layer spraying and curing, integrity test and finished product screening. The record management module only releases the E-group unit version when the second pore flux parameter, the quality of the two dry film layers, the dissolution pH boundary, the gastric segment closure result and the near-neutral opening result all meet the threshold, and then transfers the version and the physical sample to S4.

[0023] In this specific embodiment, S4 includes: The release test module reads the records of the F group and E group units of the current batch, respectively. Six test samples are taken from each group, and the elemental iron equivalent of each sample is controlled between 98% and 102% of the same target amount. A paddle dissolution device is used with a medium volume of 900 mL, a temperature of 37.0℃±0.5℃, and a rotation speed of 50 r / min. First, a pH 1.2 hydrochloric acid medium is added, and samples are taken at 0 min, 30 min, 60 min, 90 min, and 120 min. After sampling at 120 min, the test unit is transferred to an isothermal pH 6.8 phosphate medium within 5 min, and samples are taken at 135 min, 180 min, 240 min, 360 min, and 480 min. Each time, 5.0 mL of sample is taken and an equal volume of blank medium at the same temperature and pH is immediately added. The sampling time, measured pH of the medium, and test sample number are recorded in the sequential pH test record. In this specific implementation method, the cumulative release amount is operationally defined as the total amount of elemental iron that has left the iron-releasing unit of group F or group E and is present in the dissolution medium, suspended precipitate, adsorption layer of the container and transfer basket, and the retained material of the sampling filter membrane. Before sampling the conventional continuous curve unit, the medium is mixed at the original rotation speed for 2 min. 5.0 mL of unfiltered whole sample is taken and immediately acidified with analytical grade nitric acid to pH less than 1 and digested at 95°C for 30 min. The total iron is then determined by inductively coupled plasma atomic emission spectrometry. To ensure that the same release stock boundary is used for all specified time points, six sacrificial parallel units with the same formulation are set up for each group at each time point, corresponding one-to-one with the six continuous curve units. At that time, the complete iron-releasing unit is first transferred to a numbered recovery dish and its outer surface is rinsed with 5.0 mL of medium of the same pH. The rinsing solution is added to the original medium. Subsequently, the original medium, suspended precipitate, container and transfer basket rinsing solution, and specified filter membrane retained material are digested separately. Complete digestion of the iron unit alone is only used to verify that no iron has been released and is not included in the released amount. The equivalent concentration correction amount for that group and time point is calculated by dividing the adsorption and retention mass of the container, transfer basket and filter membrane measured by the sacrificial unit by 900 mL. This correction amount is then added to the concentration of the unfiltered whole sample of the corresponding continuous curve unit. The effective total release concentration for that time point is obtained when the relative standard deviation of the six correction amounts is not greater than 10% and the difference in initial elemental iron equivalent between the continuous curve unit and the sacrificial unit is not greater than 2.0%. Otherwise, the time point and its subsequent curves are invalid and must be repeated. For groups F, E and the finished product, matrix spiking is set. The absolute value of the recovery difference before and after filtration is not greater than 3.0%, and the spiked recovery rate is between 95% and 105%. At each sacrificial time point, the iron mass balance of the whole system is checked by adding the released amount to the unreleased amount of the complete unit. Only when this condition is met can the effective total release concentration of that batch be included in the curve calculation. The elemental iron calibration curve covers concentrations from 0.1 mg / L to 20 mg / L with a correlation coefficient of no less than 0.999. Each concentration result output by the instrument is first divided by 1000, converted from mg / L to mg / mL, and the original value, conversion factor, and converted value are saved. To ensure a unique mapping between the sampling sequence number and the actual minute time point, this step numbers the ten specified time points in ascending order of time. to and the corresponding actual minute time point The time intervals were sequentially set to 0 min, 30 min, 60 min, 90 min, 120 min, 135 min, 180 min, 240 min, 360 min, and 480 min; (medium stage) Pick or ,in Indicates the acidic medium stage. This indicates the local sampling sequence number for each stage in the near-neutral medium phase. All values ​​are 1 to 5, with the acidic stage using... Near neutral medium stage ;in This represents the total sampling sequence number, a discrete index where the unit is not applicable, ranging from 1 to 10. Indicates the full program number The unique corresponding actual minute, in min, is derived from the locked 10 o'clock timetable in this segment. This indicates a media stage index, a category index where the unit is not applicable, and takes... or , This indicates the local sampling sequence number within each medium stage, a discrete index (1 to 5) where the unit is not applicable; Iron source group. In the medium stage The The cumulative mass of newly released samples at each local sampling point is calculated according to the formula. Calculate, where This indicates the cumulative mass of elemental iron released during this phase, in mg. This indicates the group type and the stage of the medium. The effective total release concentration, calculated by summing the unfiltered whole sample concentration of each continuous curve sample with the equivalent concentration correction obtained from the sacrificial parallel units at the same time point and group, and dividing by 1000 (mg / L), is expressed in mg / mL. Indicates the medium stage The initial volume of the dissolution medium, in mL. This indicates the volume of each sample taken and replenished, in mL. Indicates the first stage of the same medium The effective total release concentration, calculated using the same sacrifice parallel correction rule and unit conversion, is given for each previous local time point and is expressed in mg / mL. This represents the discrete index of previous local sampling within this media stage; units are not applicable, and it ranges from 1 to... , This indicates the iron source group classification index; units are not applicable, use F or E, derived from the S4 single-group release test records; the two stages are respectively from... Start accumulating, and clear the liquid replenishment correction summation term within the stage to zero after the medium switch; This step will subsequently involve segmented accumulation, normalization, and the formulas for rates before and after switching, as well as the rate difference. All of them directly use the complete explanation from the previous section, that is This indicates an iron source group classification index that is not applicable to the unit, taking the value F or E and originating from the S4 single-group release test record; in subsequent formulas... , , and It also simply uses the respective objects, values, units, and data sources from the previous sections, without assigning any new meanings; At the end of the 120-minute acid phase, the cumulative release during the acid phase reached the baseline. The concentration of the unfiltered whole sample, the correction amount for the equivalent concentration of the sacrificed parallel at the same time point, and the aforementioned cumulative formula for each stage are still calculated based on the continuous curves identical to those at 0 min, 30 min, 60 min, and 90 min. The historical adsorption amount is not replaced or added by the full recovery result at the end of each stage. The acidic medium bulk, all previous samples, and container and transfer basket rinsing solutions collected separately at this time point are only used to verify the above cumulative values ​​of the same caliber and the overall system mass balance from 95% to 105%. If the absolute value of the difference exceeds 3.0%, all data for the acidic stage are invalid and must be repeated. Before the transfer basket is moved into the near-neutral medium, the volume of acidic medium carried by the basket is determined by quantitative rinsing and weighing, and the elemental iron content is measured separately. This carried volume is only included in the baseline of the acidic stage and is not included in the new amount added in the near-neutral stage. The total mass of released elemental iron is calculated throughout the process. Establish a unique segmentation relationship based on the media stage; this segment uses... , , and The meaning, values, and units are all directly derived from the complete explanations in the first two paragraphs; when the medium stage is Furthermore, the full program number corresponds to the local sequence number as described above. According to the formula Calculation, when the medium stage is And the full program number corresponds to the fifth full program point as mentioned above. When there are local points, according to the formula Calculate; where Indicate group In full program number The total mass of elemental iron released at the corresponding time point is expressed in mg. This is derived from the cumulative results of the acidic phase with the same sequence number. The 120-minute acidic phase endpoint baseline has been validated and locked. The cumulative increase in concentration during the near-neutral phase is calculated from the first sample in that phase, and all three values ​​are in mg; therefore, the data at 135 min and thereafter are also included. All clearly include the locked acidic stage baseline and do not count the carry liquid repeatedly; if the carry liquid volume cannot be determined, the time-by-time correction gate or the stage mass balance exceeds the limit, or the two stage records cannot be associated by the same test unit, then the full curve is invalid and must be redone from the beginning; the mass conservation curve across media and at the same inventory boundary at all time points is the only cumulative release input for S5 and S6; The total elemental iron content of each test sample was determined by complete digestion in parallel units within the same batch, and the cumulative elemental iron release ratio was calculated according to the formula. Calculate, where Indicates iron source group In full program number The corresponding actual minute time The cumulative iron release ratio is a dimensionless value between 0 and 1. This represents the total mass of iron released throughout the entire process, calculated according to the aforementioned segmented relationship, in mg. This represents the total elemental iron content measured after complete digestion of the corresponding test sample, in mg. It only represents the full sampling sequence number from 1 to 10 and It only represents the actual minute point that uniquely corresponds to the serial number; if the calculated value fluctuates by more than 1 due to analysis, the value will be marked as pending verification instead of being directly truncated. After verifying the sampling volume, replenishment record and calibration curve, the confirmed value will be entered into the database. The arithmetic mean of the cumulative elemental iron release ratios of six parallel samples at each time point is used to form a single-group curve, while the standard deviation is saved. When the relative standard deviation at any time point exceeds 10%, the integrity of the test unit and the sampling record are checked, and six additional retests are conducted. Only when the retest results are consistent with the trend of the original test and no membrane breakage or transfer loss is found are the twelve results merged. Otherwise, a single-group release anomaly record is formed and returned to the corresponding unit preparation step for investigation. Through this rule, the cumulative elemental iron release curves of group F and group E, arranged in ascending order of time, are obtained respectively. Before pH switching, the release rate was measured at two points: 90 min and 120 min. After switching, the release rate was measured at two points: 135 min and 180 min. (Iron source group) The release rate before switching is according to the formula The calculation and release rate after switching are based on the formula. Calculate, where This indicates the release rate before switching, in minutes. -1 , This indicates the release rate after switching, in minutes. -1 This section uses the convention of specifying fixed minute times for easier reading. , , and They are respectively satisfied min、 min、 min and min's unique full program ID Corresponding Abbreviation, 90, 120, 135 or 180 are not used as summation numbers; all four are the total cumulative iron release ratio of the corresponding group at the marked minute time point, which are dimensionless values, and the two fixed sampling time intervals are 30min and 45min respectively; The difference in release rate before and after pH switching for each individual group is calculated according to the formula. Calculate, where Indicates iron source group The difference in release rate before and after the pH switch, in min. -1 , This indicates the release rate after switching, in minutes. -1 , This indicates the release rate before switching, in minutes. -1 The release test module correlates the curve points, parallel standard deviation, release rate, and rate difference of the two groups with the medium batch number, instrument number, analytical method version, and total iron content of the batch to form an uncoverable single-group release curve version. After both groups F and E pass the parallelism check, the system aligns the two single-group cumulative elemental iron release curves according to the same sampling time. If any specified time point is missing, interpolation should not be used to replace it, but the test for that group should be performed again. The aligned curve version and the corresponding unit batch number are used as read-only inputs for S5, and the traceability relationship from the batch attribute record of S1 to the unit record of S2 and S3 and then to the curve record of this step is retained. Sample data screening is first performed based on four criteria: the measured pH of the medium is within ±0.05 of the set value, the temperature is between 36.5℃ and 37.5℃, the sampling time deviation does not exceed 30s, and the correlation coefficient of the calibration curve is not less than 0.999. Samples that do not meet any of these criteria are added to the invalid candidate set and a supplementary test is triggered. When there are two sets of valid data at the same time point, the original test and the supplementary test, are sorted in order of priority based on the integrity of the test unit, the absolute value of the sampling time deviation in ascending order, and the analysis completion time in ascending order. The first set of sorted data is selected for curve calculation, and the other set is retained as verification data. During medium switching, the test unit is moved as a whole through a transfer basket with a sieve. The mass of the basket and the unit combination is weighed before and after the transfer. If the difference exceeds 1.0% of the initial mass of the test unit, it is considered a transfer loss and the entire sample is invalidated. The transfer time is counted from the time the sample is removed from the acidic medium until it is completely immersed in the near-neutral medium. The actual time is recorded and controlled within 5 minutes to ensure that the time reference of the first sampling point after the switch can be kept consistent among all parallel samples. After mixing according to the stated mass ratio and filling into capsules or pressing into tablets to maintain the integrity of the F group and E group iron release units, the resulting product is subjected to the sequential pH release test of step S4. This step establishes the same media, temperature, rotation speed, sampling and replenishment fields as the single group test for the finished product retest, so that the cumulative elemental iron release ratio of the finished product can be directly compared with the total release curve of the approved candidate in S5 at each time point. At the same time, the formulation batch number and the approved mixing ratio version are used instead of the single group batch number as the test index. After the release test record is completed, the verification module recalculates each cumulative mass, normalization ratio, and switching rate. When the absolute difference between the recalculated result and the original calculation result is no greater than 0.0001, the curve version is locked. The locked objects include F group curves, E group curves, and the method parameter set for retesting and reuse of finished products. When any original concentration, sampling volume, or total elemental iron is corrected, a new version is generated and the old version is stopped from being used for S5 ratio screening.

[0024] In this specific embodiment, S5 includes: The proportional screening module reads the cumulative elemental iron release curves of groups F and E with completely consistent time points in S4, and reads the same version of the preset target curve specification; in this specific embodiment, the predetermined elemental iron equivalent fraction window of group F is set to 0.30 to 0.70, and 41 candidate values ​​are generated with a step size of 0.01. The candidate values ​​are written into the candidate score table in ascending order. The table also records the target specification version, the versions of the two single-group curves, and the production batch identifier. The endpoints and step sizes of the proportional window must not be changed after the screening begins. For candidate values and the At each experimental time point, the candidate total release ratio is calculated according to the formula. Calculate, where Indicates candidate value The corresponding number The total release percentage at each candidate time point is a dimensionless value between 0 and 1. This represents the iron equivalent fraction of elements in group F, a dimensionless value between 0.30 and 0.70. Indicates that group F is in the th order. The cumulative percentage of elemental iron released at each time point is a dimensionless value. This represents the cumulative percentage of elemental iron released from group E at the same point in time, and is a dimensionless value. This indicates the sampling point number arranged in ascending order of time. This represents the iron equivalent fraction of elements in group E; the calculation uses unrounded curve values, and the displayed value is rounded to four decimal places. The preset target curve specification uses ten sampling times of S4 in a fixed order: 0 min, 30 min, 60 min, 90 min, 120 min, 135 min, 180 min, 240 min, 360 min, and 480 min. The corresponding target cumulative element iron release ratio vector is uniquely set to 0.0000, 0.0400, 0.0900, 0.1500, 0.2200, 0.3000, 0.4500, 0.6000, 0.7800, and 0.9000. The creation date, approver, checksum, and version number are written into the target specification record. Any change in time or value will generate a new version. Once screening begins, the record is locked and cannot reference external, unregistered target values. This batch of constraints also includes an upper limit of 0.25 for the cumulative release ratio in the gastric segment at 120 min, a lower limit of 0.40 for the cumulative release ratio in the intestinal segment at 240 min, a lower limit of 0.60 for the cumulative release ratio in the intestinal segment at 360 min, a cumulative release ratio range of 0.80 to 1.00 at the endpoint at 480 min, and an upper limit of 0.0030 min for the difference in release rate before and after pH switching. -1 The proportional screening module first calculates the release rate before switching and the release rate after switching from each candidate total release curve according to the same points of S4. Then it takes the absolute value of the difference between the two and then performs the judgments in sequence: less than or equal to the upper limit of the gastric segment, greater than or equal to the lower limit of the intestinal segment, in the terminal closed interval, and less than or equal to the upper limit of the rate difference. Only when all judgments are true will the candidate value be written into the feasible score set. For each candidate total release curve, its point-by-point deviation from the preset target curve is also calculated, and the cumulative deviation is calculated according to the formula. The absolute value peak value is calculated according to the formula. Calculate, where Indicates candidate value The cumulative deviation is a dimensionless value. Indicates candidate value The absolute peak value is a dimensionless value. This represents the total release percentage of the candidates, and is a dimensionless value. This indicates that the preset target curve is at the th The cumulative percentage of elemental iron released at each time point is a dimensionless value. Indicates the sequence number of the test time point. This indicates the total number of test time points included in the currently locked target specification and S4 timeline, with the count being an inapplicable unit. The data is derived from the same version of the 10 o'clock timetable; the smaller the two deviation values, the closer the candidate curve is to the preset target curve; When the feasible score set is empty, the module outputs a state of no feasible solution and writes the first unmet constraint and corresponding curve value of each candidate value into the exception details. Production cannot continue by relaxing the specifications or expanding the scale window. When the feasible score set contains only one candidate value, the value is directly submitted as the approved iron equivalent score of the F group element. When there are multiple candidate values, they are first sorted in ascending order of cumulative deviation. If the cumulative deviations are the same, they are sorted in ascending order of absolute value peak value. If both are the same, they are sorted in ascending order of iron equivalent score of the F group element. The candidate value ranked first is used as the approved iron equivalent score of the F group element, so that the determination rule obtains a unique result under the same input. The proportion screening module writes the approved iron equivalent fraction of group F elements, the corresponding iron equivalent ratio of group F to group E elements, two single-group curves for the current batch, the total release curve of the approved candidates, all constraint judgment values, cumulative deviation, absolute value peak value, and feasible score set into the batch mixing record; the approved mixing ratio is expressed as the iron equivalent ratio of group F elements to group E elements, and the version number and check value of the record are sent to S6. S6 can only read records with an approved status and curve version consistent with the current production batch; pH perturbation validation established four perturbation conditions after baseline screening: 90 min in acidic medium, 150 min in acidic medium, pH 6.5 in the near-neutral medium after transfer, and pH 7.1 in the near-neutral medium after transfer. Other temperature, rotation speed, and elemental iron determination conditions followed S4. To ensure a one-to-one correspondence between the ten measured curves for different acidic residence times, the total acidic residence time was set as follows: ,in This represents the total dwell time under the disturbance conditions from the start of the acidic medium test to the medium switching, in minutes, and can be 90, 120, or 150. The five local points in the acidic phase are fixed at 0, 120, or 150. , , and The five local points in the near-neutral phase are fixed at 15 min, 60 min, 120 min, 240 min, and 360 min after the switch. Therefore, the full-range measured time points for the 90-min perturbation are 0, 22.5, 45, 67.5, 90, 105, 150, 210, 330, and 450 min, and the full-range measured time points for the 150-min perturbation are 0, 37.5, 75, 112.5, 150, 165, 210, 270, 390, and 510 min. The near-neutral pH perturbation maintains the baseline 120-min acidic stay and the S4 ten-point time table. Each perturbation curve still uses the newly added cumulative formula of S4 for each of the two medium phases, with local numbers 1 to 5. The fifth local point in the acidic phase forms the locked switching baseline for this perturbation version. After the switch, the liquid replenishment summation term is cleared to zero, and the carryover liquid is only included in the... The acidic baseline is used, and the increase in the near-neutral phase is added to the baseline to form the total cumulative amount. The ten points of the perturbation version are matched point by point with the 120-minute baseline curve according to the same phase position rather than the same absolute minute value. All points must be actually sampled and no interpolation is allowed. The F group, E group, prediction curve and finished product curve must use the same perturbation time axis version. The time-aligned cumulative elemental iron release curves of the F group and E group units in the current batch are obtained under each perturbation condition. The predicted total perturbation release curve is formed by using the approved F group elemental iron equivalent fraction according to the aforementioned weighting rules. The perturbation curve record is indexed by perturbation type, measured medium pH, residence time, time axis version, single group curve version and approval record status. The approval record status only allows three types: old approved version, version to be re-verified, and currently valid version. At any time, at most one version can be currently valid. The initial approval score obtained from the baseline screening is used to establish a version to be retested, and the corresponding baseline candidate total release curve is generated simultaneously. The system also generates a one-time validation sample preparation authorization, which only allows S6 to perform weighing, mixing, formulation, and baseline and perturbation tests on the version to be retested under an isolated, locked, and non-released validation batch. Normal production or finished product release permissions are not granted. For the finished product prepared under this authorization, the perturbation total release curve is obtained under the same perturbation conditions. All predicted perturbation total release curves and finished product perturbation total release curves in this round are only compared with the baseline candidate total release curve within the same version to be retested, point by point. In this specific embodiment, the pH perturbation deviation range given by the preset target curve specification is that the absolute difference at each time point is no greater than 0.08. When all time points of the two types of comparisons under all perturbation conditions meet this range, the version to be retested becomes the current valid version and is granted normal production permissions. The original current valid version becomes the old approved version and is no longer available for S6 to read. If any disturbance time point is exceeded, the F-group and E-group curves of the disturbance condition are added to the candidate evaluation input and all constraints within the proportional window are re-executed. During the re-screening, each candidate value is referenced to its own baseline candidate total release curve generated according to the aforementioned weighting rules, and the point-by-point difference between the predicted total release curve of the candidate value under each disturbance condition and its own baseline curve is required to be no greater than 0.08, while satisfying the baseline gastric segment, intestinal segment, endpoint, and rate difference constraints. If no feasible candidate value exists, the disturbance infeasibility solution state is output and the production batch is intercepted. If a feasible candidate value exists, the three-level ascending rule of cumulative deviation, absolute value peak value, and F-group score is used to determine the new approval score. The new approval score, along with its baseline candidate total release curve, all predicted perturbation curves, perturbation timeline version, target specification version, and single-group curve version, is written into a new version to be retested, and a one-time validation sample preparation authorization is issued only to S6. S6, according to this authorization, re-prepares the finished product in an independent validation batch and repeats all perturbation conditions. The validation batch inventory remains locked and cannot be released as merchandise. When both the predicted curve and the finished product curve in the repeated validation meet the pH perturbation deviation range relative to the baseline curve of this version to be retested, this version becomes the current valid version, the one-time authorization is revoked, and the old version becomes invalid. The validation batch remains permanently prohibited from release. If any value exceeds the limit in the repeated validation, the version to be retested is immediately marked as the most... If the final retest fails, the one-time authorization is revoked, the verification batch and the corresponding inventory of this production batch are locked, and the batch interception record is output. Candidates will no longer be deleted, returned to screening, or a third version to be retested will be generated in the same production batch. The authorization will automatically become invalid and the current verification sample preparation will be terminated if the authorization exceeds 30 days, the target specification, the disturbance time axis, or any single-group curve version changes. The proportion screening module will finally output to S6 the only currently valid approved mixing record for normal production, the retest record for isolation verification only, and the one-time authorization, or the interception record for no feasible solution or final retest failure, to ensure that the mixing ratio, the baseline curve, the single-group curve, the target specification, the disturbance time axis, and the disturbance verification result use the same version number. In a gradient iron release method using ferrous fumarate and EDTA iron-sodium, the proportional input in this step is simultaneously associated with the elemental iron content data of S1. S1 uses an elemental iron determination method that can distinguish between ferrous iron and total iron to obtain elemental iron content data and form the particle size elemental iron equivalent accordingly. This step only reads the batch attribute records that have passed the verification. If the elemental iron content version associated with the F group or E group curve is different from the version registered in the candidate score table, the screening is stopped and the curve normalization is required to be re-executed to prevent weighting with incorrect elemental iron equivalent scores. Disturbance conditions Next candidate value The predicted total release ratio of disturbances is calculated according to the formula. Calculate, where Indicates candidate value Under disturbance conditions and time points The predicted total release ratio of the disturbance is a dimensionless value. This represents the iron equivalent fraction of elements in group F, and is a dimensionless value. This indicates that group F is under perturbation conditions. and time points The cumulative percentage of elemental iron released is a dimensionless value. This represents the cumulative proportion of elemental iron released from group E under the same perturbation conditions and time points, and is a dimensionless value. This represents a category index for perturbation conditions. Units are not applicable. The categories are: acidic residence time 90 min, acidic residence time 150 min, near-neutral medium pH 6.5, or near-neutral medium pH 7.1. These categories are derived from locked perturbation condition records. The sampling time point number is indicated; the absolute values ​​of all test time points are added together to obtain the cumulative deviation, and the upper limit of the point-by-point difference of 0.08 is used as the disturbance constraint budget; The disturbance recalculation is performed using three types of records: status field, action field, and judgment target. The status field includes the current approved score, four types of disturbance single-group curves, and the baseline target specification. The action field is limited to retaining the approved score, updating the approved score, or intercepting the batch. The judgment target is to minimize the cumulative deviation within the proportional window while simultaneously satisfying the baseline constraint and the budget for all disturbance deviations. Each time a complete set of disturbance curves is obtained, a screening cycle is performed. If any group or any specified time point is missing, the batch will not be sorted. After obtaining the new approved score, S6 performs the sequential pH release test of step S4 on the obtained product and completes the retest under the same conditions. Only when the retest is passed will the batch screening task be closed. The system filters all candidate values ​​according to the baseline constraints, sorts feasible candidate values ​​according to cumulative deviation and peak absolute value, and selects the first ranked item as the approval score for re-verification. The deletion and rearrangement of candidates in this section is only allowed to occur in a single re-screening phase after the initial isolation verification exceeds the limit and must be completed before issuing a one-time authorization to the updated version to be re-verified: when the predicted disturbance curve of a candidate value exceeds the deviation budget under any disturbance condition, the system deletes the feasible state of that item and updates the candidate score table. If the updated set is empty, the production batch is blocked. If there are still candidate values, the same screening, sorting, and selection rules are re-executed and the unique result is written to the updated version to be re-verified. Once the updated version to be re-verified is issued a one-time authorization, subsequent repeated verification failures will be blocked according to the aforementioned final verification failure state, and this rearrangement cannot be executed again. The currently valid approved mixed record output in this step is the only proportional input for S6 to perform normal production formulation operations; the record to be retested can only be used as the proportional input for S6 to isolate the validation sample preparation when it exists simultaneously with an unexpired one-time validation sample preparation authorization, and the resulting validation batch must not be released; S6 mixes according to the stated stoichiometric ratio and fills it into capsules, or compresses it into tablets to maintain the integrity of the F group iron-releasing unit and the E group iron-releasing unit, and performs the sequential pH release test of the resulting product in step S4; S5 only maintains or promotes the approved mixed record after the finished product curve is compared point by point with the total release curve of the same version of the approved candidate and all constraints are passed, otherwise the record to be retested or the currently valid record is invalidated and the interception status is output.

[0025] In this specific embodiment, S6 includes: The finished product preparation module first verifies the production batch identifier, single-group curve version, target specification version, status, and operation permissions of the S5 output record. Normal production only accepts the currently valid approved version. The version to be retested is only allowed to enter the weighing and mixing of the isolation verification batch when it is accompanied by a one-time verification sample preparation authorization that is not expired, has the exact same version number, and has not been used. The verification batch is locked from the time of feeding and the generation of release records is prohibited. When the feasible score set is empty, the record status is infeasible, the version to be retested lacks a valid authorization, or there is no currently valid approved version after perturbation verification, the system generates an abnormal record containing the batch identifier, failure constraint, candidate value range, curve version, and timestamp, locks the F group and E group unit inventory, and blocks normal production. When a valid approval record exists, the system reads the actual elemental iron content of the iron-releasing units in groups F and E from the S1 batch attribute record and the S2 and S3 unit records, and calculates the metrological mass of the two groups of units according to the target total elemental iron content; the conversion relationship is as follows: and In the formula This indicates the mass of the F-group iron-releasing unit to be weighed, in grams. This indicates the mass of the E-group iron-releasing unit to be weighed, in grams. This indicates the approved iron equivalent fraction of group F elements, which is a dimensionless value. This indicates the total amount of elemental iron contained in the mixed batch plan, in mg. This indicates the elemental iron content of the F-group iron-releasing units in that batch, expressed in mg / g. This indicates the elemental iron content of the E-group iron-releasing units in that batch, expressed in mg / g. This indicates the approved iron equivalent fraction of Group E elements; the weighing system weighs the calculated mass separately and writes the theoretical value, measured value, and weighing equipment number into the feeding record; The two iron-releasing units were mixed using a low-shear three-dimensional mixer. In this specific embodiment, the loading coefficient was 40% to 60%, the rotation speed was 12 r / min, and the mixing time was 10 min. Samples were taken from the top, middle, and bottom positions 3 min after the start of mixing and at the end of mixing, respectively. The group was determined by an orthogonal dual signal composed of the sodium ascorbate signal unique to group F and the phthalic acid signal after hydrolysis of hydroxypropyl methylcellulose phthalate unique to group E, which was determined by high performance liquid chromatography. Before each batch was mixed, a bivariate calibration model was established using five known proportion calibration samples of pure group F, pure group E, and group F elemental iron equivalent fractions of 0.30, 0.40, 0.50, 0.60, and 0.70. The sample dual signal was converted into group F elemental iron equivalent fraction according to the model only when the pure group cross-response was not greater than 2.0%, the spiked recovery rate of each signal was between 95% and 105%, and the calibration correlation coefficient was not less than 0.995. Mixing is terminated when the absolute deviation of the iron equivalent fraction of F group elements converted from samples at all six locations relative to the approved value is no greater than 0.03. If any pure group specificity, spike recovery rate, or calibration correlation coefficient fails to meet the requirements, the model shall not be used to determine the mixing homogeneity, and a new calibration sample must be prepared or the sample extraction must be verified. If the deviation of a sample at a location exceeds 0.03, an additional 3 minutes of low-shear mixing shall be performed and the sample shall be retested. If the deviation still exceeds the requirement after retesting, an abnormal mixing homogeneity record shall be generated and the batch of mixture shall be intercepted. Multi-unit materials with acceptable uniformity are filled into hard capsules. The target elemental iron content of a single capsule is set according to the product batch record, and the content difference is eliminated by online weighing. When tableting is required, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose that can form a buffer layer during compression are added. The tableting pressure is set to the process confirmation value that makes the tablet form without breaking the F or E group coating units, and the integrity criterion is that the difference in the film breakage rate of 100 random units before and after tableting is no more than 1.0%. The elemental iron content of capsules or tablets is determined by ten dose units. When the individual result is between 85% and 115% of the labeled amount and the relative standard deviation is no more than 6%, it enters the release retest. The final product release retest strictly followed the S4 method, including media volume, temperature, rotation speed, pH sequence, sampling time, liquid replenishment correction, and elemental iron determination, to obtain the cumulative elemental iron release curve of the final product; The deviation of the finished product curve at each time point is calculated according to the formula. Calculate, where Indicates the finished product curve at the 1st The absolute deviation of each time point relative to the total release curve of the approved candidates is a dimensionless value. Indicates the finished product at the [number]th [year]. The cumulative percentage of elemental iron released at each time point is a dimensionless value. Indicates the approval of the mixed record. The total release percentage of candidates at each time point is a dimensionless value. Indicates the test time point number; in this specific embodiment, the predetermined deviation range of the finished product curve is that the absolute deviation at each time point is no greater than 0.05; The release decision simultaneously checks all finished product curve deviations and the upper limit of cumulative release in the gastric segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the release rate difference before and after pH switching for S5. Only when the absolute deviation at each time point is not greater than 0.05 and the finished product curve meets all four types of constraints is the finished product curve marked as a gradient total iron release curve confirmed by retesting. If any condition is not met, an abnormal release record is formed, recording the time point of exceeding the limit, the measured value, the approved value, the deviation and the constraint name, and the multi-unit oral preparation is blocked. For the acidic medium residence time and near-neutral medium pH disturbance conditions specified in S5, the finished product preparation module reads the currently valid approved version for normal production, and reads the version to be retested with a one-time verification sample preparation authorization for the first or updated ratio verification. It then completes the finished product disturbance release test condition by condition according to the locked disturbance timeline version. The measured finished product disturbance curve is compared point by point with the corresponding predicted total disturbance release curve and the same version's benchmark approved candidate total release curve at the same stage position. When all differences in the version to be retested are within 0.08, the result is returned to S5 to be promoted to the current valid version. The verification batch remains locked before and after promotion and is never released as a product. If any difference in the first version to be retested exceeds the limit, the verification batch is frozen, the authorization is invalidated, and only one rescreening is allowed by calling S5. If S5 returns an updated version to be retested and a one-time authorization, a second isolated verification batch is established according to the new mass ratio. If no feasible solution is returned, the production batch is intercepted. If any difference in the repeated verification of the updated version to be retested exceeds the limit, screening is no longer called, and the process directly enters the final retest failure state of the next stage. The second isolation validation batch of the updated version to be retested still uses the same set of perturbation conditions, the same perturbation timeline version, and the same analytical method; when all predicted differences and finished product differences in the repeated validation are within the preset pH perturbation deviation range, only the newly approved version is promoted to the current validity and the one-time authorization is revoked. The two isolation validation batches remain permanently locked and no product release record is generated; after the promotion is completed, the system will separately feed, mix, and formulate the product using the current valid version and the new normal production batch identifier. The normal production batch must complete the baseline sequence pH release and the same set of perturbation release retests. Only after all finished product curve deviations and S5 constraints are passed can a finished product release record belonging only to this normal production batch be generated; if any value exceeds the limit in the repeated validation of the updated version to be retested, a final perturbation retest failure record will be generated immediately, the authorization will be revoked, the version to be retested will be invalidated, the two validation batches and the corresponding inventory of this production batch will be locked, and the batch will be terminated and will not be returned to S5 rescreening; The release record for a normal production batch includes its independent batch identifier, the current valid version used, the actual feed quality of the two units, elemental iron content, theoretical elemental iron equivalent, formulation quantity, fill volume difference, unit membrane breakage verification results, and all curve verification values. It also explicitly states that the batch number or inventory of the isolated validation batch must not be cited. Verifiers make the final material balance judgment based on the difference between the theoretical total elemental iron and the actual measured total elemental iron of the normal production product not exceeding 5.0%. Only when the material balance, baseline sequence pH release, and disturbance verification of the normal production batch are all qualified will the inventory lock of the normal production batch be released and the gradient total iron release curve confirmed by the finished product retest and the release status of the multi-unit oral formulation be output. The inventory lock and restricted release status of the two isolated validation batches are not affected by this record.

[0026] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

[0027] This invention uses the differentiated structures of two types of iron release units to sequentially link the controlled gastric release of ferrous fumarate with the intestinal-opening release of sodium EDTA. The batch single-group curve after normalizing the total elemental iron content is used as the input for calculating the mixing ratio, so that the material structure characteristics and release detection results jointly participate in the control of the total iron release process of the finished product.

[0028] Compared to the method of fixed mixing according to nominal amount, the present invention adds curve constraint screening within the ratio window, batch interception of infeasible solution, finished product curve retesting and pH disturbance recovery branch, thereby enabling the approved mixing ratio to be adjusted according to the single-group release characteristics of the batch, and making the judgment criteria for cross-pH release continuity and finished product release reproducible.

Claims

1. A method for releasing iron via a gradient of ferrous fumarate and EDTA iron-sodium mixture, characterized in that, include: S1. The particle size distribution and elemental iron content of ferrous fumarate and sodium iron ethylenediaminetetraacetate from the same production batch were determined and the particle size was classified to obtain two types of iron source graded materials measured in elemental iron equivalent. S2. F-group iron release units with first pore flux parameter, carrier microenvironment regulation components and non-pH-dependent barrier membrane are prepared using ferrous fumarate fractionation material. S3. Using sodium iron ferric ethylenediaminetetraacetate fractionation material, E group iron release units with a second pore flux parameter, an inner retardation layer and an outer enteric layer were prepared. S4. Conduct acidic to near-neutral pH release tests on the two groups of iron release units, and normalize the release amount according to the total amount of elemental iron to obtain the cumulative elemental iron release curve of group F and the cumulative elemental iron release curve of group E. S5. Within the predetermined iron source ratio window, using the iron equivalent fraction of group F elements as the decision factor, the two cumulative elemental iron release curves are weighted by elemental iron equivalent to obtain the candidate total release curve, and feasible group F elemental iron equivalent fractions are screened according to the upper limit of cumulative release in the stomach segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the difference in release rate before and after pH switching. S6. Determine the approved mixing ratio based on the feasible iron equivalent fraction of group F elements, mix the two groups of iron-releasing units according to the approved mixing ratio, and prepare a multi-unit oral formulation.

2. The method for releasing iron using a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 1, characterized in that, S1 includes: Representative samples from each batch of ferrous fumarate and sodium ferric ethylenediaminetetraacetate were taken, and the volume distribution particle size data were obtained using the same particle size determination method. The elemental iron content data were obtained using an elemental iron determination method that can distinguish between ferrous iron and total iron. Based on the volume distribution particle size data of each iron source, the corresponding particle size classification boundary is set, and the particle size range, mass and elemental iron content of each particle size are recorded. The elemental iron equivalent of each particle size is calculated based on the mass and elemental iron content. The particle size range, elemental iron content, and elemental iron equivalent are associated with the production batch identifier to form a batch attribute record for steps S2, S3, and S5.

3. The method for releasing iron using a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 1, characterized in that, S2 include: The ferrous fumarate fraction is loaded into a pharmaceutical porous carrier with interconnected internal channels, and microenvironment-regulating components screened by iron valence state retention ability, complexation stability and outward migration quality are set in the internal channels. The first pore flux parameter is determined based on the liquid permeation rate per unit time of the porous carrier under a specified pressure difference and a specified temperature. A pH-independent barrier membrane is formed on the outside of the loaded pharmaceutical porous carrier. The first pore flux parameter, the amount of iron per unit element of the microenvironment regulating component, and the dry membrane mass per unit area of ​​the pH-independent barrier membrane are determined together based on the upper limit of cumulative release in the target gastric segment and the continued release requirements after transfer to a near-neutral medium.

4. The method for releasing iron via a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 1, characterized in that, S3 include: The ethylenediaminetetraacetic acid iron sodium fraction is loaded into a pharmaceutical porous carrier, and the second pore flux parameter is determined based on the liquid permeation rate per unit time of the pharmaceutical porous carrier under a specified pressure difference and a specified temperature. An inner blocking layer and an outer enteric coating layer are sequentially formed on the outside of the loaded pharmaceutical porous carrier. The dry film mass per unit area of ​​the inner blocking layer is determined according to the target release time after the outer enteric coating layer is opened. The dry film mass per unit area of ​​the outer enteric coating layer and the dissolution pH boundary are determined according to the gastric segment closure requirements and the near-neutral medium opening requirements.

5. The method for releasing iron via a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 1, characterized in that, S4 include: The F group iron-releasing units and the E group iron-releasing units of the same batch were placed in an acidic medium with a pH of 1.

2. After sampling at the gastric segment test time point, they were transferred to a near-neutral medium with a pH of 6.8, and samples were taken at multiple intestinal segment test time points. The amount of iron released in each sample was measured and normalized according to the total amount of iron in the corresponding test unit to obtain the cumulative iron release ratio at each time point. Using the last two adjacent sampling points before pH switching and the first two adjacent sampling points after pH switching as point pairs, the cumulative difference in the elemental iron release ratio of each point pair is divided by the corresponding sampling time interval to obtain the release rate before switching and the release rate after switching. The absolute value of the difference between the two release rates is taken as the difference in release rates before and after pH switching in step S5.

6. The method for releasing iron via a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 1, characterized in that, S5 include: Multiple candidate values ​​for the iron equivalent fraction of F group elements are set within the predetermined iron source ratio window; For each candidate value, the product of the cumulative iron release ratio of group F at each time point and the candidate value is added to the product of the cumulative iron release ratio of group E at each time point and the difference obtained by subtracting the candidate value, to obtain the corresponding candidate total release curve. The candidate total release curves are sequentially determined to satisfy the constraints of the upper limit of cumulative release in the stomach segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the difference in release rate before and after pH switching. Candidate values ​​that simultaneously satisfy all constraints are formed into a feasible score set, and the approved mixing ratio is determined based on the feasible score set.

7. The method for releasing iron via a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 6, characterized in that, S6 include: When the set of feasible scores is empty, an exception record of no feasible solution is generated and the production batch is intercepted; When the set of feasible fractions is not empty, the approved mixing ratio is converted into the mass ratio of the iron-releasing units of the current batch F group to the iron-releasing units of the current batch E group. The elemental iron content of the current batch recorded in step S1 is used for the conversion. After being mixed according to the stated mass ratio, the mixture is filled into capsules or compressed into tablets to maintain the integrity of the F group iron-releasing units and the E group iron-releasing units; The obtained finished product is subjected to a sequential pH release test in step S4. The cumulative elemental iron release ratio of the finished product is compared with the candidate total release curve corresponding to the approved mixing ratio at time points. When the difference at each time point is within the predetermined deviation range of the finished product curve and the cumulative elemental iron release ratio of the finished product meets all the constraints of step S5, a gradient total iron release curve confirmed by the finished product retest is obtained and the multi-unit oral formulation is released. Otherwise, an abnormal release record of the finished product is formed and the multi-unit oral formulation is blocked.

8. The method for releasing iron using a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 3, characterized in that, The screening of the microenvironment regulation components includes: Carrier samples containing candidate microenvironment-regulating components and control samples without candidate microenvironment-regulating components were prepared, and the two types of samples were then exposed to acidic and near-neutral media in sequence. In each medium stage, the proportion of divalent iron in the carrier to the total iron in the carrier and the proportion of soluble iron complexes in the carrier were determined for both types of samples. The mass of candidate microenvironment regulation components that migrated to the outside of the carrier in the carrier sample containing candidate microenvironment regulation components was also determined. Calculate the difference in the proportion of divalent iron and the difference in the proportion of soluble iron complexes between the carrier sample containing the candidate microenvironment regulation components and the control sample. Candidate microenvironment conditioning components are selected based on the following conditions: the proportions of ferrous iron and soluble iron complexes are within their respective predetermined stability ranges; the difference between the proportions of ferrous iron and soluble iron complexes is not less than the corresponding predetermined lower limit of improvement; and the migration quality does not exceed the predetermined upper limit of migration. The amount of iron per unit element required to achieve the predetermined stability range and the predetermined lower limit of improvement is used as the amount of microenvironment conditioning component used in step S2.

9. The method for releasing iron via a gradient of ferrous fumarate and EDTA iron-sodium reaction according to claim 6, characterized in that, The upper limit of cumulative release in the stomach segment, the lower limit of cumulative release in the intestinal segment, the cumulative release range at the endpoint, and the constraints on the difference in release rate before and after pH switching are given by the same preset target curve specification. Calculate the absolute value of the cumulative elemental iron release ratio difference between each candidate total release curve and the preset target curve at each test time point, add the absolute values ​​at all test time points to obtain the cumulative deviation, and record the peak value of the absolute value at each test time point; When the feasible score set includes multiple candidate values, the candidate values ​​are first sorted in ascending order according to the cumulative deviation. If the cumulative deviations are the same, they are sorted in ascending order according to the peak value of the absolute value. If both the cumulative deviation and the peak value of the absolute value are the same, they are sorted in ascending order according to the iron equivalent score of the F group element. The candidate value with the first ranking is selected as the iron equivalent score of the F group element. The iron equivalent fraction of the F group elements, the corresponding approved mixing ratio, the cumulative iron release curve of the F group elements in the current batch, the cumulative iron release curve of the E group elements in the current batch, the corresponding candidate total release curve, and the feasibility judgment result are all written into the batch mixing record.

10. The method for releasing iron via a gradient of ferrous fumarate and EDTA iron-sodium as described in claim 9, characterized in that, It also includes pH perturbation verification: for each perturbation condition that changes the residence time in the acidic medium and changes the pH value of the near-neutral medium after transfer, release tests are conducted on the iron release units of the F group and the iron release units of the E group in the current batch, respectively, to obtain the cumulative elemental iron release curves of the F group and the cumulative elemental iron release curves of the E group under the corresponding perturbation conditions. According to the approved mixing ratio, the two cumulative elemental iron release curves under each disturbance condition are weighted by elemental iron equivalent to obtain the predicted total disturbance release curve. The finished product prepared according to the approved mixing ratio is then subjected to a release test under the corresponding disturbance condition to obtain the total disturbance release curve of the finished product. The predicted total release curve of disturbance and the total release curve of finished product disturbance are compared with the candidate total release curve corresponding to the approved mixing ratio at time points. When all differences are within the pH disturbance deviation range given by the preset target curve specification, the approved mixing ratio is retained. When any difference exceeds the pH perturbation deviation range, S5 is re-executed with the cumulative elemental iron release curves of group F and group E under each perturbation condition as input, and the pH perturbation deviation range under all perturbation conditions is used as an additional constraint. If no feasible iron equivalent fraction of group F elements is found after re-execution, the production batch is intercepted. If a feasible iron equivalent fraction of group F elements is found, a new iron equivalent fraction of group F elements is determined according to the sorting rule of claim 9 and the approved mixing ratio is updated. The finished product is prepared again according to the updated approved mixing ratio and the pH perturbation verification is repeated. If all the differences in the repeated verification are within the pH perturbation deviation range, the updated approved mixing ratio is retained and the finished product is released; otherwise, the production batch is intercepted.

Images