Analysis control method based on monitoring data of iron proteinsuccinylate oral solution

Abstract

The invention relates to the technical field of analysis of monitoring data, in particular to an analysis control method based on monitoring data of an iron proteinsuccinylate oral solution, which comprises the following steps: determining whether the diffusion rate of a bulk drug is qualified or not according to the turbidity fluctuation amplitude, and adjusting the stirring speed of a stirring paddle in a liquid preparation tank based on the condition that the diffusion rate of the bulk drug is unqualified; under the condition of determining that the diffusion rate of the raw material medicine is qualified, determining whether the initial dissolution process of the raw material medicine is qualified or not according to the gradient deviation of the axial concentration distribution; determining solid residues at the bottom of the liquid preparation tank on the basis of unqualified conditions of the initial dissolution process of the raw material medicine so as to determine optimization of the speed adjustment coefficient or adjustment of the grinding duration of the colloid mill; and determining whether the uniformity of the solution in the solution preparation tank is qualified or not according to the similarity of the plurality of particle size distribution curves of the solution in the solution preparation tank so as to optimize the preset proportion. According to the invention, the production efficiency of the iron protein succinate oral solution is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of monitoring data analysis, in particular to a protein ferric succinate oral solution monitoring data analysis control method. BACKGROUND

[0002] As a commonly used organic iron supplement in clinical practice, protein ferric succinate oral solution has the advantages of small gastrointestinal irritation and high bioavailability because iron ions exist in the form of protein succinate complex. It is widely used for the prevention and treatment of iron deficiency anemia. However, the core technical problem faced in the production process of this preparation is that the drug substance (protein ferric succinate) is in powder form, which is easily formed into dense agglomerates due to the influence of intermolecular van der Waals force, electrostatic attraction and drying process in the production process. This agglomeration phenomenon directly leads to the chain problem in the subsequent liquid preparation process. In the feeding stage of the liquid preparation tank, the agglomerated drug substance is difficult to be uniformly dispersed by conventional stirring, and local concentration accumulation is easy to form in the tank, leading to uneven axial and radial diffusion, and concentration gradient of upper dilution and lower concentration. When entering the dissolution stage, the drug particles in the agglomerates cannot fully contact with the solvent (purified water and cosolvent system), and the solvation effect can only act on the surface of the agglomerates. Even after the colloidal mill grinding treatment, there may still be micron-sized agglomerated particles that are not completely dissociated, resulting in incomplete dissolution.

[0003] The above-mentioned uneven diffusion and dissolution problems can further lead to turbidity and local color difference in the intermediate liquid system. The un-dissolved particles can easily block the filter membrane in the subsequent filtration process, reducing the production efficiency. The finished product after filling may have quality defects such as non-compliance of content uniformity (single dose iron content deviation exceeding the provisions of Chinese Pharmacopoeia), particle sedimentation and stratification during storage, rough taste, etc. In severe cases, the un-dissolved particles cannot be effectively absorbed by the human body, leading to reduced drug efficacy, or excessive release of free iron ions, increasing the risk of gastrointestinal irritation, and ultimately causing the finished product to be unqualified.

[0004] Currently, the control of such problems in the industry mainly relies on manual visual observation and offline sampling detection, which has the limitations of monitoring lag and insufficient data representation, making it difficult to capture the diffusion and dissolution abnormalities caused by agglomeration in real time. Therefore, it is urgent to establish an analysis control method based on real-time monitoring data to realize precise control of the whole process of drug substance agglomeration-diffusion-dissolution and ensure the stability of the finished product quality.

[0005] Chinese patent application publication No. CN117752768A discloses a prescription composition of a protein ferric succinate oral solution and a preparation method thereof. The method first reduces the viscosity of the preparation and increases the filtration speed of the raw material by concentrating and high-pressure homogenizing the active ingredient protein ferric succinate. By controlling the temperature of the liquid medicine, the structure of the protein in the protein ferric succinate is not damaged, and the ultrafiltration membrane is used for filtration and sterilization. This patent not only controls the microbial level of the preparation from the source, but also optimizes the amount of bacteriostatic agent in the prescription of the preparation, ensures that the stability of the preparation meets the specified requirements, and also ensures the clinical efficacy, achieving a four-in-one effect. In addition, through the optimization and control of the liquid preparation parameters, the preparation process is greatly simplified while ensuring the quality attributes of the product. Ultimately, a prescription composition of a protein ferric succinate oral solution and a preparation method thereof are developed to meet the needs of commercial production.

[0006] There are also the following problems in the prior art: the monitoring of the preparation process of the protein ferric succinate oral solution in the prior art has a lag, which causes the raw material to be unable to be adjusted in time due to the uneven diffusion and dissolution of the raw material with the characteristics of easy agglomeration in the production process, thereby reducing the production efficiency of the protein ferric succinate oral solution. SUMMARY

[0007] Therefore, the present application provides an analysis control method based on protein ferric succinate oral solution monitoring data to overcome the problem of the lag in the monitoring of the preparation process of the protein ferric succinate oral solution in the prior art, which causes the raw material to be unable to be adjusted in time due to the uneven diffusion and dissolution of the raw material with the characteristics of easy agglomeration in the production process, thereby reducing the production efficiency of the protein ferric succinate oral solution.

[0008] To achieve the above-mentioned purpose, the present application provides an analysis control method based on protein ferric succinate oral solution monitoring data, comprising:

[0009] Mixing the raw material of the protein ferric succinate oral solution with the solvent at a predetermined ratio and then putting it into a liquid preparation tank;

[0010] Obtaining the turbidity fluctuation amplitude of the solution at the feeding point position, determining whether the diffusion rate of the raw material is qualified according to the turbidity fluctuation amplitude, and setting a plurality of speed adjustment coefficients based on the unqualified condition of the diffusion rate of the raw material to adjust the stirring speed of the stirring paddle in the liquid preparation tank;

[0011] Under the condition that the diffusion rate of the raw material is qualified, obtaining the axial concentration distribution of the solution in the liquid preparation tank, and determining whether the preliminary dissolution process of the raw material is qualified according to the gradient deviation of the axial concentration distribution;

[0012] determine the solid residue at the bottom of the solution preparation tank based on the preliminary dissolution process unqualified condition of the raw material drug, determine the optimization of the speed adjustment coefficient or the adjustment of the grinding time of the colloid mill based on the distribution difference of the solid residue;

[0013] obtain the particle size distribution curves of the solutions at several positions in the solution preparation tank after the raw material drug is ground by the colloid mill, and determine whether the uniformity of the solutions in the solution preparation tank is qualified according to the similarity of the several particle size distribution curves, and optimize the preset proportion based on the unqualified condition of the uniformity of the solutions in the solution preparation tank.

[0014] Further, the process of determining whether the diffusion rate of the raw material drug is qualified based on the turbidity fluctuation amplitude comprises:

[0015] comparing the turbidity fluctuation amplitude with a preset fluctuation amplitude;

[0016] determining that the diffusion rate of the raw material drug is unqualified based on the comparison result that the turbidity fluctuation amplitude is greater than the preset fluctuation amplitude;

[0017] determining that the diffusion rate of the raw material drug is qualified based on the comparison result that the turbidity fluctuation amplitude is less than or equal to the preset fluctuation amplitude.

[0018] Further, under the condition that the diffusion rate of the raw material drug is determined to be unqualified, the process of adjusting the stirring speed of the stirring paddle in the solution preparation tank comprises:

[0019] obtaining a turbidity difference by subtracting the preset fluctuation amplitude from the turbidity fluctuation amplitude;

[0020] comparing the turbidity difference with a preset turbidity difference;

[0021] setting a plurality of speed adjustment coefficients to increase the stirring speed of the stirring paddle based on the comparison result of the turbidity difference and the preset turbidity difference.

[0022] Further, under the condition that the diffusion rate of the raw material drug is determined to be qualified, the process of determining the gradient deviation of the axial concentration distribution comprises:

[0023] obtaining a first distribution concentration of the raw material drug at the top of the solution preparation tank, a second distribution concentration of the raw material drug in the tank, and a third distribution concentration of the raw material drug at the bottom of the tank;

[0024] obtaining a first concentration difference by subtracting the first distribution concentration from the second distribution concentration, and obtaining a second concentration difference by subtracting the second distribution concentration from the third distribution concentration;

[0025] determining the absolute concentration difference of the first concentration difference and the second concentration difference as the gradient deviation of the axial concentration distribution.

[0026] Further, the process of determining whether the preliminary dissolving process of the bulk drug is qualified based on the gradient deviation comprises:

[0027] comparing the gradient deviation with a preset deviation;

[0028] determining that the preliminary dissolving process of the bulk drug is unqualified based on a comparison result that the gradient deviation is greater than the preset deviation.

[0029] Further, the process of determining the distribution difference of the solid residues at the bottom of the liquid preparation tank under the condition that the preliminary dissolving process of the bulk drug is unqualified comprises:

[0030] dividing the bottom of the liquid preparation tank into a plurality of annuli at equal intervals with the geometric center of the bottom of the liquid preparation tank as a reference point;

[0031] determining the solid residues of any of the annuli, and determining the standard deviation of the plurality of solid residues as the distribution difference of the solid residues.

[0032] Further, the process of optimizing the speed adjustment coefficient based on the distribution difference comprises:

[0033] comparing the distribution difference with a preset difference;

[0034] optimizing the speed adjustment coefficient based on a comparison result that the distribution difference is greater than the preset difference;

[0035] comparing a first difference value between the distribution difference and the preset difference with a preset difference value;

[0036] setting a plurality of speed optimization coefficients to optimize the speed adjustment coefficient based on a comparison result of the first difference value and the preset difference value.

[0037] Further, the process of adjusting the grinding duration of the colloid mill based on the distribution difference comprises:

[0038] comparing the distribution difference with a preset difference;

[0039] adjusting the grinding duration of the colloid mill based on a comparison result that the distribution difference is less than or equal to the preset difference;

[0040] comparing a second difference value between the preset difference and the distribution difference with a preset difference value;

[0041] setting a plurality of duration adjustment coefficients to increase the grinding duration of the colloid mill based on a comparison result of the second difference value and the preset difference value.

[0042] Further, the process of determining whether the uniformity of the solution in the liquid preparation tank is qualified according to the similarity of the plurality of particle size distribution curves comprises:

[0043] compare the similarity with a preset similarity;

[0044] determine that the uniformity of the solution in the liquid preparation tank is unqualified based on a comparison result that the similarity is less than the preset similarity.

[0045] Further, samples are taken at several positions of the liquid preparation tank respectively, and the characteristic coordination peak area ratios of the samples are determined after the samples are left to stand;

[0046] determine the maximum deviation of the characteristic coordination peak area ratios;

[0047] set a plurality of proportion optimization coefficients based on the determination result of the maximum deviation of the characteristic coordination peak area ratios to optimize the preset proportion.

[0048] Compared with the prior art, the present application has the beneficial effects that firstly, whether the diffusion rate of the raw drug is qualified is determined by the turbidity fluctuation range of the feeding point position, in the preparation of the protein ferric succinate oral solution, the feeding point is the core area of the raw drug just entering the solvent system, and the turbidity fluctuation range thereof can be directly related and judged whether the diffusion rate of the raw drug is qualified, the protein ferric succinate raw drug is easy to agglomerate, and after feeding, it needs to diffuse to the surrounding solvent through stirring, and the turbidity is the scattering degree of light by the suspended particles (including the raw drug particles which are not completely dispersed, and the micro-agglomerates) in the solution, the turbidity value of the feeding point directly reflects the concentration of the raw drug particles in the area, if the diffusion rate is qualified, the raw drug will be continuously and uniformly taken away from the feeding point, the particles will not be excessively accumulated or rapidly lost in the area, the local particle concentration is maintained in a stable range, the turbidity fluctuation range is small, if the diffusion rate is not qualified, the raw drug particles are accumulated at the feeding point, the local particle concentration is suddenly increased, the upper limit of the turbidity is significantly increased, and at the same time, due to the uneven dispersion of the particles, the local particles may be temporarily sparse, resulting in the decrease of the lower limit of the turbidity, and finally the turbidity fluctuation range is too large. In addition, the feeding point is the starting end of diffusion, and the turbidity fluctuation thereof is more sensitive than that of other areas, the area far from the feeding point has completed diffusion, and the turbidity changes gently, and cannot directly reflect the rate problem in the initial stage of diffusion, while the turbidity fluctuation of the feeding point can capture the dynamic balance of particle generation-diffusion removal in real time, and then accurately judge whether the diffusion rate meets the qualified standard of uniform dispersion of the raw drug and no local accumulation, so that the problems of uneven dissolution and uneven content of the finished product caused by unqualified diffusion rate are avoided; under the condition that the diffusion rate of the raw drug is qualified, whether the preliminary dissolution process of the raw drug is qualified is further determined according to the axial concentration distribution of the solution in the liquid preparation tank, the qualified diffusion rate ensures that the raw drug particles are uniformly dispersed in each area of the axial direction of the liquid preparation tank, that is, after feeding, the particles do not appear local accumulation or sparseness due to insufficient diffusion, and the initial amount of the raw drug particles at each axial position is consistent.At this time, the difference in axial concentration distribution is no longer determined by whether the particles are dispersed or not, but by whether the particles are dissolved or not. If the preliminary dissolution process is qualified, the drug particles at each axial position will be dissolved synchronously and uniformly under stirring and solvation. The protein ferric succinate complex produced by dissolution will be further uniformly dispersed by convection in the tank. The amount of undissolved residual particles is basically consistent at each axial position. The final axial concentration distribution is flat, and the gradient deviation is minimal. The axial concentration gradient deviation in the preliminary dissolution stage has a predictive effect on the subsequent process. When the colloidal mill is not used for grinding, the dissolution relies on the natural contact between the particles and the solvent. If a significant axial concentration gradient appears at this time, it means that some particles in the region have been blocked due to dissolution and have accumulated in the form of dissolution lag. Even after the subsequent colloidal mill grinding, the undissolved particles may still remain after grinding due to the poor initial dissolution, which may eventually cause problems such as uneven concentration and substandard clarity of the finished product. On the contrary, if the axial concentration gradient deviation is small, it indicates that the preliminary dissolution progress of each region is consistent, and the undissolved particles are uniformly distributed. The subsequent colloidal mill can efficiently handle the residual small particles to ensure complete final dissolution. The preparation parameters are adjusted in a targeted manner for the case of unqualified diffusion rate and the case of unqualified preliminary dissolution process to improve the production efficiency of the protein ferric succinate oral solution.

[0049] Further, the present application determines whether the uniformity of the oral solution is qualified by the similarity of the particle size distribution curves of the solution at several positions in the colloidal mill grinding solution tank. The core function of the colloidal mill is to break up the agglomerates of the raw material to make the residual incompletely dissolved particles in the system meet the process requirements of small particle size and uniform distribution. Although the protein ferric succinate raw material has been prepared into soft material, diffused and preliminarily dissolved, there may still be dense agglomerates that have not been completely dissociated. The colloidal mill breaks them into micrometer or even nanometer particles through high-speed shearing and grinding. If the grinding is sufficient and the system is uniformly mixed, these broken particles will form a stable dispersed state in the solvent, and there should be no significant difference in the particle size composition of each region. Otherwise, if the grinding is insufficient or the broken particles are not uniformly dispersed, there will be a situation where large particles are dominant in some regions and small particles are dominant in other regions, which directly reflects the low similarity of the particle size distribution curve and is directly related to the subsequent process and the quality of the finished product. The semi-finished product after colloidal mill needs to go through the links of filtration, filling, etc. If the uniformity is unqualified, it will cause the large particle concentration area to easily block the filter membrane during filtration, reducing the production efficiency and possibly causing the iron content uniformity to be unqualified or causing the product to easily separate during storage, affecting the stability and taste of the product. Therefore, the pre-set proportion of the solvent is increased in a targeted manner for the case of unqualified uniformity to further improve the production efficiency of the protein ferric succinate oral solution. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 The flowchart of the analysis and control method of the present application based on the monitoring data of the protein ferric succinate oral solution is shown in the figure.

[0051] Figure 2 A flow chart for determining whether the diffusion rate of the raw material drug is qualified for the embodiment of the present application;

[0052] Figure 3 A flow chart for determining whether the preliminary dissolution process of the raw material drug is qualified for the embodiment of the present application;

[0053] Figure 4 A flow chart for determining whether the uniformity of the solution in the liquid preparation tank is qualified for the embodiment of the present application. DETAILED DESCRIPTION

[0054] In order to make the objectives and advantages of the present application clearer and more apparent, the present application will be further described below in conjunction with embodiments; it should be understood that the specific embodiments described herein are merely used to explain the present application and are not used to limit the present application.

[0055] The preferred embodiments of the present application will be described below with reference to the accompanying drawings. It should be understood by those skilled in the art that the embodiments are merely used to explain the technical principles of the present application and are not used to limit the protection scope of the present application.

[0056] Please refer to Figures 1-4 as shown, Figure 1 A flow chart for the analysis control method based on the monitoring data of the protein ferric succinate oral solution for the embodiment of the present application; Figure 2 A flow chart for determining whether the diffusion rate of the raw material drug is qualified for the embodiment of the present application; Figure 3 A flow chart for determining whether the preliminary dissolution process of the raw material drug is qualified for the embodiment of the present application; Figure 4 A flow chart for determining whether the uniformity of the solution in the liquid preparation tank is qualified for the embodiment of the present application.

[0057] The analysis control method based on the monitoring data of the protein ferric succinate oral solution for the embodiment of the present application comprises:

[0058] Step S1, mixing the raw material drug of the protein ferric succinate oral solution with a solvent at a preset ratio and then putting it into a liquid preparation tank;

[0059] Step S2, obtaining the turbidity fluctuation amplitude of the solution at the feeding point position, determining whether the diffusion rate of the raw material drug is qualified according to the turbidity fluctuation amplitude, and setting a plurality of speed adjustment coefficients based on the unqualified condition of the diffusion rate of the raw material drug to adjust the stirring speed of the stirring paddle in the liquid preparation tank;

[0060] Step S3, under the condition that the diffusion rate of the raw material drug is qualified, obtaining the axial concentration distribution of the solution in the liquid preparation tank, and determining whether the preliminary dissolution process of the raw material drug is qualified according to the gradient deviation of the axial concentration distribution;

[0061] Step S4, determining the solid residue at the bottom of the liquid preparation tank based on the unqualified conditions of the preliminary dissolution process of the raw material drug, to determine the optimization of the speed adjustment coefficient or the adjustment of the grinding time of the colloid mill based on the distribution difference of the solid residue;

[0062] Step S5, obtaining the particle size distribution curves of the solution at several positions in the liquid preparation tank after the colloid mill grinding, to determine whether the uniformity of the solution in the liquid preparation tank is qualified according to the similarity of the several particle size distribution curves, and to optimize the preset ratio based on the unqualified conditions of the uniformity of the solution in the liquid preparation tank.

[0063] Specifically, the raw material of the protein ferric succinate oral solution is protein ferric succinate powder, and the preparation process of the protein ferric succinate oral solution is: raw material pretreatment, weighing purified water-assist stirring and dissolving-raw material stirring and dissolving-raw material colloid mill grinding and dissolving-adjusting pH-constant volume-filtering-filling-lamp inspection.

[0064] It can be understood that the pretreatment process of the raw material is to pre-mix the raw material powder with the solvent, i.e. purified water, to obtain wet particles in a preset ratio. The purpose is to solve the problem of uneven distribution of iron ion concentration caused by the inherent characteristics of raw material powder, such as easy agglomeration and gradual dissociation during dissolution, by early soaking and preliminary dispersion. Protein ferric succinate, as an organic iron-protein complex, is prone to form dense hard agglomerates due to the influence of intermolecular forces and particle surface tension. If the dry agglomerated raw material is directly put into the subsequent liquid preparation tank, it will be difficult for the solvent to penetrate into the interior of the agglomerates. During subsequent stirring or grinding, only the surface of the agglomerates can be affected, and the interior particles cannot be effectively broken, ultimately resulting in the presence of large particles in the finished product, affecting the dissolution uniformity and taste. After pre-mixing, purified water will gradually penetrate into the interior of the raw material agglomerates, break the inter-particle forces, and make the agglomerates loose into smaller secondary particle groups, or even single dispersed particles. During subsequent colloid mill grinding, there is no need to overcome the strong cohesion of hard agglomerates, and only fine breaking of loose particles is needed, which can improve the grinding efficiency and ensure the uniformity of the final particle size. The preset ratio is purified water / raw material powder mass = 8%.

[0065] Specifically, the process of determining whether the diffusion rate of the raw material drug is qualified based on the turbidity fluctuation amplitude includes:

[0066] Comparing the turbidity fluctuation amplitude with a preset fluctuation amplitude;

[0067] Based on the comparison result that the turbidity fluctuation amplitude is greater than the preset fluctuation amplitude, it is determined that the diffusion rate of the raw material drug is unqualified;

[0068] Based on the comparison result that the turbidity fluctuation amplitude is less than or equal to the preset fluctuation amplitude, it is determined that the diffusion rate of the raw material drug is qualified.

[0069] Specifically, the feeding point position refers to an instantaneous mixing zone extending from the feeding port to the solution in the tank, and the specific range is directly proportional to the volume of the liquid preparation tank. For example, for a liquid preparation tank with a volume of 1000L, the feeding point position refers to a cylindrical region with a radius of 10-20cm and a height of 5-15cm below the feeding port, and the specific range is not limited.

[0070] Specifically, the fluctuation amplitude of turbidity is determined based on the monitoring data of the turbidity sensor in the liquid preparation tank. A real-time turbidity curve is established according to the monitoring data of the turbidity sensor. The maximum turbidity and the minimum turbidity are determined every 1min. The difference between the maximum turbidity and the minimum turbidity is determined as the fluctuation amplitude of turbidity.

[0071] Specifically, the value range of the preset fluctuation amplitude is set to [5NTU, 15NTU], and the embodiment of the present application preferably is 8NTU.

[0072] Specifically, under the condition that the diffusion rate of the raw material drug is unqualified, the process of adjusting the stirring speed of the stirring paddle in the liquid preparation tank includes:

[0073] The turbidity difference is obtained by subtracting the fluctuation amplitude of turbidity from the preset fluctuation amplitude.

[0074] The turbidity difference is compared with the preset turbidity difference.

[0075] Based on the comparison result of the turbidity difference and the preset turbidity difference, a plurality of speed adjustment coefficients are set to increase the stirring speed of the stirring paddle.

[0076] Specifically, based on the comparison result that the turbidity difference is greater than or equal to the preset turbidity difference, the first speed adjustment coefficient is determined to increase the stirring speed.

[0077] Based on the comparison result that the turbidity difference is less than the preset turbidity difference, the second speed adjustment coefficient is determined to increase the stirring speed.

[0078] Specifically, the value range of the preset turbidity difference is set to [2NTU, 5NTU], and the embodiment of the present application preferably is 3NTU. The value range of the first speed adjustment coefficient is set to [1.15, 1.3], and the embodiment of the present application preferably is 1.2. The value range of the second speed adjustment coefficient is set to [1.05, 1.14], and the embodiment of the present application preferably is 1.1.

[0079] It can be understood that the diffusion rate of the raw material drug is unqualified, and the essential problem is that the diffusion rate of the raw material drug in the feeding point region to the remaining region is uneven. Increasing the stirring speed of the stirring paddle can strengthen the hydrodynamic effect and improve the mass transfer efficiency of the raw material drug.

[0080] Specifically, under the condition that the diffusion rate of the raw material drug is qualified, the determination process of the gradient deviation of the axial concentration distribution includes:

[0081] obtaining a first distribution concentration of the drug substance at the top of the tank, a second distribution concentration of the drug substance in the tank and a third distribution concentration of the drug substance at the bottom of the tank;

[0082] determining a first concentration difference by subtracting the first distribution concentration from the second distribution concentration, and determining a second concentration difference by subtracting the second distribution concentration from the third distribution concentration;

[0083] determining an absolute concentration difference between the first concentration difference and the second concentration difference as a gradient deviation of the axial concentration distribution.

[0084] Specifically, the first distribution concentration, the second distribution concentration and the third distribution concentration all refer to the mass concentration of iron ions, which are determined by using an online spectrophotometric sensor.

[0085] Specifically, the process of determining whether the preliminary dissolution process of the drug substance is qualified based on the gradient deviation includes:

[0086] comparing the gradient deviation with a preset deviation;

[0087] determining that the preliminary dissolution process of the drug substance is unqualified based on a comparison result that the gradient deviation is greater than the preset deviation;

[0088] determining that the preliminary dissolution process of the drug substance is qualified based on a comparison result that the gradient deviation is less than or equal to the preset deviation.

[0089] It can be understood that, before being ground by the colloid mill, the solution is prone to cause high-density materials to settle due to gravity because of the easy-agglomeration particles of the drug substance. The particles will gradually gather from the top of the tank, the middle of the tank to the bottom of the tank, resulting in obvious concentration stratification in the axial direction, with the highest concentration at the bottom of the tank, the lowest concentration at the top of the tank, and the concentration in the middle of the tank between the two. The qualified diffusion rate will cause the particles to be preliminarily dispersed. Even if there is natural settlement, the particles will preliminarily disperse under the action of stirring, and the particle settlement speed will be relatively gentle. The axial concentration will change slowly and uniformly. The settlement does not cause a sudden increase / decrease in local concentration. The particles are still in a relatively uniform dispersed state. After subsequent grinding by the colloid mill, the particles can be quickly dissolved, and the preliminary dissolution is qualified. If the gradient deviation exceeds the standard, the settlement causes the concentration to stratify sharply, which will cause the particle size to be larger and the settlement speed to be faster. The axial concentration will change sharply and unevenly. A precipitate layer may be formed. Subsequent grinding is difficult to disperse. This state will directly affect the final dissolution efficiency and the uniformity of the product concentration, and thus the preliminary dissolution is unqualified.

[0090] Specifically, the preset deviation is set to [0.03 g / L, 0.06 g / L], and the embodiment of the present application preferably is 0.04 g / L.

[0091] Specifically, in the case that the preliminary dissolution process of the bulk drug is determined to be unqualified, the process of determining the distribution difference of the solid residues at the bottom of the solution tank includes:

[0092] The bottom of the solution tank is equally divided into a plurality of annular rings with the geometric center of the bottom of the solution tank as the reference point;

[0093] The solid residues of any of the annular rings are determined, and the standard deviation of the plurality of solid residues is determined as the distribution difference of the solid residues.

[0094] Specifically, the bottom of the solution tank is equally divided into a plurality of annular rings, for example, a solution tank with a radius of 60 cm can be divided into 6 annular rings with a spacing of 10 cm, and the specific division is not limited.

[0095] Specifically, the bottom of the solution tank is equally divided into annular rings in the radial direction (from the center to the edge of the radius direction), and the solid residue amount of each annular ring directly reflects the uniformity of the radial diffusion ability of the stirring paddle. When the stirring paddle rotates, it will transfer the bulk drug particles in the tank to the radial direction (center→edge, edge→center) through shear force and fluid turbulence, which is called radial diffusion. In an ideal state, when the radial diffusion is uniform, the solid residue amount of each annular ring should be close, but in practice, the radial diffusion ability of the stirring paddle will be affected by the distance from the stirring paddle blade. The fluid turbulence is strong near the stirring paddle blade, the radial diffusion is fast, and the solid residue is less. The fluid turbulence is weak far from the blade, the radial diffusion is slow, and the solid residue is more. Ultimately, it leads to the difference in residue amount of each annular ring. If the standard deviation is large, it means that the residue amount of different annular rings is different (such as the center annular ring has little residue and the edge annular ring has a lot of residue), which directly reflects that the radial diffusion ability of the stirring paddle is seriously uneven, and the solid particles cannot be effectively transferred in the radial direction. The bulk drug particles cannot be evenly distributed in the radial direction of the tank bottom, so the speed adjustment coefficient is optimized to further enhance the radial fluid turbulence intensity of the stirring paddle. A faster stirring speed will generate stronger shear force on the blade, breaking the weak turbulence zone in the edge area and promoting the diffusion of the residual particles in the edge annular ring to the center, reducing the difference in residue amount.

[0096] Specifically, the process of optimizing the speed adjustment coefficient based on the distribution difference includes:

[0097] Comparing the distribution difference with a preset difference;

[0098] Optimizing the speed adjustment coefficient based on the comparison result that the distribution difference is greater than the preset difference;

[0099] Comparing the first difference value of the distribution difference and the preset difference with a preset difference value;

[0100] Setting a plurality of speed optimization coefficients to optimize the speed adjustment coefficient based on the comparison result of the first difference value and the preset difference value.

[0101] Specifically, based on the comparison result that the first difference value is greater than the preset difference value, it is determined to increase the speed adjustment coefficient by a first speed optimization coefficient;

[0102] Based on the comparison result that the first difference value is less than or equal to the preset difference value, it is determined to increase the speed adjustment coefficient by a second speed optimization coefficient.

[0103] Specifically, the detection of the solid residue amount can install a laser emitter and a receiver in a target area at the bottom of the liquid preparation tank. When the laser passes through the tank bottom area, if there is solid residue, the laser will be reflected / scattered, and the laser intensity detected by the receiver will decrease, so as to determine the solid residue amount according to the decrease amplitude of the laser intensity, which is not limited in particular.

[0104] Specifically, the preset difference value is set to [0.2mg, 0.7mg], and the embodiment of the present application is preferably 0.4mg. The first speed optimization coefficient is set to [1.08, 1.14], and the embodiment of the present application is preferably 1.12. The second speed optimization coefficient is set to [1.03, 1.07], and the embodiment of the present application is preferably 1.06.

[0105] Specifically, the process of adjusting the grinding time of the colloid mill based on the distribution difference includes:

[0106] Comparing the distribution difference with a preset difference;

[0107] Based on the comparison result that the distribution difference is less than or equal to the preset difference, adjusting the grinding time of the colloid mill;

[0108] Comparing a second difference value between the preset difference and the distribution difference with a preset difference value;

[0109] Based on the comparison result of the second difference value and the preset difference value, setting a plurality of time adjustment coefficients to increase the grinding time of the colloid mill.

[0110] Specifically, based on the comparison result that the second difference value is greater than the preset difference value, it is determined to increase the grinding time by a first time adjustment coefficient;

[0111] Based on the comparison result that the second difference value is less than or equal to the preset difference value, it is determined to increase the grinding time by a second time adjustment coefficient.

[0112] Specifically, the first time adjustment coefficient is set to [1.3, 1.6], and the embodiment of the present application is preferably 1.4. The second time adjustment coefficient is set to [1.2, 1.29], and the embodiment of the present application is preferably 1.25.

[0113] It can be understood that the generation of solid residues at the bottom of the liquid preparation tank not only has local residues caused by uneven distribution, but also has overall residues caused by undissolved particles. When the distribution difference of solid residues is large, it means that the residue amount of different areas at the bottom of the liquid preparation tank is significantly different. The root cause of this difference is that the radial diffusion capacity of the stirring paddle is insufficient, so that the solid particles of the raw drug cannot be uniformly dispersed in the tank. When the distribution difference is small or equal to the preset difference, it means that the solid particles have been uniformly distributed at the bottom of the liquid preparation tank, but there are still solid residues. At this time, the core problem is no longer uneven distribution, but the particle size of the raw drug particles is too large, the specific surface area is insufficient, which leads to slow or incomplete dissolution. At this time, the grinding time of the colloidal mill is increased to increase the specific surface area of the particles. The larger the specific surface area of the particles, the larger the contact area with the solvent, and the faster the dissolution rate.

[0114] Specifically, the process of determining whether the uniformity of the solution in the liquid preparation tank is qualified according to the similarity of a plurality of particle size distribution curves comprises:

[0115] Comparing the similarity with a preset similarity;

[0116] Based on the comparison result that the similarity is less than the preset similarity, it is determined that the uniformity of the solution in the liquid preparation tank is unqualified;

[0117] Based on the comparison result that the similarity is greater than or equal to the preset similarity, it is determined that the uniformity of the solution in the liquid preparation tank is qualified.

[0118] Specifically, the process of determining the similarity comprises:

[0119] Aligning all particle size distribution curves with the coordinate origin;

[0120] Determining the ratio of the overlapping area to the area surrounded by the standard particle size distribution curve and the coordinate axis as the similarity.

[0121] Specifically, the particle size distribution curve is determined by a laser particle size analyzer, which is not limited in particular.

[0122] Specifically, the preset similarity is set to [0.6, 0.8], and the embodiment of the application preferably 0.7.

[0123] Specifically, under the condition that the uniformity of the solution in the liquid preparation tank is unqualified, the process of optimizing the preset proportion comprises:

[0124] Respectively sampling at a plurality of positions of the liquid preparation tank, and determining the characteristic coordination peak area ratio after the plurality of samples are placed;

[0125] Determining the maximum deviation of a plurality of the characteristic coordination peak area ratios as the difference between the maximum value and the minimum value in a plurality of the characteristic coordination peak area ratios;

[0126] Set a plurality of proportional optimization coefficients based on the maximum deviation determination result to optimize the preset proportion.

[0127] Specifically, the sampling position is determined randomly, and is not limited in particular.

[0128] Specifically, the maximum deviation is compared with a preset area ratio.

[0129] Based on the comparison result that the maximum deviation is greater than the preset area ratio, it is determined to increase the preset proportion by a first proportional optimization coefficient.

[0130] Based on the comparison result that the maximum deviation is less than or equal to the preset area ratio, it is determined to increase the preset proportion by a second proportional optimization coefficient.

[0131] Specifically, the characteristic coordination peak area ratio refers to the ratio of the characteristic coordination peak area to the reference peak area of the target active ingredient (ferric protoporphyrin) in dissolved state in the ferric protoporphyrin oral solution, which is obtained by a specific detection technology. The characteristic coordination peak refers to the exclusive signal peak generated by the coordination bond (such as Fe-O bond, Fe-N bond, depending on the coordination mode) between iron ion (Fe 2+ / Fe 3+ ) and protoporphyrin in the ferric protoporphyrin molecule under specific detection conditions. The peak cannot be generated by undissolved drug substance particles, and therefore only reflects the effective dissolution concentration of the target active ingredient. It can be determined by Fourier transform infrared spectroscopy (FTIR) or ultraviolet-visible spectrophotometry (UV-Vis) method, which is prior art and will not be described in detail.

[0132] Specifically, the preset area ratio is set to [0.2, 0.4], and the first proportional optimization coefficient is preferably 1.5. The value range of the second proportional optimization coefficient is set to [1.1, 1.3], and the second proportional optimization coefficient is preferably 1.2.

[0133] It can be understood that the uniformity of the solution in the liquid preparation tank refers to the uniformity of the distribution of the particles of the raw drug that are not sufficiently dissolved in the solvent. If the uniformity is unqualified, it indicates that there is a significant difference in the distribution of the particles that are not sufficiently dissolved in different positions of the solution. If the uniformity is qualified, it indicates that there is no difference in the distribution of the particles that are not sufficiently dissolved in different positions of the solution. The essence of the dissolution process is the diffusion of solute molecules on the surface of solid particles into the solution. Therefore, the spatial distribution of particles directly determines the density of dissolution sites. If the particles are uniformly distributed, the dissolution sites are uniformly distributed in the solution, the solute diffusion area around each particle is not easy to overlap, and the solute molecules can more uniformly diffuse into the solution. At this time, the distribution of the effective dissolution concentration is more likely to be uniform. If the particles are not uniformly distributed, the dissolution sites in the dense area are highly overlapped, and the diffusion boundary layers of multiple particles interfere with each other. The solute concentration in this area will quickly increase. If the diffusion rate of the solute molecules to the sparse area cannot catch up with the local dissolution rate, a concentration gradient difference will be formed, resulting in uneven distribution of the effective dissolution concentration. Therefore, the distribution of the effective dissolution concentration of the solution can be characterized according to the uniformity of the distribution of the undissolved particles in the liquid preparation tank. In some areas, the raw drug is sufficiently dissolved and has a high concentration. In some areas, the raw drug is not sufficiently dissolved and has a low concentration. The effective dissolution concentration of the raw drug and the characteristic coordination peak area ratio are in a positive correlation relationship. Therefore, the degree of unqualified uniformity of the solution in the liquid preparation tank can be determined according to the deviation of the characteristic coordination peak area ratio, and the dissolution kinetics efficiency can be improved by increasing the preset proportion, thereby increasing the dissolution degree of the raw drug.

[0134] So far, the technical solutions of the present application have been described in combination with the preferred embodiments shown in the drawings. However, those skilled in the art can easily understand that the protection scope of the present application is obviously not limited to these specific embodiments. Those skilled in the art can make equivalent changes or replacements to the related technical features without departing from the principles of the present application. The technical solutions after the changes or replacements will fall within the protection scope of the present application.

Claims

1. An analytical control method based on monitoring data from an oral solution of ferric protein succinate, characterized in that, include: The active pharmaceutical ingredient and solvent of the ferric protein succinate oral solution are mixed in a preset ratio and then added to the dispensing tank. The turbidity fluctuation range of the solution at the feeding point is obtained, and the diffusion rate of the active pharmaceutical ingredient is determined to be qualified based on the turbidity fluctuation range. Several speed adjustment coefficients are set based on the condition that the diffusion rate of the active pharmaceutical ingredient is unqualified in order to adjust the stirring speed of the stirring paddle in the mixing tank. Under the condition that the diffusion rate of the active pharmaceutical ingredient is qualified, the axial concentration distribution of the solution in the mixing tank is obtained, so as to determine whether the initial dissolution process of the active pharmaceutical ingredient is qualified based on the gradient deviation of the axial concentration distribution. Based on the unqualified conditions of the initial dissolution process of the active pharmaceutical ingredient, the solid residue at the bottom of the dispensing tank is determined, and the optimization of the speed adjustment coefficient or the adjustment of the grinding time of the colloid mill is determined based on the distribution difference of the solid residue. The particle size distribution curves of the solution at several locations in the mixing tank after grinding with a colloid mill are obtained. The homogeneity of the solution in the mixing tank is determined based on the similarity of the particle size distribution curves. The preset ratio is then optimized based on the condition that the homogeneity of the solution in the mixing tank is not qualified.

2. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 1, characterized in that, The process of determining whether the diffusion rate of the active pharmaceutical ingredient is qualified based on the turbidity fluctuation amplitude includes: The turbidity fluctuation amplitude is compared with the preset fluctuation amplitude; Based on the comparison results showing that the turbidity fluctuation amplitude is greater than the preset fluctuation amplitude, it is determined that the diffusion rate of the active pharmaceutical ingredient is unqualified. The diffusion rate of the active pharmaceutical ingredient is determined to be qualified based on the comparison results of the turbidity fluctuation amplitude being less than or equal to the preset fluctuation amplitude.

3. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 2, characterized in that, When the diffusion rate of the active pharmaceutical ingredient is determined to be substandard, the process of adjusting the stirring speed of the impeller in the mixing tank includes: The turbidity difference is obtained by subtracting the turbidity fluctuation amplitude from the preset fluctuation amplitude. The turbidity difference is compared with a preset turbidity difference; Based on the comparison result between the turbidity difference and the preset turbidity difference, several speed adjustment coefficients are set to increase the stirring speed of the stirring paddle.

4. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 3, characterized in that, Under the condition that the diffusion rate of the active pharmaceutical ingredient is qualified, the process of determining the gradient deviation of the axial concentration distribution includes: Obtain the first distribution concentration of the active pharmaceutical ingredient at the top of the mixing tank, the second distribution concentration of the active pharmaceutical ingredient in the tank, and the third distribution concentration of the active pharmaceutical ingredient at the bottom of the tank; The first concentration difference is obtained by subtracting the second distribution concentration from the first distribution concentration, and the second concentration difference is obtained by subtracting the third distribution concentration from the second distribution concentration. The absolute concentration difference between the first concentration difference and the second concentration difference is defined as the gradient deviation of the axial concentration distribution.

5. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 4, characterized in that, The process of determining whether the initial dissolution process of the active pharmaceutical ingredient is qualified based on the gradient deviation includes: Compare the gradient deviation with the preset deviation; Based on the comparison results of the gradient deviation being greater than the preset deviation, it is determined that the initial dissolution process of the active pharmaceutical ingredient is unqualified.

6. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 5, characterized in that, The process for determining the distribution differences of solid residues at the bottom of the mixing tank when the initial dissolution process of the active pharmaceutical ingredient is determined to be substandard includes: Using the geometric center of the bottom of the mixing tank as a reference point, the bottom of the mixing tank is divided into several equally spaced rings; Determine the solid residue of any of the aforementioned rings, and determine the standard deviation of several of the solid residues as the distributional difference of the solid residues.

7. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 6, characterized in that, The process of optimizing the velocity adjustment coefficient based on the distribution differences includes: Compare the distribution difference with a preset difference; The speed adjustment coefficient is optimized based on the comparison result that the distribution difference is greater than the preset difference; The first difference between the distribution difference and the preset difference is compared with the preset difference; Based on the comparison result between the first difference and the preset difference, several speed optimization coefficients are set to optimize the speed adjustment coefficient.

8. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 7, characterized in that, The process of adjusting the grinding time of the colloid mill based on the aforementioned distribution differences includes: Compare the distribution difference with a preset difference; The grinding time of the colloid mill is adjusted based on the comparison result that the distribution difference is less than or equal to the preset difference; Compare the second difference between the preset difference and the distribution difference with the preset difference; Based on the comparison result between the second difference and the preset difference, several time adjustment coefficients are set to increase the grinding time of the colloid mill.

9. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 8, characterized in that, The process of determining whether the homogeneity of the solution in the mixing tank is qualified based on the similarity of several particle size distribution curves includes: The similarity is compared with a preset similarity. Based on the comparison results where the similarity is less than the preset similarity, it is determined that the homogeneity of the solution in the mixing tank is unqualified.

10. The analysis and control method based on monitoring data of ferric protein succinate oral solution according to claim 9, characterized in that, The process of optimizing the preset ratio when the homogeneity of the solution in the mixing tank is determined to be unsatisfactory includes: Samples were taken from several locations in the mixing tank, and the area ratio of the characteristic coordination peaks was determined after the samples were allowed to stand. Determine the maximum deviation of the area ratio of several of the aforementioned characteristic coordination peaks; Based on the determination result of the maximum deviation of the area ratio of the characteristic coordination peak, several proportional optimization coefficients are set to optimize the preset ratio.

Images