A method for preparing a compound anticoccidial preparation containing diclazuril

Abstract

This invention relates to the field of veterinary drug formulation technology, and discloses a method for preparing a compound anticoccidial formulation containing diclazuril. The method includes: mixing and heating diclazuril, amprolium hydrochloride, and a hydrogen bond donor to form a homogeneous liquid eutectic system; then adding an anhydrous organic acid to the system and dispersing it evenly to obtain a drug-loaded system; finally, adsorbing the drug-loaded system onto an inert carrier, and drying and granulating it to obtain the formulation. This invention utilizes eutectic technology to amorphously disperse the poorly soluble diclazuril at the molecular level and introduces an anhydrous organic acid as a water-responsive structural disintegration component. When the formulation encounters water, this component preferentially hydrates, disrupting the hydrogen bond network of the eutectic system, leading to system disintegration. The formulation prepared by this method solves the technical problems of slow dissolution of diclazuril and asynchronous release with amprolium hydrochloride, achieving simultaneous and rapid release of the two active ingredients. Furthermore, the resulting amorphous system exhibits high physical stability, and the final product has good flowability.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug formulation technology, and in particular to a method for preparing a compound anticoccidial formulation containing diclazuril. Background Technology

[0002] Coccidiosis is a common parasitic disease caused by Eimeria coccidia, which seriously harms poultry and livestock farming. Diclazuril and amprolium hydrochloride are widely used anticoccidial drugs in clinical practice. The combination of the two has a synergistic effect and delays the development of drug resistance, making it a commonly used compound combination for the prevention and treatment of coccidiosis.

[0003] However, the physicochemical properties of these two active ingredients differ significantly. Aminopropionate hydrochloride is a water-soluble drug, while diclazuril is almost insoluble in water, classifying it as a poorly soluble drug. This difference leads to a lack of synchronization in the release of the two drugs in conventional compound solid dosage forms. When the formulation disintegrates in the animal's digestive tract, amprolium hydrochloride dissolves rapidly, while diclazuril, due to its stable crystal structure and slow dissolution rate, experiences a significantly delayed dissolution process. This asynchronous release prevents the two drugs from reaching their target sites simultaneously, affecting their synergistic effect.

[0004] To improve the dissolution of poorly soluble drugs, existing technologies often employ methods to prepare them into an amorphous state, such as solid dispersions. Amorphous drugs, lacking the constraint of lattice energy, typically exhibit higher apparent solubility and faster dissolution rates. However, amorphous states are thermodynamically metastable, exhibiting a tendency to spontaneously transform into the more stable crystalline state. This physical instability is particularly pronounced under high-temperature and high-humidity storage conditions; once recrystallization occurs, the dissolution advantage of the formulation is lost, consequently affecting the product's quality uniformity and efficacy. Therefore, developing a preparation method that can solve the dissolution problem of diclazuril, ensure the simultaneous release of both drugs, and produce a product with high physical stability is a pressing technical challenge in this field. Summary of the Invention

[0005] The technical problem solved by this invention is that existing compound preparations containing diclazuril have the problems of slow dissolution rate of the poorly soluble drug diclazuril and asynchronous release behavior with the water-soluble drug amprolium hydrochloride; at the same time, conventional amorphous technology, such as solid dispersion, can improve the dissolution of diclazuril, but its physical stability is insufficient and it is prone to recrystallization under humid and hot conditions, which affects product quality.

[0006] To address the above problems, the present invention provides the following technical solution:

[0007] In a first aspect, the present invention provides a method for preparing a compound anticoccidial preparation containing diclazuril, using the following technical solution:

[0008] A method for preparing a compound anticoccidial preparation containing diclazuril includes the following steps:

[0009] (a) Mix diclazuril, amprolium hydrochloride, and a hydrogen bond donor;

[0010] (b) Heating the mixture obtained in step (a) to form a homogeneous liquid eutectic system;

[0011] (c) Add anhydrous organic acid to the liquid eutectic system and disperse it evenly to obtain a drug-loaded system;

[0012] (d) The drug delivery system is adsorbed onto an inert carrier to obtain the formulation.

[0013] By employing the above technical solution, this invention alters the physical state of the drug and controls its release behavior by constructing a eutectic system and introducing moisture-responsive structural disintegration components into the system. Its working principle is as follows:

[0014] First, during the preparation process, heating causes the two solid-state crystalline active ingredients, diclazuril and amprolium hydrochloride, to interact with hydrogen bond donor molecules, disrupting their original crystal structures and forming new, stable hydrogen bond networks. This allows the mixture to transform into a thermodynamically stable, homogeneous liquid single phase, i.e., a eutectic system, at a temperature far below the melting points of each component.

[0015] In this system, the sparingly soluble diclazuril is dispersed at the molecular level, and its dissolution process is no longer limited by lattice energy, which is the basis for achieving subsequent rapid release.

[0016] Secondly, the anhydrous organic acid introduced into this stable eutectic system acts as a moisture-responsive structural disintegration component, and its mechanism of action involves two stages:

[0017] 1. In the anhydrous environment of the formulation, the anhydrous organic acid is dispersed as a stabilizing component in the eutectic system without interfering with the hydrogen bond network and physical stability of the system.

[0018] 2. When the formulation enters an aqueous environment, anhydrous organic acid molecules, due to their strong hydrophilicity and hydration capacity, will preferentially bind to water molecules over components of the eutectic system. This competitive hydration disrupts the original hydrogen bond network that maintains the stability of the eutectic system.

[0019] Ultimately, the disruption of the original hydrogen bond network leads to the collapse of the supramolecular structure of the entire eutectic system, allowing the simultaneous release of diclazuril and amprolium hydrochloride, which were dispersed at the molecular level. The released high-energy amorphous diclazuril can form a temporary supersaturated microenvironment on the support surface, thereby increasing its apparent dissolution rate and extent. Therefore, this preparation method solves the problems of low diclazuril dissolution and asynchronous release with amprolium hydrochloride through the synchronous disintegration of the system. Simultaneously, the resulting eutectic system itself exhibits good physical stability, effectively inhibiting recrystallization of diclazuril during storage.

[0020] Preferably, before step (a), the method further includes a drying step of the aminopropionic acid hydrochloride and / or the anhydrous organic acid.

[0021] By adopting the above technical solution, residual moisture in the raw materials can be removed in advance, which can prevent moisture from interfering with the construction of hydrogen bond networks during the formation of the eutectic system, while ensuring the efficiency of anhydrous organic acids in the final formulation and the storage stability of the product.

[0022] Preferably, the heating temperature in step (b) is 45–70°C and the heating time is 1.5–4 hours.

[0023] By adopting the above technical solution, this process parameter range can ensure the complete formation of the eutectic system, while avoiding drug degradation that may be caused by excessively high temperatures or excessively long periods of time.

[0024] Preferably, the average particle size D50 of diclazuril in step (a) is 1.6 to 4.5 μm.

[0025] By adopting the above technical solution, the use of micronized diclazuril raw material can increase its specific surface area, improve its dispersion uniformity in the mixture, and accelerate the formation rate of the eutectic system.

[0026] Preferably, the hydrogen bond donor is propylene glycol or glycerol. The anhydrous organic acid is anhydrous citric acid or anhydrous malic acid. The inert support is highly dispersible silica or microcrystalline cellulose.

[0027] Preferably, step (d) is implemented by spraying the drug-loaded system onto the inert carrier using a fluidized bed granulator; or by dripping the drug-loaded system onto the inert carrier for adsorption granulation using a high-shear mixing granulator. Following step (d), the process further includes drying and granulating the inert carrier with the adsorbed drug-loaded system.

[0028] By adopting the above technical solution, a liquid drug-loaded system can be uniformly loaded onto an inert carrier to obtain a solid dosage form with uniform content and good flowability, and to ensure that the moisture content and particle size of the final product meet the quality standards.

[0029] Preferably, the weight parts of each component of the formulation are: diclazuril 100-250 parts; amprolium hydrochloride 100-180 parts; hydrogen bond donor 15-50 parts; anhydrous organic acid 5-40 parts; and inert carrier 585-695 parts.

[0030] In summary, the present invention has at least one of the following beneficial technical effects:

[0031] 1. This invention constructs a eutectic system to disperse the poorly soluble diclazuril at the molecular level, while simultaneously introducing a water-responsive disintegration mechanism. When the formulation enters an aqueous environment, the entire system structure disintegrates synchronously, thereby achieving the simultaneous and rapid release of the two active ingredients, solving the problem of inconsistent release rates caused by differences in the physicochemical properties of the components in compound formulations.

[0032] 2. The formulation prepared by this invention exhibits high physical stability. In a eutectic system, diclazuril molecules are immobilized in a stable amorphous matrix through hydrogen bonding, effectively suppressing their recrystallization tendency during storage and transportation. Compared to conventional amorphization techniques such as solid dispersions, the formulation of this invention demonstrates superior physical stability.

[0033] 3. The preparation process of this invention improves the physical properties of the final product. By adsorbing the formed liquid drug-loaded system onto an inert carrier, this method is essentially a granulation process. Compared with direct physical dry mixing of the components, the resulting powder or granules have a smaller angle of repose and exhibit excellent flowability, which is beneficial for subsequent automated dispensing and practical applications. Attached Figure Description

[0034] Figure 1 Differential scanning calorimetry spectra of the eutectic system prepared in Example 1 of this invention, pure diclazuril, pure amprolium hydrochloride, and the product of Comparative Example 1. Detailed Implementation

[0035] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0036] Preparation Example 1:

[0037] This preparation example provides a method for obtaining diclazuril micron powder with a small average particle size, comprising the following steps:

[0038] Veterinary-grade diclazuril raw material was placed in an air jet mill and pulverized at a feed pressure of 0.9 MPa and a pulverizing pressure of 1.1 MPa. The resulting powder was collected and analyzed by a laser particle size analyzer, and its average particle size (D50) was measured to be 1.6 μm and its D90 to be 4.2 μm. The resulting product was sealed and stored for later use.

[0039] Preparation Example 2:

[0040] This preparation example provides a method for obtaining diclazuril micron powder with a relatively large average particle size, including the following steps:

[0041] Veterinary-grade diclazuril raw material was placed in an air jet mill and pulverized at a feed pressure of 0.6 MPa and a pulverizing pressure of 0.7 MPa. The resulting powder was collected and analyzed by a laser particle size analyzer, and its average particle size (D50) was measured to be 4.5 μm and its D90 to be 9.8 μm. The resulting product was sealed and stored for later use.

[0042] Preparation Example 3:

[0043] This preparation example provides a method for drying moisture-sensitive raw materials required in subsequent steps, including the following steps:

[0044] The prescribed amounts of amprolium hydrochloride and anhydrous citric acid were separately spread evenly on clean trays and placed in a vacuum drying oven. They were dried continuously for 6 hours at 60°C and a vacuum of -0.09 MPa. After drying, the products were cooled to room temperature and removed. The moisture content of amprolium hydrochloride was determined to be 0.38% and that of anhydrous citric acid was 0.07% by Karl Fischer method, both meeting the requirements for subsequent processes. The resulting products were sealed and stored in a desiccator for later use.

[0045] Example 1:

[0046] This embodiment provides a method for preparing a compound anticoccidial preparation containing diclazuril, comprising the following steps:

[0047] (1) Weigh 150g of diclazuril powder obtained in Preparation Example 1, 120g of aminopropionic acid hydrochloride dried in Preparation Example 3, 15g of propylene glycol, 20g of anhydrous citric acid dried in Preparation Example 3, and 695g of highly dispersible silica dried.

[0048] (2) Add diclazuril powder and aminopropionic acid hydrochloride into a jacketed heating reactor, and add propylene glycol dropwise while stirring (50 rpm) until the mixture is homogeneous.

[0049] (3) Start the jacket heating and raise the temperature to 55°C at a rate of 2°C / min. Stir the reaction at this temperature for 2 hours until the material in the reactor forms a uniform and clear viscous liquid, thus obtaining a eutectic system.

[0050] (4) Stop heating and introduce cooling water to lower the system temperature to 35°C. Slowly add anhydrous citric acid microcrystalline powder while stirring, and continue stirring for 30 minutes to disperse it evenly.

[0051] (5) The above-mentioned drug-loaded system is transported to a fluidized bed granulator by a peristaltic pump and uniformly sprayed onto a pre-fluidized, highly dispersible silica carrier by top spraying. The inlet air temperature is set to 60°C and the material temperature to 40°C until all liquids are sprayed.

[0052] (6) Continue drying in the fluidized bed for 20 minutes to reduce the total moisture content of the material to less than 3.0%. Granulate the resulting product through a 40-mesh sieve to obtain a free-flowing powder, and then seal and package it.

[0053] Example 2:

[0054] This embodiment provides a method for preparing a compound anticoccidial preparation containing diclazuril, comprising the following steps:

[0055] (1) Weigh 100g of diclazuril powder obtained in Preparation Example 2, 180g of dried aminopropionyl hydrochloride, 20g of propylene glycol, 30g of dried anhydrous citric acid and 670g of dried highly dispersible silica.

[0056] (2) Add diclazuril powder and aminopropionic acid hydrochloride into the reactor, and add propylene glycol while stirring (40 rpm) until the mixture is homogeneous.

[0057] (3) Start heating and raise the temperature to 45°C. Stir and react at this lower temperature for 4 hours until the material forms a homogeneous eutectic system.

[0058] (4) Reduce the system temperature to 30°C, add anhydrous citric acid microcrystalline powder, and continue stirring for 45 minutes to disperse it evenly.

[0059] (5) The drug-loaded system is slowly added dropwise to a high-dispersibility silica carrier that is stirred at high speed through a high-shear mixing granulator for adsorption and granulation.

[0060] (6) Transfer the obtained soft material to a vacuum drying oven and dry it at 50°C for 3 hours to reduce the total moisture content to less than 3.0%. Granulate the obtained product through a 20-mesh sieve to obtain granules, and then seal and package them.

[0061] Example 3:

[0062] This embodiment provides a method for preparing a compound anticoccidial preparation containing diclazuril, comprising the following steps:

[0063] (1) Weigh 200g of diclazuril powder obtained in Preparation Example 1, 150g of dried amprolium hydrochloride, 25g of glycerol, 40g of dried anhydrous malic acid and 585g of dried microcrystalline cellulose.

[0064] (2) Add diclazuril powder and amprolium hydrochloride into the reaction vessel, add glycerol while stirring (60 rpm), and mix evenly.

[0065] (3) Start heating and raise the temperature to 70°C. Stir and react at this higher temperature for 1.5 hours until the material forms a homogeneous eutectic system.

[0066] (4) Reduce the system temperature to 40°C, add anhydrous malic acid microcrystalline powder, and continue stirring for 25 minutes to disperse it evenly.

[0067] (5) Using a method similar to that in Example 1, the drug-loaded system was sprayed onto the microcrystalline cellulose carrier via a fluidized bed. The inlet air temperature was set to 70°C and the material temperature to 45°C.

[0068] (6) Continue drying for 30 minutes after spraying to reduce the total moisture content to below 3.0%. Granulate the resulting product through a 40-mesh sieve to obtain a free-flowing powder, and then seal and package it.

[0069] Example 4:

[0070] This embodiment provides a method for preparing a compound anticoccidial preparation containing diclazuril, comprising the following steps:

[0071] (1) Weigh 250g of diclazuril powder obtained in Preparation Example 1, 100g of dried aminopropionyl hydrochloride, 50g of propylene glycol, 5g of dried anhydrous citric acid and 595g of dried highly dispersible silica.

[0072] (2) Add diclazuril powder and aminopropionic acid hydrochloride into the reactor, and add propylene glycol while stirring (50 rpm) until the mixture is homogeneous.

[0073] (3) Start heating and raise the temperature to 60°C. Stir and react at this temperature for 2.5 hours until the material forms a uniform eutectic system.

[0074] (4) Reduce the system temperature to 35°C, add anhydrous citric acid microcrystalline powder, and continue stirring for 30 minutes to disperse it evenly.

[0075] (5) The carrier adsorption and granulation were carried out using a method similar to that in Example 2, by a high-shear mixing granulator.

[0076] (6) The obtained product was vacuum dried at 60°C for 2.5 hours to reduce the total moisture content to less than 3.0%. The obtained product was granulated through a 40-mesh sieve to obtain granules, which were then sealed and packaged.

[0077] Comparative Example 1:

[0078] Compared with Example 1, the difference is that all the components in the prescription amount (dicazulin, amprolium hydrochloride, propylene glycol, anhydrous citric acid, and highly dispersible silica) are directly placed in a three-dimensional mixer for physical dry mixing, without the step of heating to form a eutectic system, and the rest are the same.

[0079] Comparative Example 2:

[0080] Compared with Example 1, the difference is that: firstly, 150g of diclazuril and 150g of polyvinylpyrrolidone K30 are prepared into a solid dispersion by solvent evaporation. Then, the solid dispersion is mixed with other formulation components (aminopropyl hydrochloride, anhydrous citric acid, and highly dispersible silica) by physical dry mixing without heating to form a eutectic system. All other steps are the same.

[0081] Comparative Example 3:

[0082] Compared with Example 1, the difference is that the formulation does not contain anhydrous citric acid, and the step of adding and dispersing the smart release module into the eutectic system is omitted in the preparation process; otherwise, they are the same.

[0083] Comparative Example 4:

[0084] Compared to Example 1, the difference lies in that the amount of propylene glycol in the formulation is increased to 200g, and anhydrous citric acid is not included. During preparation, the two active ingredients are directly heated and stirred in propylene glycol at 55°C to dissolve the active ingredients in propylene glycol as much as possible, forming a supersaturated solution or a partially dissolved suspension. Then, they are immediately adsorbed with a correspondingly reduced amount of highly dispersible silica. All other aspects are the same.

[0085] Test Example 1:

[0086] The experimental steps are as follows:

[0087] (1) Weigh out pure diclazuril, pure aminopropionic acid, the final product of Comparative Example 1, and the eutectic liquid system before carrier adsorption during the preparation of Example 1. The sample mass is controlled at 3-8 mg and placed in a sealed aluminum crucible.

[0088] (2) Place the sample crucible and an empty reference crucible together into the sample chamber of the differential scanning calorimeter.

[0089] (3) In a nitrogen atmosphere (flow rate 50 mL / min), start the thermal analysis program and heat the sample from 25 °C to 250 °C at a heating rate of 10 °C / min, and record the change of heat flow signal with temperature.

[0090] (4) Analyze the collected DSC curves to determine the crystallization melting peaks or glass transitions present in them.

[0091] The experimental results are shown in Table 1 and Figure 1 As shown.

[0092] Table 1. Differential Scanning Calorimetry (DSC) Test Results for Each Sample:

[0093]

[0094] DSC test results showed that diclazuril and amprolium hydrochloride raw materials exhibited sharp melting endothermic peaks at 243.7℃ and 249.2℃, respectively, confirming that their initial state was crystalline. The physical mixture of Comparative Example 1 retained these two independent melting peaks at similar temperature points (242.9℃ and 248.8℃), indicating that simple physical mixing did not change the crystal phase structure of the two active ingredients, and they still coexisted in independent crystalline forms.

[0095] The eutectic system prepared in Example 1 exhibits fundamentally different thermal behavior. On the DSC curves of this system, the characteristic melting peaks of both active pharmaceutical ingredients completely disappear, while a single glass transition occurs in the low-temperature region of 18.5-23.1°C.

[0096] The disappearance of the crystallization melting peak is direct evidence of the disruption of the long-range ordered structure of the raw material lattice. The appearance of a single glass transition temperature proves that diclazuril and amprolium hydrochloride have formed a homogeneous, amorphous single phase at the molecular level. This series of thermal analysis characteristics collectively confirms that, through the method of this invention, the two initially solid crystalline active ingredients have been transformed into a thermodynamically stable eutectic system through intermolecular interactions (such as hydrogen bond recombination). This phase transformation from a multiphase crystalline mixture to a single-phase amorphous system is the basis for achieving molecular-level dispersion of the poorly soluble drug diclazuril and constitutes the fundamental mechanism for the subsequent improvement of formulation performance in this invention.

[0097] Test Example 2:

[0098] The experimental steps are as follows:

[0099] (1) Prepare two sets of solvents: Group A is anhydrous ethanol and Group B is 95% (v / v) ethanol aqueous solution.

[0100] (2) Weigh 1g of the eutectic system liquid prepared in Example 1 and add it to 20mL of solvent A; take another 1g of the sample and add it to 20mL of solvent B.

[0101] (3) Weigh 1g of the eutectic system liquid prepared in Comparative Example 3 and add it to 20mL of solvent in Group A; take another 1g of the sample and add it to 20mL of solvent in Group B.

[0102] (4) Stir the above four samples magnetically at 300 rpm at 25°C for 10 minutes.

[0103] (5) After stirring, let stand for 1 minute, observe and record the clarity of each system and whether any solid substances precipitate out.

[0104] The experimental results are shown in Table 2.

[0105] Table 2. Stability test results of each system in different solvents:

[0106]

[0107] According to the data in Table 2, the eutectic systems of Example 1 and Comparative Example 3 both remained clear and stable in anhydrous ethanol, indicating that the structures of both systems are stable in a non-aqueous environment.

[0108] When the solvent environment was changed to a 95% ethanol solution containing water, the two systems exhibited significant differences. The system of Comparative Example 3 (containing no citric acid) showed only slight turbidity, indicating that its hydrogen-bonded network structure had some tolerance to the intrusion of small amounts of water molecules, and the system structure was largely maintained. In contrast, the system of Example 1 (containing anhydrous citric acid) rapidly produced a large amount of precipitate upon contact with the aqueous solvent.

[0109] The underlying mechanism of this phenomenon is that the intervention of water molecules and the hydration of citric acid competitively disrupt the original hydrogen bond network. In the system of Example 1, anhydrous citric acid, acting as the smart release module, has extremely strong hydrophilicity, and its multiple carboxyl and hydroxyl functional groups preferentially bind to water molecules. This strong hydration, along with the direct participation of water molecules, breaks the original hydrogen bond equilibrium that maintains the molecular-level dispersion of diclazuril and amprolium hydrochloride. Once the supramolecular structure of the eutectic system disintegrates, the poorly soluble drug diclazuril in its dissolved state rapidly precipitates due to the drastic change in the polarity of the solvent environment, macroscopically manifested as the formation of a precipitate.

[0110] Therefore, the test results confirm the design mechanism of the intelligent release module in this invention: anhydrous organic acids exist as stable dispersed components in an anhydrous formulation environment, but after entering an aqueous environment (simulating the animal digestive tract), they are transformed into highly efficient hydrogen bond competitors, triggering the structural disintegration of the eutectic system, thereby achieving rapid release of the active ingredient.

[0111] Test Example 3:

[0112] The experimental steps are as follows:

[0113] (1) Liquidity test

[0114] The angle of repose for each sample was determined using the fixed funnel method. Sample powder or granules were passed through a standard-sized funnel, allowing them to naturally accumulate into a cone on a horizontal plate. The height (h) and base radius (r) of the cone were measured, and the angle of repose (θ) was calculated using the formula tan(θ) = h / r. The measurement was repeated three times for each sample, and the average value was taken.

[0115] (2) Accelerated stability test

[0116] The final product samples from Examples 1-4 and Comparative Examples 1-4 were taken in appropriate amounts and placed in weighing bottles, which were then placed open in a constant temperature and humidity chamber at 40℃ / 75%RH. After 30 days, the samples were removed and immediately subjected to powder X-ray diffraction (PXRD). The PXRD test conditions were: Cu Kα radiation source, tube voltage 40kV, tube current 40mA, scanning range 2θ of 5° to 40°, and scanning rate of 2° / min.

[0117] The experimental results are shown in Table 3.

[0118] Table 3. Physical properties and accelerated stability test results of each formulation:

[0119]

[0120] According to the data in Table 3, the angles of repose of the formulations in Examples 1–4 were all less than 32°, while the angles of repose of the physical mixtures in Comparative Examples 1 and 2 were greater than 45°. This result indicates that a final product with significantly better flowability than that obtained through adsorption granulation using a liquid eutectic system can be obtained.

[0121] PXRD results for physical stability testing showed that the samples from Examples 1-4 and Comparative Example 3, after being placed at 40°C and 75% RH for 30 days, did not exhibit crystalline diffraction peaks, maintaining their amorphous state. This confirms that the intermolecular interactions in the eutectic system form a stable amorphous matrix, which effectively inhibits molecular rearrangement and crystallization under high temperature and humidity conditions. In contrast, the samples from Comparative Examples 2 and 4 showed characteristic diclazuril diffraction peaks under the same conditions, indicating that amorphous materials prepared by solid dispersions or co-solvent adsorption lack sufficient physical stability and will undergo a transformation to a crystalline form in humid and hot environments.

[0122] Test Example 4:

[0123] The experimental steps are as follows:

[0124] (1) The second method of dissolution determination in Chinese Pharmacopoeia (paddle method) was adopted. The dissolution medium was 900 mL, the temperature was set at 37±0.5℃, and the rotation speed was 75 rpm.

[0125] (2) Take the formulation samples of Example 1, Comparative Example 1 and Comparative Example 3 equivalent to 100 mg of diclazuril as indicated in the prescription and put them into dissolution cups respectively.

[0126] (3) First, dissolution was carried out in artificial gastric fluid (containing 0.5% Tween-80) at pH 1.2. After sampling at 120 minutes, the pre-prepared phosphate buffer was immediately added to each dissolution vessel to adjust the pH of the medium to 6.8 (simulating artificial intestinal fluid), and the dissolution test was continued.

[0127] (4) At time points of 5, 15, 30, 60, 120, 180 and 240 minutes, 5 mL of solution was taken out of the dissolution vessel and immediately replenished with an equal volume of fresh dissolution medium.

[0128] (5) After all samples were filtered through a 0.45 μm microporous membrane, the concentrations of diclazuril and amprolium hydrochloride in the filtrate were determined simultaneously by high performance liquid chromatography (HPLC), and the cumulative release percentage was calculated.

[0129] The experimental results are shown in Table 4.

[0130] Table 4. Cumulative in vitro release (%) of diclazuril (DIC) and amprolium hydrochloride (AMP) in different formulations:

[0131]

[0132] According to the data in Table 4, in Comparative Example 1 (physical mixture), amprolium hydrochloride was released rapidly, while the cumulative release of diclazuril was less than 15% after 4 hours. This difference in release behavior stems from the different physicochemical properties of the two components, with the crystal structure of diclazuril limiting its dissolution.

[0133] In the formulation of Example 1, diclazuril and amprolium hydrochloride exhibited synchronous release behavior, with diclazuril achieving a cumulative release rate exceeding 90% within 60 minutes. This release characteristic was achieved on two levels: the construction of the eutectic system enabled diclazuril to be dispersed at the molecular level in an amorphous form, eliminating the lattice energy barrier during dissolution; and upon entering an aqueous medium, the anhydrous citric acid in the system hydrated, disrupting the hydrogen bond network maintaining the eutectic system and leading to structural disintegration. This system disintegration resulted in the simultaneous release of both active ingredients, with diclazuril forming a supersaturated state on the carrier surface, thus increasing its apparent dissolution rate.

[0134] The results of Comparative Example 3 (without organic acids) corroborated the above mechanism. In this formulation, diclazuril dissolved faster than in Comparative Example 1, but the final release rate was only about 70%. This indicates that in the absence of citric acid-triggered disintegration, the release of the eutectic system is incomplete, possibly limited by dissolution or diffusion processes.

[0135] In summary, the test data from the embodiments and comparative examples have verified the technical solution of the present invention from different perspectives.

[0136] Stability results from differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) jointly confirmed that this invention constructs a physically stable, homogeneous amorphous system dispersed at the molecular level through the eutectic reaction of diclazuril and amprolium hydrochloride. The release behavior of this system is regulated by a built-in organic acid module. In vitro stability and dissolution tests show that this module, in an aqueous environment, triggers the structural disintegration of the eutectic system through preferential hydration, thereby achieving the simultaneous and rapid release of the two active ingredients.

[0137] This integrated formulation strategy not only solves the dissolution rate problem of the poorly soluble drug diclazuril, but also overcomes the technical challenge of inconsistent release rates of various components in conventional compound formulations through a fundamental phase transformation. Furthermore, the angle of repose test results of the final product also indicate that the formulation prepared by the process of this invention possesses good flowability, which is beneficial for subsequent production and use.

[0138] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a compound anticoccidial preparation containing diclazuril, characterized in that, The method comprises the following steps: (a) mixing zilpaterol, anhydrous aminopyralid hydrochloride and a hydrogen bond donor; The hydrogen bond donor is propylene glycol or glycerol; (b) heating the mixture obtained in step (a) to form a homogeneous liquid eutectic system; (c) adding anhydrous organic acid to the liquid eutectic system and uniformly dispersing to obtain a drug-loaded system; the anhydrous organic acid is anhydrous citric acid or anhydrous malic acid; (d) adsorbing the drug-loaded system on an inert carrier to obtain the preparation.

2. The process for preparing diclazuril-containing compound anticoccidial preparation according to claim 1, characterized in that, Before step (a), a step of drying the anhydrous aminopyralid hydrochloride and / or the anhydrous organic acid is further included.

3. The process for preparing diclazuril-containing compound anticoccidial preparation according to claim 1, characterized in that, The heating temperature in step (b) is 45-70°C, and the time is 1.5-4 hours.

4. The process for preparing diclazuril-containing compound anticoccidial preparation according to claim 1, characterized in that, The average particle size D50 of the zilpaterol in step (a) is 1.6-4.5 μm.

5. The process for preparing diclazuril-containing compound anticoccidial preparation according to claim 1, characterized in that, The inert carrier is highly dispersed silicon dioxide or microcrystalline cellulose.

6. The process for preparing diclazuril-containing compound anticoccidial preparation according to claim 1, characterized in that, The specific implementation of step (d) is: Spraying the drug-loaded system on the inert carrier by a fluidized bed granulator; or dropping the drug-loaded system into the inert carrier by a high-shear mixing granulator for adsorption granulation.

7. The process for preparing diclazuril-containing compound anticoccidial preparation according to claim 1, characterized in that, After step (d), a step of drying and granulating the inert carrier with the adsorbed drug-loaded system is further included.

8. The process for preparing diclazuril-containing compound anticoccidial preparation according to claim 1, characterized in that, The weight parts of the components of the preparation are: zilpaterol 100-250 parts; anhydrous aminopyralid hydrochloride 100-180 parts; hydrogen bond donor 15-50 parts; anhydrous organic acid 5-40 parts; and inert carrier 585-695 parts.

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