Potassium chloride pellets, a method for obtaining a mother and a method for preparing the same

Abstract

The present application relates to the field of drug sustained-release controlled-release preparation, and particularly relates to a potassium chloride pellet and a preparation method and a mother method thereof, the mother method of the potassium chloride pellet comprising the following steps: (a) crushing potassium chloride crystals and mixing the potassium chloride crystals with a diluent having hydrogen bond forming capacity to form a potassium chloride mixed powder; (b) in a granulator, spraying the potassium chloride mixed powder with an aqueous binder to make the mixed powder wet and the surface of the potassium chloride partially dissolve, and at the same time, the diluent forms a network structure by hydrogen bond adsorption of moisture, and then initial mother core particles are formed under the action of mechanical force; (c) drying and screening the initial mother core particles to obtain potassium chloride pellet mother particles. The present application adopts direct mixing of potassium chloride and a diluent having hydrogen bond forming capacity to form a mother, discards the sucrose carrier in the traditional sugar pellet process, expands the scope of the applicable population and simplifies the process route, and the roundness, particle size uniformity and mechanical strength of the mother core particles are significantly improved.

Description

Technical Field

[0001] This invention relates to the field of sustained-release and controlled-release drug formulations, and particularly to a potassium chloride microsphere, its parent formulation method, and its preparation method. Background Technology

[0002] Potassium supplementation is a crucial medical approach for maintaining electrolyte balance in the human body, playing an irreplaceable role, especially in the treatment of hypokalemia. Potassium ions, as the main cation in intracellular fluid, participate in regulating cellular excitability, acid-base balance, and metabolic activities. Potassium deficiency can lead to serious consequences such as muscle weakness, arrhythmia, and even respiratory failure. Oral potassium supplements are the first choice in clinical practice due to their convenience and safety. However, ordinary potassium chloride tablets or solutions have problems such as strong gastrointestinal irritation and large fluctuations in blood potassium concentration, easily causing side effects such as vomiting and ulcers. Therefore, sustained-release formulation technology has been extensively studied, aiming to reduce local irritation and maintain stable blood potassium concentration by controlling the drug release rate. However, the preparation process and formulation design of existing potassium chloride sustained-release formulations still face many challenges, particularly in terms of the selection of core materials, process complexity, and the scope of applicable populations.

[0003] Traditional potassium chloride sustained-release formulations often use sugar pellets as the core carrier. For example, a sugar pellet core is formed by granulating a mixture of sucrose, starch, and dextrin, followed by multi-layer coating technology to achieve sustained release. While this process can control drug release to some extent, it has several drawbacks: First, the sucrose component in sugar pellets is contraindicated for patients with diabetes, obesity, and metabolic disorders, limiting the applicable population. Second, sugar pellet preparation requires multiple processes such as crushing, mixing, granulation, drying, and sieving, resulting in a lengthy and energy-intensive process. It also involves the addition of numerous excipients, increasing the difficulty of production management and quality control. Furthermore, sugar pellets have poor physical stability and are prone to structural collapse during coating due to changes in humidity or temperature, affecting the uniformity of the sustained-release layer and potentially triggering a burst release risk. Studies show that some sustained-release tablets are prone to local adhesion during in vivo release due to individual differences in the intestinal environment (e.g., slowed intestinal motility in the elderly), leading to mucosal damage or abnormal release, further reducing clinical safety.

[0004] To avoid the drawbacks of sugar-coated pellets, some technologies attempt to prepare sustained-release microcapsules using direct tableting or extrusion spheronization. For example, potassium chloride is mixed with excipients such as hydroxypropyl methylcellulose and lactose, then wet-granulated, followed by tableting or spheronization. However, these methods also face process complexity issues: wet granulation requires precise control of the binder dosage and drying conditions, otherwise uneven particle hardness or clumping may occur; extrusion spheronization results in low pellet yield due to the high brittleness and poor plasticity of potassium chloride crystals, requiring repeated extrusion and sieving, which not only prolongs the production cycle but also increases equipment wear and energy consumption. Furthermore, some processes use ethanol as a solvent, which can accelerate drying but poses a flammable and explosive risk, requiring explosion-proof facilities and strict exhaust gas treatment, significantly increasing production costs and environmental pressure. Other solutions use mesoporous carbon or acrylic resin as sustained-release materials, achieving controlled release through complex coating processes. However, multi-layer coating requires extremely high equipment precision, and the wide variety of excipients may lead to compatibility issues, further increasing process instability and batch-to-batch variations.

[0005] In existing technologies, the selection of the core material for sustained-release microspheres is particularly critical. For example, the applicant in this application previously used potassium chloride crystals directly as the core; however, the irregularity of its surface crystal structure easily leads to uneven coating layer thickness, thus affecting the consistency of the release curve. When using an inert core (such as a microsphere carrier) to coat the drug layer, additional binders are required, and the drug loading must be controlled, increasing process complexity. Furthermore, existing core preparation technologies largely rely on traditional granulation techniques, which are highly sensitive to moisture, temperature, and mechanical force, making it difficult to balance the relationship between particle strength and drug dissolution rate. For example, excessive moisture may cause potassium chloride to dissolve excessively, damaging the particle structure; insufficient moisture makes it difficult to form effective liquid bridges, resulting in excessive fine powder or loose particles. This contradiction is particularly prominent in large-scale production, often requiring repeated parameter adjustments and reducing production efficiency.

[0006] Despite existing technological attempts to optimize process parameters or introduce novel excipients, the core issues remain unresolved: first, the biocompatibility of the core material and limitations on applicable populations (e.g., sugar-containing components); second, the cost and quality control pressures resulting from cumbersome process flows; and third, insufficient stability and safety of sustained-release performance. Therefore, developing a simple, widely applicable method for preparing potassium chloride sustained-release microspheres without the need for glycosyl carriers has become a pressing technical challenge in this field. Such methods should ensure controllable drug release while reducing the types of excipients, simplifying production steps, and avoiding the use of high-risk solvents or complex equipment, thereby providing a safer, more economical, and adaptable potassium supplementation solution for clinical use. Summary of the Invention

[0007] The present invention aims to overcome the shortcomings of existing potassium chloride sustained-release microspheres, such as limited applicable populations, cumbersome processes, insufficient stability of sustained-release performance, and inadequate safety. Therefore, it provides potassium chloride microspheres, their parent material preparation method, and their preparation method to overcome the above-mentioned deficiencies.

[0008] To achieve the above-mentioned objectives, the present invention is implemented through the following technical solution:

[0009] In a first aspect, the present invention provides a method for producing potassium chloride microspheres, comprising the following steps:

[0010] (a) Potassium chloride crystals are crushed and mixed with a diluent that has the ability to form hydrogen bonds to form potassium chloride mixed powder;

[0011] (b) In the granulator, an aqueous binder is sprayed onto the potassium chloride mixed powder, which wets the mixed powder and causes partial dissolution and recrystallization on the surface of potassium chloride, thereby forming a salt bridge. At the same time, the diluent adsorbs water through hydrogen bonds to form a network structure, and then forms the initial core particles under mechanical force.

[0012] (c) The initial nucleus particles are dried and sieved to obtain potassium chloride pellet masterbatch.

[0013] In existing technologies, the preparation of the core for potassium chloride sustained-release formulations has long relied on sugar-coated capsules or complex granulation processes, which suffer from core drawbacks such as limited applicable populations, lengthy processes, and insufficient safety. Sugar-coated capsules, using sucrose as the core material, can achieve sustained-release effects through multi-layer coating, but their sugar content directly excludes use by patients with diabetes, obesity, and metabolic disorders, resulting in a narrow product coverage. Furthermore, sugar-coated capsule preparation involves multiple steps such as crushing, mixing, granulation, and drying, with numerous excipients and sensitive process parameters. This not only increases production energy consumption and time costs but also causes uneven coating layers due to the hygroscopic deformation of the sugar-based carrier, potentially inducing drug burst release risks. In addition, some alternatives use potassium chloride crystals directly as the core or wet granulation relying on ethanol solvents. The former results in significant differences in coating thickness due to the irregularity of the crystal surface, while the latter faces safety hazards such as flammability and explosion, as well as environmental pressures, both failing to meet the stability requirements for large-scale production. Against this backdrop, there is an urgent need for a novel core preparation method that can overcome the limitations of sugar-based materials, simplify the process, and ensure safety.

[0014] This invention proposes a method for creating potassium chloride microspheres, which fundamentally reconstructs the core formation mechanism by innovatively introducing a diluent with hydrogen bonding capabilities (such as microcrystalline cellulose). The core of the technical solution lies in mixing pulverized potassium chloride crystals with a diluent, using an aqueous binder to control the wettability of the mixture. This allows the potassium chloride surface to partially dissolve while the diluent forms a three-dimensional network structure with water molecules through hydrogen bonding. Simultaneously, the dissolved potassium chloride recrystallizes after water evaporation to form salt bridges, thus encapsulating the diluent. Combined with dynamic mechanical control, this achieves efficient core particle formation. This design eliminates the need for traditional sugar pellet carriers, completely removing the contraindications of sucrose for specific patient groups and significantly expanding the applicable population. More importantly, the introduction of the hydrogen bond network not only replaces the adhesive effect of sucrose or complex binders in traditional processes but also, through the water absorption and fiber interweaving characteristics of microcrystalline cellulose, forms a stable liquid bridge structure during the wetting stage. Subsequently, during the drying process, the recrystallization of potassium chloride and the solidification of the fiber network synergistically enhance the mechanical strength of the particles. This mechanism significantly improves the roundness and uniformity of the parent core particles, avoiding particle collapse or uneven coating caused by humidity sensitivity in the sugar pill process, thereby reducing the risk of drug burst release from the source.

[0015] Compared to existing technologies, the innovative breakthrough of this method lies in the dual optimization of process simplification and parameter controllability. In traditional processes, sugar pill preparation requires separate core granulation and drug coating. However, this invention directly uses potassium chloride mixed powder as the masterbatch material, combining core formation and drug loading into one process, eliminating multiple redundant steps such as sugar pill preparation and drug coating, and significantly shortening the production process. Simultaneously, by precisely controlling the amount of water-based binder injected and mechanical processing conditions (such as centrifugal speed and blower parameters), a dynamic balance is achieved between the degree of wetting and particle forming kinetics: appropriate moisture ensures that the potassium chloride surface is slightly soluble to promote particle adhesion, while the presence of hydrogen bond networks effectively prevents structural damage caused by excessive dissolution; the intervention of mechanical force further regulates the compactness and particle size distribution of the particles, avoiding the low pelleting rate problem caused by insufficient plasticity in traditional extrusion and rounding methods. This parameter synergistic control strategy not only reduces the process's dependence on equipment precision but also improves batch-to-batch consistency, providing a reliable foundation for large-scale production.

[0016] In terms of technical effectiveness, this method achieves multi-dimensional performance improvements through an innovative combination of materials and processes. First, replacing sucrose with a diluent such as microcrystalline cellulose not only eliminates the health risks of sugar to specific populations but also reduces the types of excipients due to its inert nature, lowering the probability of potential compatibility issues. Second, the synergistic effect of hydrogen bond networks and mechanical forces endows the core particles with excellent physical stability. Their uniform particle size distribution (0.1-0.355 mm) and high bulk density (≥1000 mg / ml) provide an ideal substrate for subsequent sustained-release coating, ensuring the uniformity of the coating layer thickness and thus precisely controlling the drug release curve, avoiding burst release or incomplete release. Furthermore, the use of water-based binders throughout the process avoids the safety and environmental hazards of organic solvents such as ethanol. Simultaneously, the optimized setting of drying temperature and time balances energy efficiency and particle structure integrity, significantly reducing production costs. These combined advantages enable this method not only to overcome the core defects of existing technologies but also to provide a novel technical pathway for developing safer, more economical, and adaptable potassium chloride sustained-release formulations.

[0017] Preferably, the diluent is a compound that contains both a hydrogen bond donor and a hydrogen bond acceptor.

[0018] In existing technologies, the selection of diluents for sustained-release formulation cores often focuses on single-functional binders or inert carrier materials. Their mechanisms of action mainly rely on physical adsorption or simple adhesion, while the synergistic effect of hydrogen bond donors and acceptors has not been systematically explored or specifically applied. For example, traditional sugar pill manufacturing processes rely on the hydroxyl groups of sucrose as hydrogen bond donors, but their acceptor capacity is limited, and the sugar molecule has a simple structure, making it difficult to form a stable three-dimensional network. While synthetic polymers (such as hydroxypropyl methylcellulose) possess hydrogen bond donor capacity, they lack complementary acceptor groups, resulting in insufficient hydrogen bond strength, requiring excessive binders or complex processes to compensate for structural defects. In this context, limiting diluents to "compounds that simultaneously contain hydrogen bond donors and acceptors" is not an obvious conventional choice, but rather an innovative optimization based on a deep analysis of the hydrogen bond network formation mechanism.

[0019] The ingenuity of this technology lies in its precise molecular structure design, which achieves dynamic complementarity between hydrogen bond donors and acceptors, thereby maximizing hydrogen bond density and stability during the wetting stage. Specifically, the coexistence of donor groups (such as hydroxyl and amino groups) and acceptor groups (such as carbonyl and ether groups) allows the diluent to form multidirectional hydrogen bond crosslinks with water molecules and the surface of potassium chloride: the donor groups provide protons to bind with the oxygen atoms of water molecules, while the acceptor groups attract hydrogen atoms from water molecules through lone pairs of electrons, forming a bidirectional force. This synergistic effect not only enhances the anchoring ability of water molecules in the mixed powder but also buffers the impact of mechanical forces on the particle structure through the extensibility of the hydrogen bond network, avoiding the problems of particle breakage or uneven agglomeration caused by local stress concentration in traditional processes.

[0020] Compared to the use of single-function diluents in existing technologies, this feature overcomes the bottleneck of hydrogen bond network strength and stability through the synergistic effect of donor and acceptor. In traditional processes, if only a single hydrogen bond donor (such as the pyrrolidone group of polyvinylpyrrolidone) is relied upon, the range of hydrogen bond interaction is limited, requiring high amounts of binder or external forced drying to maintain particle structure, which easily leads to increased process sensitivity or energy consumption. However, the introduction of acceptor groups allows the diluent to autonomously construct a denser, self-healing hydrogen bond network, reducing dependence on external conditions (such as binder concentration and drying rate), thereby maintaining particle forming stability over a wider range of process parameters. In addition, the donor-acceptor composite structure can adapt to deformation under mechanical force through the breaking and recombination of dynamic hydrogen bonds, preventing particles from breaking due to excessive rigidity or sticking together due to excessive softness during centrifugation or shearing. This characteristic is particularly important in large-scale production, significantly reducing equipment debugging difficulty and scrap rate.

[0021] Preferably, the diluent includes any one or more combinations of microcrystalline cellulose, hydroxypropyl methylcellulose and its derivatives, polyvinylpyrrolidone and its derivatives, sodium carboxymethyl cellulose and its derivatives, gelatin, gum arabic, peach gum, polyethylene glycol, and acrylic resin.

[0022] Microcrystalline cellulose is preferred as a diluent in this invention because its molecular chain is rich in both hydroxyl groups (donors) and ether bonds (acceptors). During the wetting stage, hydroxyl groups combine with water molecules to form a primary hydrogen bond network, while ether bonds further form intramolecular or intermolecular hydrogen bonds with hydroxyl groups of adjacent cellulose chains, forming a multi-layered cross-linked structure. This network gradually solidifies as water evaporates during the drying process. The recrystallization of potassium chloride and the interweaving of cellulose fibers synergistically enhance the mechanical strength of the particles, thereby significantly improving the sphericity of the parent core and the coating adaptability.

[0023] Preferably, potassium chloride accounts for 70%-95% of the total weight of the potassium chloride mixture.

[0024] Preferably, the amount of the water-based adhesive sprayed is 20-40% of the total weight of the potassium chloride mixed powder.

[0025] Preferably, the maximum spraying speed of the water-based adhesive is less than 200 r / min.

[0026] Preferably, the centrifugal speed of the pellet mill is controlled at 15-45 Hz.

[0027] In existing technologies, the preparation process of potassium chloride slow-release microspheres generally suffers from a lack of control over the amount of binder and equipment parameters, especially in the wetting and nucleation stages where the control strategy lacks a systematic approach, leading to unstable particle quality. For example, traditional wet granulation processes often rely on empirical adjustments to the amount of binder (such as excessive spraying to ensure particle adhesion), which can easily cause excessive dissolution of potassium chloride due to localized overwetting, damaging the integrity of the particle structure, or insufficient water, resulting in excessive fine powder. Furthermore, the setting of equipment parameters (such as spraying speed and centrifugal speed) is often based on general granulation requirements without being adapted to the characteristics of potassium chloride mixed powder, resulting in dispersed particle size distribution and insufficient mechanical strength.

[0028] Against this backdrop, precisely limiting the amount of water-based binder sprayed to 20-40% of the total weight of the potassium chloride mixed powder, and synergistically controlling the spraying speed (less than 200 r / min) and centrifugal speed (15-45 Hz), is an innovative technical solution based on a deep understanding of the dissolution kinetics and particle formation mechanism of potassium chloride. Its creativity lies in resolving the core contradiction of "partial dissolution without over-dissolution" during the wetting stage through a dynamic balance between parameters: the 20-40% spraying amount ensures sufficient wetting of the mixed powder to activate the micro-dissolution of the potassium chloride surface (promoting particle adhesion), while limiting the risk of complete crystal dissolution due to excessive free water through the hydrogen bonding adsorption of microcrystalline cellulose.

[0029] The maximum spraying speed of less than 200 r / min matches the low plasticity of potassium chloride mixed powder, avoiding the accumulation of droplets in local areas caused by high-speed spraying, thus uniformly dispersing and wetting the interface and preventing clumping.

[0030] The gradient control of centrifugal speed from 15 to 45 Hz, by matching the mechanical force intensity with the particle forming rate, preferentially promotes the primary agglomeration of loose powder in the low speed stage (15-25 Hz), and then gradually increases the speed (to 45 Hz) to enhance the compactness of the particles, and finally forms a mother core with uniform particle size (0.1-0.355 mm) and smooth surface.

[0031] This parameter combination is not a simple superposition of conventional process ranges, but rather a breakthrough in the limitations of fragmented control of the "wetting-nucleation-solidification" stages in traditional processes through experimentally verified synergistic effects. If the injection volume exceeds 40%, even reducing the spraying speed or increasing the centrifugal speed will still cause particle deformation or agglomeration due to excessive moisture; conversely, if the injection volume is less than 20%, even extending the spraying time will make it difficult to form effective liquid bridges, resulting in loose and brittle particles. In addition, the dynamic matching of centrifugal speed and spraying speed (such as low-speed spraying combined with medium-speed centrifugation) further optimizes the mechanical strength and roundness of the particles, avoiding performance bottlenecks caused by adjusting a single parameter. Compared to the vague "appropriate amount of liquid spraying" or wide speed range (such as 50-300 r / min) in existing technologies, this technology significantly improves process stability and batch consistency through precise quantification and linkage control, enabling key indicators such as the bulk density and release rate (≤25% in 1 hour) of the parent core particles to reach controllable thresholds, laying a reliable foundation for subsequent coating processes.

[0032] Preferably, the aqueous adhesive is purified water or an aqueous solution containing less than 2% water-soluble polymer.

[0033] Preferably, the water-soluble polymer is selected from polyvinylpyrrolidone or low-substituted hydroxypropyl methylcellulose.

[0034] Preferably, the inlet air temperature for drying is 100-110℃, and the drying time is 30-50 minutes.

[0035] Secondly, the present invention also provides a method for preparing potassium chloride sustained-release microspheres, comprising:

[0036] Potassium chloride pellet masterbatch was prepared using the aforementioned masterbatch method;

[0037] The potassium chloride pellet masterbatch was sequentially coated with an isolation layer, a sustained-release layer, and a color coating layer.

[0038] Thirdly, the present invention also provides potassium chloride sustained-release microspheres, which are prepared by the method described above;

[0039] The release rate of the microparticles meets the following requirements: release rate ≤25% after 1 hour and release rate ≤70% after 4 hours.

[0040] Therefore, this application has the following beneficial effects:

[0041] First, this application uses potassium chloride and a diluent with hydrogen bond forming ability (such as microcrystalline cellulose) to directly mix the starter, eliminating the sucrose carrier in the traditional sugar pill process, completely eliminating the health risks of sugar to patients with diabetes, obesity and metabolic disorders, and significantly expanding the range of applicable populations;

[0042] Secondly, the process route is greatly simplified, eliminating multiple redundant steps such as crushing, mixing, and granulation required for sugar pill preparation. At the same time, it avoids the problem of repeated processing caused by the brittleness of potassium chloride in the traditional extrusion and rounding method, thereby reducing energy consumption, shortening the production cycle and reducing equipment wear and tear, and significantly improving production efficiency.

[0043] Third, the synergistic effect of hydrogen bond network and mechanical force in the technical solution of this application significantly improves the roundness, particle size uniformity and mechanical strength of the core particles, providing a stable base for subsequent sustained-release coating, ensuring that the drug release curve is accurate and controllable, effectively reducing the risk of burst release and improving clinical safety.

[0044] Finally, water-based adhesives were used throughout the process to replace organic solvents such as ethanol, avoiding flammability and explosion hazards as well as environmental pressure. Meanwhile, the optimized design of drying parameters took into account both energy efficiency and particle structure integrity, resulting in a final product with a moisture content of ≤3.0%, excellent physical stability, and stronger adaptability to storage and transportation. The reduction in the types of auxiliary materials also reduced the complexity of the formulation and potential compatibility conflicts, providing an efficient, safe and economical technical path for large-scale production. Attached Figure Description

[0045] Figure 1 This is a microscope image of the potassium chloride pellets prepared in Example 1 of the present invention.

[0046] Figure 2 This is a microscope image of potassium chloride crystals. Detailed Implementation

[0047] The present invention will be further described below with reference to specific embodiments. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0048] Example 1

[0049] A method for preparing potassium chloride pellet masterbatch includes the following steps:

[0050] 1. Crushing: Crush the potassium chloride crystals and pass them through a 100-mesh sieve;

[0051] 2. Mixing: Potassium chloride and microcrystalline cellulose are mixed at a mass ratio of 9:1 to form potassium chloride mixed powder;

[0052] 3. Masterbatch preparation: Turn on the main unit of the granulator and the blower. Control the rotation speed of the main unit turntable at 15 Hz, the air volume of the blower at 10 Hz, and the air source pressure at 0.1 MPa. After feeding, control the rotation speed of the main unit at 40 Hz. Spray water as a binder. Control the maximum spraying speed to less than 200 r / min. The amount of water sprayed is 25% of the total weight of the potassium chloride mixed powder. Then stop adding purified water and polish for 5 minutes before discharging. Dry at 100℃ for 50 minutes and sieve to obtain potassium chloride pellet masterbatch of 0.1-0.355 mm.

[0053] 4. Granulation: Turn on the granulator main unit and the blower. Control the main unit's rotary table speed at 20 Hz, while controlling the blower's airflow at 10 Hz and the air source pressure at 0.2 MPa. Add potassium chloride masterbatch and gradually feed in the remaining potassium chloride mixed powder. Then, control the main unit speed at 45 Hz and spray in purified aqueous solution as a binder. Control the maximum spraying speed to less than 250 r / min. Once the pellets have grown to the target size, stop feeding powder and stop spraying liquid. Control the main unit speed at 45 Hz and polish for about 1 minute before discharging.

[0054] 5. Drying: Place the potassium chloride pellets obtained above into a fluidized bed dryer for drying. Turn on the heating switch, set the inlet air temperature to 105℃±5℃, and dry for 30 minutes;

[0055] 6. Sieving: Install the required sieve size according to production specifications. Samples of the potassium chloride masterbatch with the target particle size are taken by the quality department for quality inspection. Microscopic images of the prepared potassium chloride masterbatch and potassium chloride crystals are shown below. Figure 1 as well as Figure 2 As shown.

[0056] Example 2

[0057] A method for preparing potassium chloride pellet masterbatch includes the following steps:

[0058] 1. Crushing: Crush the potassium chloride crystals and pass them through a 100-mesh sieve.

[0059] 2. Mixing: Potassium chloride and microcrystalline cellulose are mixed at a mass ratio of 9.5:0.5 to form potassium chloride mixed powder;

[0060] 3. Masterbatch preparation: Turn on the main unit of the granulator and the blower. Control the rotation speed of the main unit turntable at 15 Hz, the air volume of the blower at 5 Hz, and the air source pressure at 0.03 MPa. After feeding, control the rotation speed of the main unit at 35 Hz. Spray water as a binder. Control the maximum spraying speed to less than 200 r / min. The amount of water sprayed is 20% of the total weight of the potassium chloride mixed powder. Then stop adding purified water and polish for 5 minutes before discharging. Dry at 110℃ for 30 minutes and sieve to obtain potassium chloride pellet masterbatch of 0.1-0.355 mm.

[0061] 4. Granulation: Turn on the granulator main unit and the blower. Control the main unit's rotary table speed at 20 Hz, while controlling the blower's airflow at 15 Hz and the air source pressure at 0.6 MPa. Add potassium chloride masterbatch and gradually feed in the remaining potassium chloride mixed powder. Then, control the main unit speed at 45 Hz and spray in purified aqueous solution as a binder. Control the maximum spraying speed to less than 250 r / min. Once the pellets have grown to the target size, stop feeding powder and stop spraying liquid. Control the main unit speed at 45 Hz and polish for about 1 minute before discharging.

[0062] 5. Drying: Place the potassium chloride pellets obtained above into a fluidized bed dryer for drying. Turn on the heating switch, set the inlet air temperature to 105℃±5℃, and dry for 50 minutes;

[0063] 6. Screening: Install the required screen size according to production specifications. The quality department takes samples of the potassium chloride pellet masterbatch with the target particle size for quality inspection.

[0064] Example 3

[0065] A method for preparing potassium chloride pellet masterbatch includes the following steps:

[0066] 1. Crushing: Crush the potassium chloride crystals and pass them through a 100-mesh sieve.

[0067] 2. Mixing: Potassium chloride and microcrystalline cellulose are mixed at a mass ratio of 8:2 to form potassium chloride mixed powder;

[0068] 3. Masterbatch preparation: Turn on the main unit of the granulator and the blower. The main unit's turntable speed is controlled at 15 Hz, while the blower's air volume is controlled at 10 Hz and the air source pressure is controlled at 0.2 MPa. After feeding, the main unit's speed is controlled at 45 Hz. Water is sprayed in as a binder, and the maximum spraying speed is controlled at less than 200 r / min. The amount of water sprayed in is 30% of the total weight of the potassium chloride mixed powder. Then, stop adding purified water and polish for 5 minutes before discharging. Dry at 105℃ for 40 minutes and sieve to obtain potassium chloride pellet masterbatch of 0.1-0.355 mm.

[0069] 4. Granulation: Turn on the granulator main unit and the blower. Control the main unit's turntable speed at 20 Hz, while controlling the blower's airflow at 5 Hz and the air source pressure at 0.03 MPa. Add potassium chloride masterbatch and gradually feed in the remaining potassium chloride mixed powder. Then, control the main unit speed at 45 Hz and spray in purified aqueous solution as a binder. Control the maximum spraying speed to less than 250 r / min. Once the pellets have grown to the target size, stop feeding powder and stop spraying liquid. Control the main unit speed at 45 Hz and polish for about 1 minute before discharging.

[0070] 6. Drying: Place the potassium chloride pellets obtained above into a fluidized bed dryer for drying. Turn on the heating switch, set the inlet air temperature to 105℃±5℃, and dry for 40 minutes;

[0071] 7. Screening: Install the required screen size according to production specifications. The quality department takes samples of the potassium chloride pellet masterbatch with the target particle size for quality inspection.

[0072] Example 4

[0073] A method for preparing potassium chloride pellet masterbatch includes the following steps:

[0074] 1. Crushing: Crush the potassium chloride crystals and pass them through a 100-mesh sieve;

[0075] 2. Mixing: Potassium chloride and sodium carboxymethyl cellulose are mixed at a mass ratio of 7:3 to form potassium chloride mixed powder;

[0076] 3. Masterbatch preparation: Turn on the main unit of the granulator and the blower. The main unit's turntable speed is controlled at 20 Hz, while the blower's air volume is controlled at 8 Hz and the air source pressure is controlled at 0.15 MPa. After feeding, the main unit's speed is controlled at 45 Hz. Water is sprayed in as a binder, and the maximum spraying speed is controlled at less than 200 r / min. The amount of water sprayed in is 30% of the total weight of the potassium chloride mixed powder. Then, stop adding purified water and polish for 5 minutes before discharging. Dry at 100℃ for 50 minutes and sieve to obtain potassium chloride pellet masterbatch of 0.1-0.355 mm.

[0077] 4. Granulation: Turn on the granulator main unit and the blower. Control the main unit's turntable speed at 20 Hz, while controlling the blower's airflow at 10 Hz and the air source pressure at 0.4 MPa. Add potassium chloride masterbatch and gradually feed in the remaining potassium chloride mixed powder. Then, control the main unit speed at 45 Hz and spray in purified aqueous solution as a binder. Control the maximum spraying speed to less than 250 r / min. Once the pellets have grown to the target size, stop feeding powder and stop spraying liquid. Control the main unit speed at 45 Hz and polish for about 1 minute before discharging.

[0078] 5. Drying: Place the potassium chloride pellets obtained above into a fluidized bed dryer for drying. Turn on the heating switch, set the inlet air temperature to 105℃±5℃, and dry for 30 minutes;

[0079] 6. Screening: Install the required screen size according to production specifications. The quality department takes samples of the potassium chloride pellet masterbatch with the target particle size for quality inspection.

[0080] Example 5

[0081] A method for preparing potassium chloride pellet masterbatch includes the following steps:

[0082] 1. Crushing: Crush the potassium chloride crystals and pass them through a 100-mesh sieve;

[0083] 2. Mixing: Potassium chloride and microcrystalline cellulose are mixed at a mass ratio of 9:1 to form potassium chloride mixed powder;

[0084] 3. Masterbatch preparation: Turn on the main unit of the pellet mill and the blower. Control the rotation speed of the main unit turntable at 15 Hz, the air volume of the blower at 6 Hz, and the air source pressure at 0.12 MPa. After feeding, control the rotation speed of the main unit at 30 Hz. Spray in a 2% polyvinylpyrrolidone aqueous solution as a binder. Control the maximum spraying speed to less than 200 r / min. The amount of 2% polyvinylpyrrolidone aqueous solution sprayed in is 25% of the total weight of the potassium chloride mixed powder. Then stop adding the 2% polyvinylpyrrolidone aqueous solution and polish for 5 minutes before discharging. Dry at 105℃ for 40 minutes and sieve to obtain potassium chloride pellet masterbatch of 0.1-0.355 mm.

[0085] 4. Granulation: Turn on the granulator main unit and the blower. Control the main unit's turntable speed at 20 Hz, while controlling the blower's airflow at 12 Hz and the air source pressure at 0.45 MPa. Add potassium chloride masterbatch and gradually feed in potassium chloride mixed powder. Then, control the main unit speed at 45 Hz and spray in a 2% polyvinylpyrrolidone aqueous solution as a binder. Control the maximum spraying speed to less than 250 r / min. Once the pellets have grown to the target size, stop feeding powder and stop spraying liquid. Control the main unit speed at 45 Hz and polish for about 1 minute before discharging.

[0086] 5. Drying: Place the potassium chloride pellets obtained above into a fluidized bed dryer for drying. Turn on the heating switch, set the inlet air temperature to 105℃±5℃, and dry for 30 minutes;

[0087] 6. Screening: Install the required screen size according to production specifications. The quality department takes samples of the potassium chloride pellet masterbatch with the target particle size for quality inspection.

[0088] Example 6

[0089] A method for preparing potassium chloride pellet masterbatch includes the following steps:

[0090] 1. Crushing: Crush the potassium chloride crystals and pass them through a 100-mesh sieve;

[0091] 2. Mixing: Potassium chloride and microcrystalline cellulose are mixed at a mass ratio of 9:1 to form potassium chloride mixed powder;

[0092] 3. Masterbatch preparation: Turn on the main unit of the pellet mill and the blower. Control the rotation speed of the main unit turntable at 15 Hz, the air volume of the blower at 8 Hz, and the air source pressure at 0.12 MPa. After feeding, control the rotation speed of the main unit at 40 Hz. Spray in a 2% polyvinylpyrrolidone aqueous solution as a binder. Control the maximum spraying speed to less than 200 r / min. The amount of 2% polyvinylpyrrolidone aqueous solution sprayed in is 25% of the total weight of the potassium chloride mixed powder. Then stop adding the 2% polyvinylpyrrolidone aqueous solution and polish for 5 minutes before discharging. Dry at 105℃ for 40 minutes and sieve to obtain potassium chloride pellet masterbatch of 0.1-0.355 mm.

[0093] 4. Granulation: Turn on the granulator main unit and the blower. Control the main unit's turntable speed at 20 Hz, while controlling the blower's airflow at 6 Hz and the air source pressure at 0.05 MPa. Add potassium chloride masterbatch and gradually feed in the remaining potassium chloride mixed powder. Then, control the main unit speed at 45 Hz and spray in purified aqueous solution as a binder. Control the maximum spraying speed to less than 250 r / min. Once the pellets have grown to the target size, stop feeding powder and stop spraying liquid. Control the main unit speed at 45 Hz and polish for about 1 minute before discharging.

[0094] 5. Drying: Place the potassium chloride pellets obtained above into a fluidized bed dryer for drying. Turn on the heating switch, set the inlet air temperature to 105℃±5℃, and dry for 30 minutes;

[0095] 6. Screening: Install the required screen size according to production specifications. The quality department takes samples of the potassium chloride pellet masterbatch with the target particle size for quality inspection.

[0096] Comparative Example 1

[0097] The difference between Comparative Example 1 and Example 1 is that the maximum spraying speed in step 3 is controlled to be less than 300 r / min, while the other conditions are the same.

[0098] Comparative Example 2

[0099] The difference between Comparative Example 2 and Example 1 is that the maximum spraying speed in step 3 is controlled to be less than 100 r / min, while the other conditions are the same.

[0100] Comparative Example 3

[0101] The difference between Comparative Example 3 and Example 1 is that the amount of water injected in step 3 is 50% of the total weight of potassium chloride mixed powder, while the other conditions are the same.

[0102] Comparative Example 4

[0103] The difference between Comparative Example 4 and Example 1 is that the amount of water injected in step 3 is 10% of the total weight of potassium chloride mixed powder, while the other conditions are the same.

[0104] Comparative Example 5

[0105] The difference between Comparative Example 5 and Example 1 is that the main engine speed is controlled at 60 Hz after feeding in step 3, while the other conditions are the same.

[0106] Comparative Example 6

[0107] The difference between Comparative Example 6 and Example 1 is that the main engine speed is controlled at 20Hz after feeding in step 3, while the other conditions are the same.

[0108] The surface of the potassium chloride pellet masterbatch prepared in Examples 1-6 and Comparative Examples 1-6 was coated to obtain a sustained-release coating layer, which consists of an isolation layer, a sustained-release layer and a color coating layer from the inside to the outside.

[0109] Specifically, their respective molding steps are as follows:

[0110] Creation of the isolation layer:

[0111] Place potassium chloride pellets in a fluidized bed and turn on the blower at a flow rate of 430 m³ / h. 3 The potassium chloride pellet masterbatch is flowed at a constant temperature. The material is heated to 60 degrees Celsius. The isolation layer solution (2% purified aqueous solution of hydroxypropyl methylcellulose) is passed through a peristaltic pump at a speed of 60 rpm and atomized by a spray gun at a pressure of 0.02 rpm. This ensures that the isolation layer solution is evenly distributed on the surface of the potassium chloride pellet masterbatch. After drying for 30 minutes, the potassium chloride pellet with isolation layer is obtained.

[0112] Preparation of the sustained-release layer:

[0113] Potassium chloride pellets in the isolation layer are placed in a fluidized bed: the blower is turned on, with an air volume of 430 m³ / h to circulate the potassium chloride pellets. The material temperature is heated to 60 degrees Celsius. The solution of the isolation layer (coating material one: 30% polymethyl methacrylate resin latex; 30% purified water; plasticizer: triethyl citrate 20%; anti-sticking agent: talc 20%; coating material two: 5% ethyl cellulose; 20% lactose; plasticizer: triethyl citrate 5%; anti-sticking agent: talc 5%; ethanol 65%; coating material three: 35% shellac; 55% ethanol; plasticizer: triethyl citrate 3%; anti-sticking agent: talc 3%; purified water for dissolving talc) is atomized by a peristaltic pump at a speed of 50 rpm through a spray gun with an air pressure of 0. 0.02, so that the isolation layer solution is evenly distributed on the surface of the potassium chloride pellets, dry for 30 minutes, and after cooling, the coated pellets are sieved. If the release rate meets the requirements, they are potassium chloride slow-release pellets.

[0114] Preparation of the dye layer:

[0115] Potassium chloride slow-release pellets were placed in a fluidized bed: the blower was turned on, with an air volume of 400 m³ / h. 3 The potassium chloride slow-release pellets are circulated at a constant temperature. The material is heated to 60 degrees Celsius. A colored solution (10% pigment solution, binder: 1% hydroxypropyl methylcellulose) is passed through a peristaltic pump at a speed of 40 rpm and atomized through a spray gun at a pressure of 0.02 ppm. This ensures the coloring solution is evenly distributed on the surface of the potassium chloride pellets, resulting in a 1% weight gain. The pellets are then dried for 30 minutes. After cooling, the colored potassium chloride slow-release pellets are sieved. Those meeting the release rate requirements are considered colored potassium chloride slow-release pellets.

[0116] Performance testing:

[0117] The in vitro release rate method is as follows:

[0118] The experiment was conducted according to the 2020 edition of the Chinese Pharmacopoeia, specifically the method for determination of dissolution and release (General Rule 0931, Method II). The content was determined by titration, and the cumulative release percentage was calculated.

[0119] The specific release rate detection method is as follows:

[0120] Take 0.5g of this product and use the apparatus of the first method of dissolution determination (rotating basket method), with 900ml of water as solvent and a rotation speed of 50 revolutions per minute. Operate according to the method. Take 20ml of solution at 1h, 4h and 8h respectively, and immediately add 20ml of water to the operating container. Accurately measure 20ml, add 4 drops of potassium chromate indicator solution, and titrate with silver nitrate titrant (0.01mol / L) until the solution turns orange-yellow. Each 1ml of silver nitrate titrant (0.01mol / L) is equivalent to 0.7455mg of KCl.

[0121] Dextrin solution: Dissolve 1g of dextrin in 50ml of water.

[0122] Fluorescein indicator solution: Dissolve 0.1g of fluorescein in 100ml of ethanol to obtain the solution.

[0123] Potassium chromate indicator: Dissolve 10g of potassium chromate in 100ml of water.

[0124] Borax solution: Dissolve 2.5g of borax in 100ml of water.

[0125] Release rate = (V*F*0.0007455*45) / m*C;

[0126] In the formula:

[0127] V represents the volume (ml) of silver nitrate titrant consumed.

[0128] F is the correction factor for the concentration of silver nitrate titrant;

[0129] m is the sample size (g);

[0130] C represents the content of potassium chloride slow-release pellets (g / g).

[0131] In addition, since 20 ml is taken from 900 ml of dissolution medium for titration after dissolution, *45 in the formula represents the amount of potassium chloride in 900 ml.

[0132] The roundness test method is as follows:

[0133] 1. Spread the potassium chloride pellets evenly on a petri dish;

[0134] 2. Visually observe using a microscope (magnification 10×4, 10×5, or 10×10), and take small potassium chloride pellets with intact edges within the field of view for observation;

[0135] 3. Measure the shortest and longest diameters of the potassium chloride pellets and calculate the roundness of the potassium chloride pellets;

[0136] The formula for calculating roundness is as follows: Roundness = (shortest diameter of potassium chloride pellet / longest diameter of potassium chloride pellet) × 100%.

[0137] The criteria for judging roundness are as follows:

[0138] When the roundness is less than 80%, the rating is poor.

[0139] When 80% ≤ roundness < 85%, the rating is poor;

[0140] When 85% ≤ roundness < 88%, the rating is qualified;

[0141] When 88% ≤ roundness < 90%, the rating is good;

[0142] When the roundness is ≥90%, the rating is excellent.

[0143] Friability: Potassium chloride slow-release microspheres were placed in a friability tester for testing.

[0144] The specific performance characteristics of potassium chloride sustained-release microcapsules are shown in Table 1 below.

[0145] Table 1

[0146] project Roundness 1-hour release rate 4h release rate 8h release rate Bulk density (g / ml) friability Surface smoothness (%) Moisture Other situations Example 1 excellent 18.25 58.11 97.13 1.01 0.45 93.86 0.83 - Example 2 excellent 15.62 59.10 88.58 1.07 0.36 95.58 0.69 - Example 3 excellent 13.50 54.01 90.35 0.98 0.25 92.24 0.58 - Example 4 excellent 14.58 54.79 92.71 1.05 0.64 95.00 0.65 - Example 5 qualified 13.58 52.47 93.47 0.95 0.37 90.87 0.62 - Example 6 excellent 17.68 60.22 95.57 0.97 0.35 89.25 0.71 - Comparative Example 1 qualified 29.82 71.28 99.47 1.04 0.98 79.57 0.74 - Comparative Example 2 Difference 25.58 62.44 86.52 1.12 1.15 57.22 0.66 - Comparative Example 3 Difference 27.41 63.36 89.24 1.19 0.39 64.81 0.87 - Comparative Example 4 - - - - - - - - Unable to start mother Comparative Example 5 Difference 23.52 54.58 78.57 1.21 1.10 47.82 0.54 - Comparative Example 6 qualified 19.21 57.62 79.63 1.09 0.82 73.58 0.67 - Commercially available potassium chloride tablets - 61.13 77.74 94.01 - - - - -

[0147] As can be seen from the data in Table 1 above, the potassium chloride sustained-release microspheres prepared by the present invention have good sphericity and mechanical properties. At the same time, the release standard of 1 hour is <40%, the release standard of 4 hours is <75%, and the release standard of 8 hours is >75%, which shows that the potassium chloride sustained-release microspheres prepared by the present invention can release steadily and slowly within 8 hours.

[0148] The specific embodiments described herein are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains may make various modifications or additions to the described specific embodiments or use similar methods to substitute them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

Claims

1. A method for producing potassium chloride micro-pellets, characterized in that, Includes the following steps: (a) Potassium chloride crystals are crushed and mixed with a diluent that has the ability to form hydrogen bonds to form potassium chloride mixed powder; The diluent is any one or a combination of microcrystalline cellulose and sodium carboxymethyl cellulose. (b) In a granulator, an aqueous binder is sprayed onto the potassium chloride mixed powder. The amount of aqueous binder sprayed is 20-40% of the total weight of the potassium chloride mixed powder. The maximum spraying speed of the aqueous binder is less than 250 r / min and not less than 100 r / min, so that the mixed powder is wetted and the potassium chloride surface undergoes partial dissolution and recrystallization, thereby forming a salt bridge. At the same time, the diluent adsorbs water through hydrogen bonds to form a network structure. Then, the centrifugal speed of the granulator is controlled at 15-45 Hz, thereby forming the initial core particles under mechanical force. (c) The initial nucleus particles are dried and sieved to obtain potassium chloride pellet masterbatch.

2. The method for raising the mother as described in claim 1, characterized in that, In the potassium chloride mixed powder, potassium chloride accounts for 70%-95% of the total weight of the mixed powder.

3. The method for raising the mother as described in claim 1, characterized in that, The water-based adhesive is purified water or an aqueous solution containing less than 2% water-soluble polymer.

4. The method for raising the mother as described in claim 3, characterized in that, The water-soluble polymer is selected from polyvinylpyrrolidone or low-substituted hydroxypropyl methylcellulose.

5. The method for raising the mother as described in claim 1, characterized in that, The air inlet temperature for drying is 100-110℃, and the drying time is 30-50 minutes.

6. A method for preparing potassium chloride sustained-release microspheres, characterized in that, include: Potassium chloride pellet masterbatch was prepared using the method described in any one of claims 1-5; Potassium chloride pellet masterbatch was used as the core for granulation to obtain potassium chloride pellets; The potassium chloride pellets were sequentially coated with an isolation layer, a sustained-release layer, and a color coating layer.

7. A potassium chloride sustained-release microsphere, characterized in that, It is prepared by the method described in claim 6; The release rate of the microparticles meets the following requirements: release rate ≤25% after 1 hour and release rate ≤70% after 4 hours.

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